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Neurology
Volume
51

Number
5

November
1,
1998
Copyright

1998
American
Academy
of
Neurology

S008
Articles

Treatment of seizures and epilepsy in children and

adolescents
John M. Pellock MD

Medical College of Virginia, Virginia Commonwealth University, Richmond, VA.

Address correspondence and reprint requests to Dr. John M. Pellock, Director, MCV
Comprehensive Epilepsy Institute, MCV Station, Box 980-211, Richmond, VA
23298-0211.
Copyright 1998 by the American Academy of Neurology

Article abstract-Certain epilepsy types occur more commonly or exclusively in children and
adolescents. Proper diagnosis of the specific seizure type and the etiology
of the seizure is the cornerstone for appropriate management of these
patients. When treatment is determined to be necessary, antiepileptic drug
(AED) selection should focus on the agent(s) that will provide the best
risk:benefit ratio. A number of new AEDs are now available for use in
patients who are refractory to or intolerant of classic medications. These
recent additions to the therapeutic armamentarium are also receiving
consideration as first-line therapy in some indications. As with the classic
AEDs, optimizing efficacy and safety of the new compounds requires
adherence to recommended dosing regimens and careful monitoring for
adverse effects.
Although epilepsy can occur at any age, certain seizure types and etiologies are
unique to or are more common among infants and children. Epilepsy syndromes are
classified by seizure type(s), age at onset, family history, anatomic correlation,
precipitating factors, severity, chronicity, presence of clusters or cycles, natural
history, and prognosis. The syndromic diagnosis provides a guide for optimal
selection of antiepileptic drug (AED) therapy. [1] [2]

West syndrome (infantile spasms).

West syndrome is an age-dependent malignant epilepsy with onset usually
occurring during infancy. Infantile spasms, developmental arrest or regression, and
an interictal EEG pattern of hypsarrhythmia form the diagnostic triad. The hallmark
of infantile spasms is recurrent, brief (less than 2 seconds) massive spasms of the
flexor or extensor muscle groups, or both.
The optimal therapy for children with infantile spasms remains somewhat
controversial. Most US clinicians treat this disorder with adrenocorticotropin (ACTH)
or glucocorticoids, but the optimal dosage of ACTH and whether or not ACTH is
superior to prednisone remain subjects of debate. Prednisone 2 mg/kg/day was
reported to be comparable with low-dose (20 to 30 U/day) ACTH in one study [3] but
was less effective than high-dose (120 to 160 U/day) ACTH in another
investigation. [4]
European studies have demonstrated the efficacy of vigabatrin in the treatment of
infantile spasms, particularly in infants with tuberous sclerosis. [5] [6] [7] The results
of these trials have led some investigators to suggest that vigabatrin be considered
as initial therapy for infantile spasms. [5] [6] In a retrospective review, use of
vigabatrin (mean dose 99 mg/kg/day) as first-line therapy resulted in complete
spasm cessation in 68.2% of 192 infants with a diagnosis of classic infantile
spasms. The most commonly reported side effects were somnolence (n = 15) and
hyperkinesia (n = 8). [5] Vigevano and Cilio [6] directly compared vigabatrin with
ACTH as first-line treatment for infantile spasms in 42 patients. Although vigabatrin
had a lower overall success rate than ACTH (48% versus 74%), vigabatrin was
more effective for treatment of spasms associated with tuberous sclerosis, was
associated with fewer relapses after 3 months, was and better tolerated.
Alternative treatments for infantile spasms include valproate and the
benzodiazepines. [8] [9] [10] [11] [12] [13] Although diazepam, nitrazepam, and
clonazepam reduce spasm frequency in the short term, they seldom demonstrate
permanent benefit and are associated with significant adverse effects. Among the
newer AEDs, lamotrigine, felbamate, and topiramate have also been reported to
significantly reduce infantile spasms. [14] [15] [16] [17] Felbamate doses of 45 to 75
mg/kg/day achieved 90% or greater reduction in spasms, with a median reduction
rate of 72%. [15] [18]
Although infantile spasms are considered a generalized epilepsy, PET has
demonstrated focal zones of cortical abnormality in some cases, [19] and surgical
intervention ranging from focal excision to hemispherectomy has been successful in
ameliorating or stopping seizures in these children. [19] [20]
The overall prognosis for children with infantile spasms remains poor. Some series
suggest that children who respond to early and aggressive intervention with
surgery or medication have the best developmental outcomes. [21] Other
researchers following infants treated with ACTH found that only 5% had a normal
outcome, whereas most had severe impairments regardless of their response to
medication or the time of treatment initiation. [22] Those children who are more
neurologically and developmentally normal and show less regression with
cryptogenic

