WITHDRAWING AEDS IN CHILDREN WITH EPILEPSY WHO HAVE BEEN SEIZURE FREE FOR 2 OR MORE

YEARS

The available data indicate that children who are seizure free on medication for 2 or more years have
a very high likelihood of remaining in remission on medication (39). In selected populations,
withdrawal may be feasible after an even shorter seizure-free interval (39–42). How long should a
child be maintained on medication before the attempt is made to withdraw it? This decision will be
influenced by a variety of factors, including the probability of remaining seizure free after withdrawal
in a given patient, the potential risk of injury from a seizure recurrence, and the potential adverse
effects of continued AED therapy. The majority of children who are seizure free on medications for at
least 2 years will remain seizure free when medications are withdrawn. A large number of well-
designed studies involving over 700 children have been done over the past 20 years (39, 43–54). The
overall results have been very similar. Between 60% and 75% of children with epilepsy who have
been seizure free for more than 2 (39, 43, 44, 49–53) or 4 (44–48) years on medications remain
seizure free when antiepileptic medication is withdrawn. Furthermore, the majority of recurrences
occur shortly after medication withdrawal, with almost half the relapses occurring within 6 months of
medication withdrawal and 60% to 80% within 1 year (39, 53, 54). These studies are supported by a
follow-up of patients for 15 to 23 years after medication withdrawal (47, 55). Although late
recurrences do occur, they are rare

40729 • TREATMENT DECISIONS IN CHILDHOOD SEIZURES

(47, 53, 55). In a recent randomized study, the increased risk of relapse following AED withdrawal
occurred only in the first 2 years after AED withdrawal. The rate of late recurrences was the same in
those who remained on AED therapy and those whose AEDs were discontinued (48). The important
question is, Can one identify risk factors such as etiology, age of onset, type of seizure, EEG features,
or the specific epilepsy syndrome, that will enable one to identify subgroups of children with an even
better prognosis and subgroups with a much less favorable prognosis for maintaining seizure
remission off medication? There is much less consensus in this area. A discussion of the potential risk
factors that have been looked at and their possible significance is presented next.

Etiology and Neurologic Status In general, children with epilepsy associated with a prior neurologic
insult have a smaller chance of becoming seizure free in the first place than do children with
cryptogenic epilepsy (21, 22, 24). In children with remote symptomatic epilepsy who are seizure free
on medication, most studies indicate a higher risk of recurrence following discontinuation of
medication than in children with cryptogenic epilepsy (44–47, 49, 50, 53). In a recent meta-analysis
of this literature, the relative risk of relapse in those with remote symptomatic seizures was 1.55
(95% CI 1.21–1.98) (54). However, almost half of these children will remain seizure free after
withdrawal of medication (45, 53, 54). Furthermore, even within this group one can identify
subgroups with favorable and unfavorable risk factors (53).

Age of Onset and Age at Withdrawal Age of onset above 12 years is associated with a higher risk of
relapse following discontinuation of medications (39, 42, 45, 49–51, 53, 54). In our data this was the
singlemost important risk factor for recurrence (relative risk 4.24, 95% CI 2.54–7.08). A meta-analysis
(54) also found adolescent-onset seizures to be associated with a higher risk of recurrence than
childhood-onset (relative risk 1.79, 95% CI 1.46–2.19). There is some controversy as to whether a
very young age of onset (under 2 years) may be a poor prognostic factor (45). In our data, a young
age of onset was associated with a less favorable prognosis only in those with remote symptomatic
seizures and was associated with more severe neurologic abnormalities (53). As most childhood
epilepsy is readily controlled with AED therapy, the age at withdrawal of AEDs will be highly
correlated with age of onset. However, the age at AED withdrawal does not appear to be important
once age of onset is taken into account. In particular, there is no evidence that discontinuation of
AEDs during the pubertal

period is associated with a higher risk of recurrence (39, 43, 44, 53).

Duration of Epilepsy and Number of Seizures These two variables are closely interrelated. A long
duration of epilepsy may increase the risk of recurrence, though the magnitude of the effect is small
(39, 42, 46, 47). One study also reported that having more than 30 generalized tonic-clonic seizures
was associated with a high risk of recurrence after discontinuation of therapy (45). In a community-
based practice, most children will be easily controlled within a short time after therapy is initiated, so
these factors will rarely be important.

Seizure Type Studies on the effect of seizure type on the risk of recurrence after medication
withdrawal in children have produced inconsistent results. Children with multiple seizure types have
a poorer prognosis (46, 47). The data regarding partial seizures are conflicting (39, 43–54). At this
time it is not clear that any specific seizure type is associated with an increased risk of recurrence
following discontinuation of medication.

EEG

In several studies (39, 40, 43–45, 53, 54), the EEG prior to discontinuation of medication was one of
the most important predictors of relapse in children with cryptogenic epilepsy. However, the specific
EEG abnormalities of significance varied across studies. Two other studies found no correlation
between the EEG and outcome (46, 50). A meta-analysis found that an abnormal EEG prior to AED
withdrawal was associated with a relative risk of relapse of 1.45 (95% CI 1.18–1.79) (54). The
preponderance of evidence indicates that an abnormal EEG is associated with an increased
recurrence risk in children with cryptogenic/idiopathic epilepsy. The EEG obtained at the time of
initial diagnostic evaluation may also have predictive value. Certain characteristic EEG patterns
associated with specific epileptic syndromes, such as benign rolandic epilepsy or juvenile myoclonic
epilepsy, provide additional prognostic information (24, 33, 34, 53). Changes in the EEG over time
may also have prognostic value (40, 43).