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Purpose: Intractability in epilepsy is difficult to define, and little is known about its onset, course, and duration. We investigated these aspects (as well as the occurrence of intractability) during long-term follow-up in patients with epilepsy, focusing on possible explanations for the variation in time of onset and duration of intractability.
Methods: After diagnosis, 453 patients with childhood-onset epilepsy had a 5-year follow-up with regular visits and data collection. Ten years later they received a questionnaire with items concerning epilepsy, which was completed by 413 patients resulting in a mean follow-up of 15 years. Intractability during the first 5 years was compared with that in the last year of follow-up. Intractability was defined as having no 3-month remission during a 1-year period despite adequate medical treatment.
Key Findings: At least 12.1% of the cohort had a period of intractability during the 15-year follow-up, and 8.5% were intractable in the final year. Of the patients with idiopathic etiology 4.3% had a period of intractability versus 17.0% for those with cryptogenic, and 22.6% for those with remote symptomatic etiology (p < 0.001). Other risk factors at baseline were younger age at first seizure, generalized cryptogenic/symptomatic or localization-related symptomatic epilepsy, mental retardation, and febrile convulsions before enrollment. The cumulative risk of a period of intractability was 6.1% (95% confidence interval [CI] 3.7–8.5) at 2 years follow-up and 8.2% (95% CI 5.4–11.0) at 5 years. The mean time to onset of intractability during the first 5 years of follow-up was 1.6 (95% CI 1.3–2.0; median 1.0) years and the mean duration of intractability during these 5 years was 3.3 (95% CI 2.8–3.8; median 3.6) years. Fifteen patients were intractable only during the first 5 years of follow-up (group A), and 19 subjects were intractable both during the first 5 years and the last year of follow-up (group B). Compared with group A, group B had shorter remission and a longer time to intractability during the first 5 years and more were intractable in the fifth year of follow-up. Sixteen other patients had a late onset of intractability after 5 years of follow-up, sometimes after long periods of remission (group C). No significant differences in baseline characteristics were found among groups A, B, and C, but slightly more children in groups B and C became mentally retarded during the follow-up. In all groups, antiepileptic drugs were of little use in preventing and ending intractability.
Significance: There is a large unpredictable variation in time of onset, course, and duration of intractability, with a higher chance of final intractability after a poor course during the first 5 years of follow-up. The natural course of epilepsy probably best explains the variable course of intractability. The effect of medication seems to be minor.
Recent studies indicate that the course of childhood-onset epilepsy may vary during long-term follow-up. Periods of remission and periods with frequent seizures can interchange (Berg et al., 2004, 2006; Sillanpää & Schmidt, 2006a; Berg et al., 2009; Geerts et al., 2010). The end of an episode with frequent seizures could result from the effectiveness of treatment, or from the self-limiting character of some types of epilepsy. Conversely, persistent seizures (or so-called intractability) starting late in the course of epilepsy could result from poor adherence with the prescribed treatment, from development of drug resistance or tolerance, or from an ongoing process of epileptogenesis that is insensitive to treatment (Loscher & Schmidt, 2006; Abou-Khalil, 2007; Brown et al., 2009; Vervloet et al., 2011).
Studying the course of intractability, especially its time of onset and the interchanging pattern with periods of remission, may enable one to find explanations for the development, discontinuation, or chronicity of intractability, and to distinguish the natural course of epilepsy from treatment effects.
Between 1988 and 1992, we recruited 494 consecutive children who presented at the hospital with new-onset epilepsy. Results of the clinical course at 2 and 5 years after diagnosis have been published (Arts et al., 1999, 2004) as well as the results of 413 patients with a mean 15-year follow-up (Geerts et al., 2010); this latter publication presented risk factors for final intractability (nonidiopathic etiology, febrile seizures before enrollment, no 3-month remission in the first 6 months of follow-up, and having a eriod of intractability during the first 5 years of follow-up).
This report focuses on the course of intractability during follow-up and possible reasons for its variation. A comparison is made between intractability in the first 5 years and intractability in the final year.
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The present study was a pragmatic investigation. Our main interest was the time of onset of intractability, its course over time, and the variables that might influence it. The definition of intractability itself was not the issue; any other definition could have been used and probably would have yielded similar results.