S009
infantile spasms may demonstrate a better cognitive outcome.

Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome is characterized by mixed seizures, consisting primarily

of atypical absence, tonic, and atonic seizures, mental retardation, and EEG
findings of slow spike and wave as well as generalized background slowing.
Generalized, tonic-clonic, partial, and myoclonic seizures may also be noted, but
care must be taken to distinguish Lennox-Gastaut syndrome from other early
childhood encephalopathies or benign syndromes in which myoclonic seizures
predominate. The typical age at onset is between 1 and 6 years and may evolve
from infantile spasms. Although marked improvement in alertness, motivation, and
academic progress may be seen when the child is seizure free, 40 to 80% of these
patients have associated neurologic abnormalities and the prognosis is generally
poor.
Seizure frequency is high in children with Lennox-Gastaut syndrome, and the
seizures are difficult to control. Therefore, this syndrome is frequently referred to
as one of the catastrophic encephalopathic epilepsies of childhood. Treatment must
consider all seizure types, with a focus on achieving seizure control without
inducing excessive medication-related toxicity or exacerbation of nonconvulsive
seizures. A tendency to place these children on many AEDs often results in both
neurologic and systemic toxicity without achieving the desired therapeutic
response.
At present, monotherapy with valproate is currently the first-line choice in the
treatment of Lennox-Gastaut syndrome because it offers the best risk:benefit ratio
among the classic AEDs. [2] However, high-dose therapy is frequently needed, and
this may increase the incidence of dose-related side effects, including tremor,
neurologic toxicity, and thrombocytopenia. Valproate hepatotoxicity is most
common in young children who have possible underlying, unidentified metabolic
disorders. As part of the etiologic evaluation and before valproate treatment is
initiated, almost all children with Lennox-Gastaut syndrome should undergo a
metabolic evaluation. [23]
In the treatment of Lennox-Gastaut syndrome, ACTH, other steroids, phenytoin,
barbiturates, and carbamazepine have also been used. Phenobarbital,
carbamazepine, and phenytoin have little effect on myoclonic, atypical absence, or
atonic seizures and may even exacerbate these epilepsy types. [24] Treatment with
benzodiazepines, including clobazam, clonazepam, diazepam, clorazepate, and
nitrazepam, has been successful. Because tolerance develops in many cases,
benzodiazepines may be best used as acute intermittent or "rescue" therapy. [2]
The ketogenic diet also shows promise in the treatment of this entity. [25]
Lamotrigine, topiramate, and felbamate have a definite role in the treatment of
Lennox-Gastaut syndrome. [26] [27] [28] [29] Motte et al. [27] reported that, after 16
weeks, the addition of lamotrigine to an existing AED regimen was associated with
a significantly greater reduction in the median frequency of all major seizures
compared with placebo; 33% of lamotrigine patients had a reduction of
50% in
seizure frequency compared with 16% of placebo patients ( p = 0.002). Significant
benefits were seen, particularly in analyses of changes in the frequency of drop
attacks and tonic-clonic seizures, and the drug was well tolerated.
Some suggest that felbamate may be superior to lamotrigine for controlling
myoclonic seizures. [30] [31] Both lamotrigine and felbamate show an overall alerting
effect. The outcomes achieved with topiramate were initially not as robust as those
with lamotrigine and felbamate. However, follow-up studies with higher doses of
topiramate were more encouraging. [32] Careful dosing titration is recommended to
reduce neurotoxic and cognitive defects in children receiving topiramate. Although
vigabatrin has been effective in some children with Lennox-Gastaut syndrome, this
agent may not be as effective overall as topiramate because of its tendency to
exacerbate myoclonic seizures. It has also been found to increase hyperactivity. [29]
[33] [34]

