Prognostic Significance of Failure of the Initial Antiepileptic Drug in Children with Absence Epilepsy
Address correspondence and reprint requests to Dr. E. Wirrell at Department of Pediatrics, Division of Neurology, Alberta Children's Hospital, 1820 Richmond Rd. SW, Calgary, AB, Canada, T2T 5C7. E-mail: firstname.lastname@example.org
Summary: Purpose: In children with childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE), to determine the impact of failure of initial antiepileptic drug (AED) for lack of efficacy in eventual seizure control and long-term remission of epilepsy.
Methods: Centralized EEG records for the province of Nova Scotia allowed identification of all children seen with CAE or JAE between 1977 and 1985. Information regarding success or failure of initial AED in fully controlling seizures and long-term seizure control and remission of epilepsy was collected by patient questionnaire and chart review.
Results: Eighty-six of 92 eligible patients were followed up (75 CAE, 11 JAE). Initial AED treatment was successful in 52 (60%) of 86. Success tended to be greater for valproate (VPA) than for other AEDs (p = 0.07), and lower if generalized tonic–clonic or myoclonic seizures coexisted (p < 0.004 and p < 0.03). Terminal remission was more likely if the initial AED was successful than if it had failed (69% vs. 41%; p < 0.02). Compared with those in whom the initial AED was successful, subjects whose initial AED had failed were more likely to progress to juvenile myoclonic epilepsy (JME) at last follow-up (32% vs. 10%; p < 0.02) and to develop intractable epilepsy (17% vs. 2%; p < 0.04).
Conclusions: Initial AED was successful in 60% of children with AE. If the first AED failed, the outcome was less favorable, with a lower rate of terminal remission and a higher rate of progression to JME and intractable epilepsy.
In children with epilepsy, if the initial antiepileptic drug (AED) fails to control seizures, the prognosis for seizure control is often thought to be poor. However, only two studies have looked at this question in the pediatric population. Camfield et al. (1) studied 417 children with partial, primary, and secondarily generalized seizures and found that 17% required a second AED for seizure control. Long-term remission of epilepsy occurred in 61% of children successfully treated with one medication versus only 42% of those requiring more than one AED for seizure control (p < 0.002). A second study looking at 24 children with partial epilepsy found that 29% achieved seizure control with a second AED (2).
The prognostic significance of initial AED failure in children with absence seizures has not been published. We studied a population-based group of children with absence epilepsy to determine (a) how often absence seizures will be controlled after failure of the initial AED for lack of efficacy, and (b) whether failure of the initial AED predicts against long-term remission of absence epilepsy and for development of intractable epilepsy.
Potential cases of childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE) were identified by review of electroencephalogram (EEG) records from the IWK-Grace Health Center between 1977 and 1985, for the presence of typical generalized spike-and-wave discharge. All pediatric EEGs performed in the province of Nova Scotia (population younger than 16 years, 214,500 in 1981) are reported at this tertiary center. In addition, all four pediatric neurologists in Nova Scotia work at this hospital and follow up all children with epilepsy in both outpatient and outreach clinics, which cover all regions of the province.
Patients with typical 3- to 4-Hz generalized spike-and-wave discharge on EEG, who met criteria for CAE, as defined by Loiseau (3) or JAE, as defined by Wolf (4), were eligible for study. Criteria for CAE were (a) onset of absence seizures before puberty, (b) previously normal child, (c) absences as the initial seizure type, (d) very frequent absence seizures occurring multiple times per day, and (e) absence seizures associated with bilateral, symmetric, and synchronous discharge of regular 3-Hz spike-and-wave complexes with background activity that was normal or mildly abnormal. Criteria for JAE were (a) onset of seizures around puberty; (b) previously normal child; (c) possible preceding generalized tonic–clonic seizures; (d) absence seizures occurring less frequently, often not daily; and (e) generalized, symmetric 3- to 4-Hz spike-and-wave discharge, with background activity that was normal or mildly abnormal.