Unfortunately, our results and the resulting conclusions are limited by the lack of data on the onset of intractability in the period after the fifth year of follow-up. Nevertheless, we think that the data provide valuable insight into the onset and course of intractability during the long-term follow-up of our cohort, even though intractability in some years could not be established. However, in our opinion, the latter is not a significant drawback. In fact, if all subjects with possible intractability in the intervening years had been intractable, our conclusions about a fluctuating course and temporary intractability would have been strengthened. The main outcome of this prospective study is that at least 12% of our cohort with childhood-onset epilepsy experienced a period of intractability during a 15-year follow-up since diagnosis, and 8.5% were intractable in the final year. The majority became intractable within 5 years after epilepsy onset, but approximately 50% of the patients were no longer intractable at the last contact; some even reached a 5-year terminal remission. Other patients had a late onset of intractability after 5 years of follow-up, and in some, intractability was interrupted by long periods of remission. This has also been reported by others (Takenaka et al., 2000; Sillanpää & Schmidt, 2006a). These findings show that time of onset, course, and duration of intractability vary considerably between subjects. According to the present study, these aspects of intractability are hardly predictable, even though intractability itself can be predicted to a certain extent. The risk factors for intractability found in the present study (younger age at onset, remote symptomatic etiology, type of epilepsy, and mental retardation) have also been reported by others (Huttenlocher & Hapke, 1990; Berg et al., 1996; Casetta et al., 1999; Kwong et al., 2003; Altunbasak et al., 2007). However, in the present study none of these risk factors were associated with a temporary, continuing, or late onset of intractability. In practice this means that a treating physician can only estimate the risk of intractability for an individual patient, but not the time of onset or duration of intractability, and the sustainability of remission following intractability. Especially for surgery candidates, it would have been valuable if these aspects of intractability could have been predicted.
Intractability as a temporary phenomenon
The finding that intractability can be followed by remission has also been reported by others (Berg et al., 2006, 2009; Callaghan et al., 2007, 2011; Choi et al., 2008, 2011), and some state that the natural history of intractable seizures in children follows a gradual line of slow improvement, especially in patients with normal intelligence (Huttenlocher & Hapke, 1990). In our opinion this might particularly apply to children with a period of intractability early in the course of their epilepsy.
In a prevalence cohort study of adults with intractable epilepsy no clear predictors for remission were found (Choi et al., 2008, 2011), whereas in a similar study, developmental delay, symptomatic generalized epilepsy, longer duration of intractability, and number of failed AEDs were negatively associated with remission, although in multivariate analysis only the number of failed AEDs remained significant (Callaghan et al., 2011). In a prospective childhood-onset study, idiopathic epilepsy and lower seizure frequency were positively associated with remission (Berg et al., 2009). In the present study no clear predictors were found for temporary intractability versus ongoing or repeating intractability. However, although the numbers were small, there were some significant differences between subjects with temporary intractability and those intractable again at the end, indicating that the epilepsy of the latter patients was probably more severe from the beginning and deteriorated further during follow-up.
It has been shown that remission after intractability started after medication changes in 28–76% of adult subjects, although the relapse rate was high (Luciano & Shorvon, 2007; Callaghan et al., 2011; Choi et al., 2011). In our cohort, we found a medication effect in 27% (4 of 15) of patients with temporary intractability, with 2 of the 4 subsequently entering terminal remission for at least 10 years. In our cohort, apart from the patients with a positive effect of AEDs or surgery, and the patient not considered intractable in the final year, we think that the improvement resulted from the natural course of the patients’ epilepsy.
More than 30% of our intractable patients had a late onset of intractability, starting 5 years or more after diagnosis; this has also been reported by others (Berg et al., 2003; Berg, 2004; Sillanpää & Schmidt, 2006a). Three years or more after diagnosis, Berg et al. (2006) found a late-onset intractability in 32% of children meeting their stringent definition of intractability. This occurred even after long periods of remission, a result that was confirmed in the present study. In line with this, Sillanpää et al. found a worsening course in 14% of their cohort, defined as a relapse occurring after a 5-year remission without regaining a final 5-year terminal remission (Sillanpää & Schmidt, 2006a). So far, no clear explanation for the occurrence of late-onset intractability is available, although a poorer adherence to medication during follow-up might be one (Sabaté, 2003). In addition, AED failure after restart has been reported as a possible reason (Takenaka et al., 2000; Schmidt & Loscher, 2005; Sillanpää & Schmidt, 2006b). Two studies found that reinstitution of medication that worked for years failed to achieve control in one of three or four relapsed patients (Bouma et al., 2002; Sillanpää & Schmidt, 2006b). In our study this occurred in five patients. During ongoing treatment, mechanisms such as developing drug tolerance or resistance might lead to deterioration or intractability. However, it remains uncertain whether late-onset intractability or a worsening course results from these mechanisms, or from the progressive nature of some types of epilepsy (Takenaka et al., 2000; Abou-Khalil, 2007). In view of this, we doubt that late-onset intractability is a temporary phenomenon, like part of the early-onset intractability, but rather that it might be severe and persistent.