Proper titration and dosing are mandatory when these new drugs are used.
Felbamate may need to be administered at a dosage of 75 to 90 mg/kg/day to
achieve efficacy. This is significantly higher than the maximal recommended dosage

of 45 mg/kg/day and may be associated with an increased incidence of anorexia

and insomnia. [35] Because of the increased incidence of rash when lamotrigine is
administered rapidly, particular attention must be given to the dosing titration
schedule, especially when children are receiving valproate concomitantly. For
patients receiving valproate, the initial lamotrigine dosage is 0.2 mg/kg/day. This
can be doubled at 2-week intervals to reach a maintenance dosage of 1 to 5
mg/kg/day. Children not receiving valproate can be started on a dose of 2
mg/kg/day with increases every second week to a maintenance dose in the range
of 5 to 15 mg/kg/day. [36] Children can start topiramate at 1 mg/kg/day, with a
maximum of 25 to 50 mg/day, and can increase the dosage at weekly intervals. [37]

Primary generalized epilepsy.

A number of syndromes are grouped together under this rubric because of their
benign nature, generalized seizure types, and genetic predisposition. Three of
these benign, generalized, tonic-clonic epilepsy syndromes are labeled "childhood
absence," "juvenile absence," and "juvenile myoclonic epilepsy." A fourth, possibly
related syndrome is labeled generalized tonic-clonic epilepsy on awakening.
Childhood absence epilepsy (petit mal) has its onset in the preschool or school-age
child and is characterized by frequent seizures manifesting as brief lapses or
staring spells. An estimated 40% of patients with childhood absence also have
generalized tonic-clonic seizures. Juvenile absence has an onset nearer to puberty,
is associated with a higher incidence

S010
of tonic-clonic seizures (up to 50%), and the absences are more likely to be
clustered, i.e., no episodes occur on some days, whereas there may be multiple
bouts on others. Juvenile myoclonic epilepsy occurs most commonly in the teen
years. It is characterized primarily by myoclonic seizures and generalized tonicclonic seizures with onset during the first 1 to 2 hours after awakening. Absences
occur in only 10% to 30% of these patients. [1]
The pharmacotherapy of primary generalized epilepsy depends on the mix of
seizures likely to be present in each child or adolescent. Ethosuximide and
valproate have excellent antiabsence activity and are typically used to treat
childhood absence epilepsy. Because ethosuximide has no activity against
convulsive seizures, valproate is the drug of choice in children who have
convulsive epilepsy mixed with absence. Valproate is also considered a first-line
agent for treatment of juvenile absence. Generalized tonic-clonic seizures are
relatively common in this syndrome, and many children with juvenile absence
present initially with a convulsive seizure. Juvenile myoclonic epilepsy, with its
mixture of myoclonic, generalized tonic-clonic, and absence seizures, requires
treatment with a broad-spectrum agent as well, making valproate the drug of
choice. Combined treatment of absence epilepsy with ethosuximide and valproate is
often used for patients who do not achieve a satisfactory response with
monotherapy. Benzodiazepines (clonazepam or clobazam) offer another alternative,
especially for control of myoclonus. Although they are effective against absence,
clonazepam and other benzodiazepines have a high incidence of toxicity, and
tolerance frequently develops.
Lamotrigine is effective in the treatment of the primary generalized epilepsies,
although its activity against myoclonic seizures is sometimes incomplete. [30] [31]
Topiramate has been reported anecdotally to be effective in some patients with
resistant generalized epilepsy. However, its effect against atypical absence in
Lennox-Gastaut trials was somewhat disappointing. [28] Felbamate has activity
against all primary generalized seizure types and was initially believed to offer a