Children initially seen with juvenile myoclonic epilepsy (JME), defined as those children having absence, generalized tonic–clonic, and myoclonic seizures in association with fast spike-and-wave discharge and/or photoconvulsive response on EEG at the time of diagnosis were excluded.
Patients and/or their families were contacted by telephone between March 1994 and April 1995 to request participation in the study. Clinical information including sex, age at seizure onset and at onset of antiepileptic treatment, pubertal status at seizure onset, history of absence status, coexisting seizure types and when they began, type and number of AEDs used and reasons for discontinuation, perinatal complications, cognitive difficulties, family history of seizures in first-degree relatives, neurologic examination findings, and EEG findings (spike–wave frequency, photoconvulsive response, background abnormalities) were collected by chart review and mail-in questionnaire. Patients also were asked whether they were still taking AEDs, and their current seizure frequency and type(s) over the preceding year.
Subjects were included in the study if they participated in the mail-in questionnaire or if they were lost to follow-up but had been followed in the pediatric neurology clinic for a minimum of 24 months after diagnosis of absence seizures. Those lost to follow-up who had been followed for <24 months were excluded.
Perinatal complications were defined as having remained in hospital at birth for longer than 7 days because of concerns about the baby. Cognitive difficulties were defined as physician, parent, or teacher perception of learning problems at the time of diagnosis.
Success of initial AED was defined as obtaining complete seizure control with the first AED. Failure of initial AED was defined as inability to attain complete seizure control with the first appropriate AED. Our usual clinical practice was to consider absence seizures controlled if hyperventilation did not provoke a clinical absence seizure and the EEG showed no runs of generalized spike-and-wave discharge. Patients whose initial AED was discontinued because of side effects only were not considered to have had that medication fail. Three patients had been started taking carbamazepine (CBZ) before being seen by a neurologist. As this medication is known to be ineffective in treatment of absence epilepsy, failure to respond to it was not considered treatment failure. Decisions regarding initial choice of medication, dose, duration of treatment, and whether to continue or change AEDs were made on clinical grounds by the attending pediatric neurologist in consultation with the family. In general, an AED dose was increased to the maximal recommended dose or to the point at which the child showed signs of toxicity before it was declared ineffective. Seizure freedom was defined as being seizure free, with or without AEDs for ≥1 year before final follow-up. Terminal remission was defined as being seizure free without AEDs for ≥1 year before follow-up. Intractable epilepsy was defined as using three or more AEDs for seizure control during the course of epilepsy, and having more than one seizure per month over the final year of follow-up.
Data processing and analysis were performed with Epi Info Version 6.0 (5). All statistical comparisons used t tests or χ2 tests.
This study received ethical approval from the IWK-Grace Research and Ethics Committee.
Ninety-two patients with CAE or JAE were identified. The study group of 86 (93%) consisted of 79 who agreed to participate in the mail in questionnaire and seven who could not be contacted but had been followed up through the neurology clinic for ≥24 months after the diagnosis of absence seizures. The remaining six subjects could not be contacted and had <24 months of follow-up.
The study group consisted of 75 subjects with CAE and 11 with JAE. Median follow-up from diagnosis of absence epilepsy was 171 months (25th and 75th percentile, 139 and 201 months).
Fifty-two (60%) of 86 were successfully treated with the initial AED.
What factors predict response to initial AED?
There was no correlation between success of initial AED therapy and sex, age at seizure onset or treatment onset, pubertal status at seizure onset, absence status, perinatal complications, cognitive difficulties, family history of seizures in first-degree relatives, neurologic examination findings, or EEG findings.
Absence subtype at presentation predicted success with the initial AED. Forty-nine (65%) of 75 children with CAE responded to the initial AED [31 of 51 ethosuximide (ESM), 15 of 20 valproate (VPA), three of four clonazepam (CZP)] versus only three (27%) of 11 with JAE (one of nine ESM, two of two VPA; p < 0.04).