One study found evidence of a later onset of intractability in patients with focal epilepsy compared with those with catastrophic epilepsy (Berg et al., 2006). In our cohort, we found that slightly more patients with catastrophic epilepsy developed intractability during the first 5 years of follow-up (mostly during the first year) compared with those with focal epilepsy, but that there was no significant difference in the time to intractability. In addition, during the entire follow-up, the difference in intractability between these two groups was not significant (focal 18.2% vs. catastrophic 28.3%, Pearson’s χ2: 2.53, d.f. = 1, p = 0.112), unless they would have been temporarily intractable 5 years or more after enrollment. We conclude that our results do not convincingly support the findings of Berg et al., although the trend pointed in the same direction. In the study of Berg et al., more subjects with catastrophic epilepsy developed intractability during the first 5 years of follow-up than in our study (stringent definition: approximately 50.% vs. 21.7%, respectively), although for those with focal epilepsy the numbers were the same (approximately 10% vs. 11.7%). In our cohort, the difference between the catastrophic and focal group was only marginally significant.
Drug-resistant epilepsy according to the ILAE commission
Recently the ILAE proposed the following definition for drug-resistant epilepsy (Kwan et al., 2010): failure of adequate trials of two tolerated, appropriately chosen and used AED schedules to achieve sustained seizure freedom. In response to this, and to make our article as up-to-date as possible, we applied this definition to our cohort in addition to our definition at two points in time: at 5 years after enrollment and at last contact.
A comparison of both definitions shows that there is very little difference (Table 3). The overall conclusion is more or less the same; in both cases intractability or drug-resistance can be temporary, continuing, or delayed. However, the ILAE definition labels more patients as being drug-resistant. Certainly there is little doubt about treatment failure when a person still has seizures, however, we consider that in terms of severity of epilepsy, the ILAE definition may be too broad in labeling patients with only sporadic seizures as having intractable epilepsy. On the other hand, our definition may not label some highly refractory patients with brief remissions as intractable, when in fact they are. Having used the ILAE definition, we think that it is difficult to apply in a large cohort study, as the history of each individual patient has to be judged carefully, and the intraobserver and interobserver variability may be high. It should be stressed that it is not our intention to decide which definition is best or to promote our definition. We merely used our definition as a tool to study the course of intractability. In future cohort studies, we advocate the use of one worldwide accepted definition to make comparisons between studies easier. We consider the proposed definition of the ILAE as a good step forward.
Table 3. Comparison of the proposed ILAE definition of drug resistance and our definition of intractability applied to 413 subjects
|ILAE definition (Kwan et al., 2010)||Intractability definition as used in the present study||Intractability definition applied to the fifth and last year of follow-up|
|Drug resistant at the end of the fifth year of follow-up||36 (8.7%)||A period of intractability during the first 5 years of follow-up||34 (8.2%)||Intractable during the fifth year of follow-up||18 (4.4%)|
|Drug resistant at last contact||48 (11.6%)||Intractable during the last year of follow-up||35 (8.5%)||Intractable during the last year of follow-up||35 (8.5%)|
|Only drug resistant at the end of the fifth year of follow-up||12 (2.9%)||Only a period of intractability during the first 5 years of follow-up||15 (3.6%)||Only intractable during the fifth year of follow-up||4 (1.0%)|
|Drug resistant at the end of the fifth year of follow-up and at last contact||24 (5.8%)||A period of intractability during the first 5 years of follow-up and in the last year of follow-up||19 (4.6%)||Intractable during the fifth year and last year of follow-up||14 (3.4%)|
|Only drug resistant at last contact||24 (5.8%)||Only intractable during the last year of follow-up||16 (3.9%)||Only intractable during the last year of follow-up||16 (3.9%)|
Considering the high proportion of patients with temporary intractability, one could argue that the time span used in our definition of intractability was too short, leading to the inclusion of too many subjects not fundamentally intractable. Table 4 shows our attempt to predict intractability in the final year of the 15-year follow-up with intractability in the first 5 years, while varying the period of continuous seizures. However, a longer period of continuous seizures in the first 5 years led to a decreased sensitivity of the prediction, whereas specificity remained almost the same. In this case, fewer subjects being intractable in the final year of follow-up would have been identified. Consequently, a longer period of continuous seizures as part of the definition of intractability does not solve the problem. Moreover, of the 14 patients with intractability lasting 4–5 years, two reached a 5-year and two a 1-year terminal remission. Therefore, determining how long a patient has to have frequent seizures to be labeled intractable remains arbitrary.