favorable alternative to ethosuximide and valproate because of its beneficial

cognitive properties. [26] Its association with aplastic anemia has significantly
decreased its use for these relatively benign entities, however.
Complete seizure control is more likely to be achieved in the primary generalized
epilepsies than in any of the other childhood epilepsies. Children with childhood
absence can usually be safely removed from medication after 2 years or less
without exacerbation of their seizures. Recurrence of generalized convulsions is
more likely in juvenile absence, and these children may need to be continued on
their medication for longer periods. Juvenile myoclonic epilepsy almost always
recurs if medication is withdrawn. Therefore, lifetime treatment is necessary, most
commonly with valproate (despite the potential increased risk for neural tube defect
in infants of women receiving this agent). [38]

Partial seizures.
At least one-half of all childhood seizures are partial onset and may appear as
simple partial, complex partial, or secondarily generalized seizures. These partial
seizures in children can be further classified as primary (genetic/idiopathic) or
secondary (acquired), and they may be either benign or very difficult to treat.
The most common of the primary benign partial seizures of childhood is benign
epilepsy with centrotemporal spikes (benign rolandic epilepsy). Age at onset is
between 3 and 13 years and, in most affected children, EEG abnormalities and
seizures disappear by age 16. The less benign syndromes of partial epilepsy
include Landau-Kleffner syndrome and Kojewnikoff syndrome. Landau-Kleffner
syndrome is characterized by an acquired aphasia with epileptiform EEG and both
partial and generalized seizures. Kojewnikoff syndrome, or epilepsia partialis
continua, may become progressive and is termed Rasmussen's encephalitis. The
latter occurs in a previously healthy child who, in addition to partial seizures,
develops a progressive hemiplegia and dementia. [1] [2]
Given the benign nature of rolandic epilepsy and the complete normality of the
affected individuals, it remains controversial whether single or even multiple rare
seizures should be treated. When intervention is indicated for benign and less
benign syndromes, carbamazepine, phenytoin, and valproate have all shown nearly
equal efficacy and acceptability for the control of partial epilepsy with or without
secondary generalization in children. [39] [40] [41] Phenobarbital and primidone may be
equally effective but are associated with increased behavioral adverse reactions. [41]
[42]
[43]
Vigabatrin, gabapentin, lamotrigine, topiramate, and tiagabine have
demonstrated efficacy in children with partial or secondarily generalized seizures
comparable with that achieved in adults. [44] [45] [46] [47]
Initial studies of gabapentin for the treatment of seizures in children used a
starting dose of 5 mg/kg/day and a mean maximum dose of approximately 25
mg/kg/day. [47] Subsequent experience indicated that gabapentin should be initiated
at least at 10 mg/kg/day and increased to at least 30 to 60 mg/kg/day to achieve
desired therapeutic levels and efficacy. [44] [45] Doses above 90 mg/kg/day have been
needed to achieve complete efficacy in some children with refractory partial
seizures with or without secondary generalization. Adverse effects are typically
transient and dose dependent.

Generalized tonic-clonic seizures.

These seizures, previously termed grand mal, are certainly the most dramatic and
frightening seizures seen in patients with epilepsy. They may be primarily or
secondarily generalized; distinguishing these types may require ictal or interictal
EEG.

S011

TABLE 1 -- Probable spectrum of new antiepileptic drugs in childhood epilepsy

Seizure/epilepsy type
Antiepileptic
drug
Partial

LennoxInfantile Gastaut
Generalized spasms syndrome Myoclonic Absence

Felbamate

Gabapentin

Lamotrigine

Tiagabine

Topiramate

Vigabatrin

+ =Efficacious, reported or highly suspected; - = no efficacy proven; = mixed

results among populations; ? = needs further evaluation.
There is no consensus on the drug of choice for generalized tonic-clonic seizures.
Phenobarbital, phenytoin, carbamazepine, and valproic acid appear equally
effective, but the barbiturates have the highest associated number of adverse
effects. [41] [48] Felbamate, lamotrigine, gabapentin, tiagabine, and vigabatrin have
also been reported to control generalized tonic-clonic seizures. The decision about
whether or not to use the newer drugs might be based on whether the seizure
type is the manifestation of a partial or generalized epilepsy, the presence of
associated seizures likely, concomitant medical or behavioral disorders, and side
effect profiles.