There was a nonsignificant trend for more subjects who were initially treated with VPA to experience seizure control compared with initial therapy with other AEDs. Of the 22 initially treated with VPA, 17 (77%) responded compared with only 35 (55%) of 64 treated with either ESM (32 of 59) or CZP (three of five; p = 0.07). Thirty-one of 34 subjects for whom initial AED treatment failed were tried on one or more subsequent AEDs; again VPA was superior, with 19 (83%) of 23 responding to VPA (used second line, 16 of 20 responders; used third line, three of three responders) versus only three (30%) of 10 to either ESM (used second line, one of five responders) or CZP (used second line, two of five responders; p < 0.01). Of the 27 children for whom ESM failed as initial AED, nine developed other seizure types that are known not to be responsive to this medication (two developed generalized tonic–clonic seizures, two developed myoclonic seizures, and five developed both generalized tonic–clonic and myoclonic seizures). Not unexpectedly, only one of nine subjects with JAE who were initially treated with ESM experienced success with this AED.
The presence of other seizure types before or during initial AED treatment also predicted against success of initial AED. Forty-three (70%) of 61 subjects who did not experience generalized tonic–clonic seizures before or during initial AED treatment were successfully treated with their initial AED versus only nine (36%) of 25 who did (p < 0.004). Forty-six (67%) of 69 subjects who had no myoclonic seizures before or during initial AED treatment were treated successfully with the first AED versus only six (35%) of 17 who did (p < 0.03).
Does success with initial AED predict long-term outcome?
Fifty (58%) of 86 subjects were in terminal remission at the end of follow-up. Remission was significantly more likely in cases in which initial AED treatment was successful [36 (69%) of 52] than in cases in which initial AED treatment had failed [14 (41%) of 34; p < 0.02)]. Two or more AEDs had failed for 11 subjects, and their prognosis for terminal remission was grim, with only one of 11 being seizure free and without AEDs after a mean follow-up of 171 months (range, 32–328 months).
Sixty (70%) of 86 subjects were seizure free at follow-up and there was a nonsignificant trend for successful initial AED treatment to predict seizure freedom. Forty (77%) of 52 who responded favorably to their initial AED versus 19 (56%) of 34 who did not were seizure free (p = 0.06).
Sixty (70%) subjects had discontinued AEDs at follow-up; however, 10 still had ongoing seizures (five frequent absences ± myoclonic seizures, four rare absences ± myoclonic seizures, and one rare myoclonic seizures only). Forty-three (83%) of 52 subjects in whom the initial AED had been successful were without medications versus only 16 (47%) of 34 in whom the initial AED had failed (p < 0.001).
Intractable epilepsy was significantly more common in subjects for whom their first AED had failed [six (17%) of 35] than those who had successful seizure control with their initial medication [one (2%) of 52; p < 0.04).
At last follow-up, 13 (17%) of 75 subjects initially diagnosed with CAE and four (36%) of 11 initially diagnosed with JAE had progressed to JME, and this progression was predicted by failure of initial AED. Eleven (32%) of 34 subjects whose initial AED had failed versus five (10%) of 52 who were successfully treated ultimately developed JME (p < 0.02).
Overall, 60% of our patients with onset of absence epilepsy in childhood responded to their initial AED. Three factors predicted response: absence subtype, type of AED used, and coexistent generalized tonic–clonic or myoclonic seizures. Subjects with CAE tended to have a higher response rate than did those with JAE, and this may be explained by the frequent use of ESM as first-line therapy in subjects with both absence subtypes in this study. Generalized tonic–clonic seizures occur in ∼83% of JAE (4) compared with only 40% of CAE (3), and myoclonic seizures also are more common. ESM is ineffective for treatment of generalized tonic–clonic or myoclonic seizures, but may be a reasonable choice for treating a young child with CAE, as generalized tonic–clonic seizures, if they are to occur, usually have their onset between ages 10 and 15 years (3). However, in JAE, the patient is usually older, and the risk of seizure types other than absence developing during the course of treatment is much greater, making ESM a poor choice in this clinical situation. Type of AED used for initial therapy also influenced response. We found that subjects treated with VPA did better than those treated with ESM or CZP. In one third of patients for whom ESM failed, other seizure types developed that are refractory to this medication. If one excludes this subgroup, response rates for ESM [32 (64%) of 50] and VPA [17 (77%) of 22] are similar. Finally, coexistent generalized tonic–clonic and myoclonic seizures correlated with treatment failure, likely reflecting the fact that most of our subjects were initially treated with ESM, which is ineffective for these seizure types.