Table 4. Intractability in the first 5 years as a predictor of intractability in the final year of follow-up depending on the length of the period of intractability during the first 5 years
|Length of the period of intractability during the first 5 years||Intractable in the first 5 years||Intractable in the final year||Sensitivity, %||Specificity, %|
Apart from the time span in our definition of intractability, using only two AEDs could be a matter of discussion. Other investigators use or recommend three AEDs (Camfield & Camfield, 1996; Kwong et al., 2003; Malik et al., 2008), although there is ample evidence that a third AED has little or no effect (Arts et al., 2004; Mohanraj & Brodie, 2006). Moreover, all patients who were intractable in the final year and 31 of the 34 patients with early onset had used at least three AEDs during follow-up. Considering this, we think that the number of AEDs in our definition is not an issue.
Furthermore, there might be discussion about subjects in our study having an intractable seizure pattern in the last year of follow-up while using only one AED. After a long period of intractability, it may be best for a patient to stop medication or to reduce polytherapy in case none of the therapies is really effective. Many physicians would probably have labeled these subjects as being intractable; however, in the present study we applied our definition strictly, and by doing so may have underreported the occurrence of intractability.
The course of intractability was studied during a period of impressive maturation of the child’s brain. The fact that many patients had temporary intractability might be the result of these processes. On the other hand, the phenomenon of late-onset intractability might result from a continuing process of epileptogenesis.
We studied the course of intractability using an objective approach and did not address the subjective severity of intractability, although we realize that this is also important, especially for patients just reaching adulthood.
In this study, incorrect diagnoses of intractability may have been made as a result of noncompliance, incorrect medication, or incorrect diagnosis or classification of epilepsy. We attempted to exclude these errors to the best of our ability. During the first 5 years, regular plasma concentrations of AEDs were taken, giving us an impression of compliance. We did not have this information for the patients in the last year of follow-up, unless it was indicated in their medical records. The Dutch Study of Epilepsy in Children was a pragmatic study, conducted with experienced physicians working according to their usual clinical practice.
To our knowledge, only a few cohort studies on childhood-onset epilepsy have aimed to identify possible reasons (other than clinical features) for the onset or ending of intractability, which makes the present study uncommon. Only a few studies reported that remission after intractability and relapse occurred in conjunction with changes in medication (Luciano & Shorvon, 2007; Callaghan et al., 2011; Choi et al., 2011). Although this is a delicate topic we think that the success or failure of treatment has to be considered at all times in future research investigating intractability.
The fact that we found no risk factors for temporary, continuing, or late-onset intractability might be due to the small numbers, even though our cohort is one of the largest with childhood-onset epilepsy. Only meta-analyses using multiple cohorts might be able to detect these risk factors.
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At least 12% of patients with childhood-onset epilepsy will have a period of intractability during a 15-year follow-up. Onset, course, and duration of intractability can fluctuate to a great extent, and periods of remission and intractability can alternate with each other. Intractability can be temporary (especially in case of early onset), but can also begin many years after diagnosis, and in that case, is more likely to persist. These findings are in line with other investigations.
Apart from the risk factors for intractability, it is difficult to predict the time of onset of intractability and whether it will be temporary. Due to the relatively low frequency of intractability, meta-analyses are almost certainly needed for this.
This study did not find a clear explanation for the variation in intractability. The most probable explanation is the natural course of the epilepsy itself, as intractability developed in some despite an early and successful start of treatment, and in only 16% could medication be held responsible for the termination or late onset of intractability. However, the effect of medication may be different in patients who did not have a period of intractability. More research is needed on the actual role of AEDs on the process of epileptogenesis; the question remains whether AEDs modify this process or merely refine it.
Despite recent reports by the ILAE commission, a solid and all-encompassing definition of intractability, also taking into account the severity of sporadically occurring seizures, remains to be established.