Febrile seizures.
Febrile seizures are the most common seizures in children. [1] Simple febrile
seizures occur in approximately 3 to 5% of children between the ages of 6 months
and 5 years who are previously healthy and have no defined cause for their seizure
except fever. The condition may be inherited and carries little risk for the
development of epilepsy.
Most experts agree that no preventive treatment is indicated for the child who has
experienced a first or even a second simple febrile seizure. Children who
experience complex febrile seizures, characterized by partial or prolonged
seizures and concomitant neurologic/developmental abnormality, are more likely
to have recurrences, are frequently considered to have epilepsy initially triggered
by fever, and may be treated more frequently with chronic AED therapy. For
children who experience recurrent febrile seizures, some have recommended
acute treatment with an oral or rectal benzodiazepine when fever develops or
rectal diazepam at the beginning of a seizure to shorten its duration. [49] [50] [51] [52]

General treatment considerations.

There is no single drug of choice in the treatment of all childhood epilepsy, but
some agents have proved to be more effective for certain seizure types or

syndromes, whereas others offer a broader spectrum of activity (table 1) . Some

AEDs may even exacerbate certain types of epilepsy. Carbamazepine and phenytoin
have been reported to exacerbate primarily generalized seizures such as the
absence, atonic, and myoclonic types. [24] [29] [53] More recently, vigabatrin has been
reported to worsen myoclonic seizures, [29] and gabapentin may unmask myoclonic
jerks in those with primarily generalized epilepsy. Therefore, establishing a firm
diagnosis before initiating therapy is critical.
Treatment should always be initiated with monotherapy. The dosage should be
titrated upward enough to achieve a median therapeutic serum concentration or
target dose without causing significant adverse effects. If this does not achieve
seizure control, further dosage increase may be needed, even though the resulting
serum concentration may result in toxicity. If the seizures still do not respond,
monotherapy with an alternative drug should be prescribed. Combination therapy
should be used only if monotherapy with first-line drugs fails. If seizure control is
established, discontinuation of the previously unsuccessful AED should be
considered.

Adverse events.
The aim of treatment of epilepsy is to reduce seizures while preserving the
patient's quality of life. However, various reviews suggest that AEDs produce
adverse effects in
50% of patients treated. [53] The most commonly reported
complaints are symptoms of neurotoxicity, including impaired cognition, behavioral
disturbances, sedation, depression, movement disorders, cerebellar/vestibular
dysfunction, other encephalopathies and, less frequently, an increased incidence of
seizures. Lack of coordination or subtle cognitive and behavioral changes are
usually dose dependent. Occasionally, however, these adverse effects are dynamic
and unpredictable, with no correlation to AED concentration. Existing neurologic
dysfunction or metabolic abnormalities may predispose individuals to these
complications. Monotherapy with one of the new AEDs, particularly gabapentin,
felbamate, lamotrigine, or topiramate where indicated, may actually improve
behavior compared with benzodiazepine or barbiturate treatment. Gabapentin may
exacerbate retardation or preexisting hyperactivity, however; rarely, hyperkinesis
and increased aggressive behavior develop in previously normal children. [47] [54]

S012

TABLE 2 -- Adverse event profiles of antiepileptic drugs

Standard
agents

Adverse events

New agents

Adverse events

Carbamazepine

Aplastic
anemia, Felbamate
hypersensitivity

Fatal aplastic anemia

and hepatitis (rare),
insomnia, weight loss

Ethosuximide

Frequent
gastrointestinal
distress

Gabapentin

Neurotoxicity
and
behavioral changes

Phenobarbital

Adverse
sedative, Lamotrigine
cognitive, or behavioral
effects;
connective
tissue effects; sexual

Benign rash (10%),

serious rash (1%)