In their study of 124 children with typical absence epilepsy, Covanis et al. (6) noted that monotherapy with either VPA or ESM was successful in 85% of children with absence seizures alone, and in 68% of those with coexisting generalized tonic–clonic seizures. In most cases, VPA rather than ESM was preferentially used as first-line therapy. Children who required treatment with polytherapy (two or more AED agents used consecutively to attain seizure control) had a higher rate of relapse if AEDs were discontinued than did those treated with monotherapy. They, however, did not report in what proportion of their patients the first AED failed, and the patients were subsequently switched to another AED as monotherapy, and what impact this failure had on long-term outcome.
It is generally accepted that failure to respond to the initial AED bodes poorly for eventual seizure remission in patients with epilepsy. However, most work in this area has been done in adult centers. In a recently published study, Kwan and Brodie (7) noted that 47% of their patient group aged 9–93 years (median age, 29 years) became seizure free with their first AED (7). However, if the first drug failed for lack of efficacy, only 11% subsequently became seizure free. In their population-based study of children with primary and secondarily generalized tonic–clonic and partial seizures, Camfield et al. (1) obtained more hopeful results for children for whom their first AED failed; 42% experienced eventual seizure remission, and only 29% developed intractable epilepsy. This study is the first to assess the implications of success with the initial AED on long-term prognosis in absence epilepsy, and our results also are optimistic. Sixty-nine percent of children who responded successfully to their first AED were in terminal remission at follow-up, and in only 2% had intractable epilepsy developed. If the first AED failed because of lack of efficacy, the outlook was not so positive; however, 41% still achieved terminal remission, and only 17% progressed to intractable epilepsy.
In our previous population-based study on long-term prognosis of typical CAE, which included these same patients, we found that after a mean follow-up of 20.4 years, 65% had achieved remission, and that 15% had progressed to JME (8). In this present study, we noted that failure to respond successfully to the initial AED predicted progression to JME, with this form of epilepsy developing in 32% of those for whom medication failed versus only 10% of those in whom medication succeeded. As these patients developed coexistent generalized tonic–clonic or myoclonic seizures, it is not surprising that ESM was ineffective.
Our study has several limitations. First, it was retrospective. Decisions to stop an AED because of lack of efficacy were made by the attending pediatric neurologist in consultation with the family. The philosophy in our center was to increase medication to the maximal recommended dose or to the point at which the child showed signs of toxicity before declaring it ineffective. However, it is possible that some patients may have tolerated a further increase in medication, as AED levels were not routinely measured, and no specific maximal dose guidelines were used for this study. If medications were stopped prematurely in a small number of subjects, the success rate for initial AED treatment may be higher than we found.
Second, a small number of patients, at follow-up, continued to have seizures but were either taking no AED or were maintained on suboptimal therapy. These subjects had not had newer, potentially effective AEDs or aggressive pharmacologic management. It is likely that these patients would either become seizure free or would be declared to have intractable epilepsy, and a clearer picture of long-term prognosis of absence epilepsy would emerge for this subgroup.
Finally, several new AEDs, such as lamotrigine (LTG) and topiramate (TPM), are effective for absence epilepsy, as well as for other seizure types. For the most part, our study cohort was treated before these medications became available, and use of them may have controlled seizures in a small number of subjects with intractable epilepsy. None of these agents, however, is considered first line in children with absence epilepsy.
In conclusion, 69% of children with absence epilepsy who respond to their initial AED will have ultimate remission of their epilepsy. Although the prognosis for those for whom initial treatment fails is less optimistic, 41% of these will still remit, and only 17% will progress to intractable epilepsy.