TABLE 2 -- Adverse event profiles of antiepileptic drugs

Standard
agents

Adverse events

New agents

Adverse events

dysfunction
Phenytoin

Cosmetic
dysmorphic effects

or Tiagabine

Neurotoxicity,
buckling

knee

Primidone

Connective
tissue Topiramate
effects,
adverse
affective
and
behavioral effects

Adverse
effects

Valproic acid

Hepatic
dysfunction, Vigabatrin
weight gain, tremor

Psychiatric symptoms
(rare),
visual
field
constriction

cognitive

Dosing adjustment or discontinuation may be necessary when these symptoms

occur. The alerting phenomena associated with felbamate, lamotrigine, and
topiramate have also led to anorexia, sleep disturbances, and sometimes
exacerbation of hyperactivity or aggressive behavior. [55]
The AEDs also are associated with a variety of other adverse events, some of which
are unique to particular agents or more common in children (table 2) . Most
importantly, one must recognize the risk for rare but potentially fatal adverse
effects. Children are more likely than adults to develop dermatologic and some
hepatic reactions to AED therapy, although many rashes in children are incorrectly
attributed to AED exposure. Dermatologic AED reactions are often the most obvious
symptoms of a more generalized systemic hypersensitivity reaction. Desquamation,
mucous membrane ulceration, and painful dermatitis can help to differentiate more
serious rashes from innocent skin changes. [56]
The recent identification of serious rash associated with lamotrigine requires that
careful attention be paid to dose titration and co-medication when this AED is used
in children. The incidence of potentially severe and life-threatening rash associated
with lamotrigine in children is approximately 0.5 to 1%, which is much higher than
the incidence in adults. [55] Aside from young age, co-therapy with valproate and
rapid dose escalation are other factors that increase risk for this adverse event.
Overall, rash occurs in up to about 10% of patients treated with lamotrigine, a
frequency similar to that associated with carbamazepine. [57] Most of these
eruptions are benign and do not develop into a life-threatening dermatitis or
hypersensitivity reaction. Although the manufacturer recommends discontinuing
lamotrigine at the appearance of any rash, it is common practice among clinicians
outside the United States to follow patients closely instead of immediately
withdrawing therapy.
Potentially fatal hepatotoxicity can occur with valproate therapy. This adverse
event appears to be age related, primarily occurring in children under the age of 2
years who are receiving polytherapy and who often have a preexisting metabolic
abnormality, typically of mitochondrial intermediary metabolism. Felbamate
treatment can also result in hepatotoxicity. The incidence of this adverse reaction is
similar to that of valproate hepatotoxicity, but no specific age predilection has been
noted for felbamate with cases reported in children. [58]
Aplastic anemia, agranulocytosis, and pancytopenia are hematologic abnormalities
reported as AED idiosyncratic reactions. A review of fatal aplastic anemia cases
possibly related to carbamazepine administration in the United States revealed an
incidence of 1/575,000 patients treated annually. [59] Felbamate has been associated
with an even higher incidence of aplastic anemia. [58] [60] Patients with preexisting
hematologic adverse reactions or autoimmune disease may be at higher risk for this

adverse event. No cases of aplastic anemia have been reported in children younger
than age 13 treated with felbamate, and young age appears to be almost protective
for carbamazepine-related aplastic anemia. However, this serious adverse effect is a
remote possibility and warrants appropriate counseling and clinical monitoring when
this medication is prescribed. Rare cases of aplastic anemia have occurred with
almost all AEDs, including ethosuximide. [61]

Conclusion.
The investigation and treatment of presumptive childhood epilepsy are
multifaceted. Proper diagnosis of the specific seizure type(s) and epilepsy
syndrome allows the development of a plan for assessment and, if necessary,
treatment. This plan may evolve over time as the patient's syndrome is better
defined. The child's medical, neurologic, and behavioral status is frequently an
important factor in therapeutic decisions.
In all children, a careful balance between AED efficacy and toxicity should be
maintained. The advent of new AEDs has allowed better seizure control and fewer
adverse effects in many patients. Nevertheless, there remain other children with
uncontrolled seizures and multiple adverse effects. New medical and surgical
treatments, along with patient

S013
reevaluation, are needed to optimize present and future therapy.
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