Articles CME
How long does it take for partial epilepsy to become intractable?
A.T. Berg, PhD; J. Langfitt, PhD; S. Shinnar, MD, PhD; B.G. Vickrey, MD, MPH; M.R. Sperling, MD; T. Walczak, MD; C. Bazil, MD; S.V. Pacia, MD; and S.S. Spencer, MD, for the Multicenter Study of Epilepsy Surgery
Abstract—Background: Much remains unknown about the natural history of intractable localization-related epilepsy, including how long it typically takes before intractability becomes evident. This information could guide the design of future studies, resolve certain discrepancies in the literature, and provide more accurate information about long-term prognosis. Methods: Individuals evaluated for resective surgery for refractory localization-related epilepsy were prospectively identified at the time of initial surgical evaluation at seven surgical centers (between 1996 and 2001). The latency time between onset of epilepsy and failure of second medication and history of remission (ⱖ1 year seizure-free) before surgical evaluation were examined with respect to age at onset, hippocampal atrophy, febrile seizures, and surgical site. Results: In the 333 patients included in the analysis, latency time was 9.1 years (range 0 to 48) and 26% reported a prior remission before surgery. A prior remission of ⱖ5 years was reported by 8.5% of study participants. Younger age at onset was strongly associated with longer latency time (p ⬍ 0.0001) and higher probability of past remission (p ⬍ 0.0001). In multivariable analyses, age at onset remained as the most important explanatory variable of both latency time and prior remission. Conclusions: A substantial proportion of localization-related epilepsy may not become clearly intractable for many years after onset. This is especially true of epilepsy of childhood and early adolescent onset. If prospective studies confirm these findings and the underlying mechanisms behind these associations become understood, this raises the possibility of considering interventions that might interrupt such a process and some day prevent some forms of epilepsy from becoming intractable. NEUROLOGY 2003;60:186 –190
Little is known about the natural history, particularly the time course of development, of refractory partial epilepsy. There has been a tacit assumption that intractability is generally evident from the initial onset of epilepsy.1-3 Others have suggested that this might not always be the case.4-8 It has never been clear how long it takes before a patient’s epilepsy becomes truly pharmacoresistant, and several aspects of the long-term natural history of epilepsy are poorly understood. This is in part because of the prolonged intensive followup needed and the difficulty in assembling, adequately characterizing, and following a sufficiently large group of patients for several decades. We have examined the histories of a series of adult patients who underwent resective surgery for
refractory localization-related epilepsy to determine how much time elapsed before the disease became intractable and whether this differed in patients as a function of age at onset, history of febrile seizures, anterior temporal lobe epilepsy, and specifically mesial temporal sclerosis. We also studied reported periods of remission prior to surgery in this series. Methods. Data are from an ongoing, prospective, multicenter study designed to examine the outcomes of resective epilepsy surgery. Six centers in the Northeast and one in the Midwest are participating. Eligible participants are identified for inclusion in the study when they first present for presurgical evaluation for refractory localization-related epilepsy. Our criteria for refractory epilepsy required 20 complex partial seizures during the 24 months preceding evaluation at the center and a history of two or more first-line drugs for partial epilepsy having failed. Given when the study was conducted and the study participants first developed epilepsy, the first drugs used were generally carbamaz-
See also pages 162 and 191 From BIOS (Dr. Berg), NIU, DeKalb, IL; Department of Neurology (Dr. Langfitt), University of Rochester School of Medicine, NY; Department of Neurology (Dr. Shinnar), Albert Einstein College of Medicine, Bronx, NY; Department of Neurology (Dr. Vickrey), University of California, Los Angeles; Department of Neurology (Dr. Sperling), Thomas Jefferson University Medical School, Philadelphia, PA; Minnesota Comprehensive Epilepsy Program (Dr. Walczak), Minneapolis; Department of Neurology (Dr. Bazil), Columbia University Medical School, New York, NY; Department of Neurology (Dr. Pacia), New York University, New York, NY; and Department of Neurology (Dr. Spencer), Yale University School of Medicine, New Haven, CT. Supported by grant no. RO1 NS 32375 from the NIH/National Institute of Neurological Disorders and Stroke. Received April 8, 2002. Accepted in final form July 17, 2002. Address correspondence and reprint requests to Dr. Anne T. Berg, Department of BIOS, NIU, DeKalb, IL 60115; e-mail:
[email protected] 186
Copyright © 2003 by AAN Enterprises, Inc.
epine, phenytoin, phenobarbital, or primidone. Only study participants who underwent resective surgery are included in this analysis. Appropriate procedures were followed for obtaining signed informed consent from each participant before inclusion in the study. All procedures were approved by the institutional review boards of all the participating institutions. Data were collected through medical records review and structured in-person interviews. Trained research associates administered the interviews to the participants at each site. The interview was designed to collect information about demographic characteristics, features of epilepsy (duration, seizure types, and frequency) and other information. Questions were presented in a closedended fashion. Because of the interest in examining the early course of epilepsy developed during the course of this study, a brief series of questions about the occurrence of remission (ⱖ1 year seizure-free) between the onset of epilepsy and the presentation for surgical evaluation was incorporated into the study and administered after the initial intake interview. Research associates asked these supplemental questions without any knowledge of the specific research hypotheses or without reference to details of the individual’s history. Time to intractability was assessed based on review of the cumulated medical records and was defined as the time between the occurrence of the second unprovoked seizure (when someone met the criteria for having epilepsy)9 and failure of the second antiepileptic drug. The determination of drug failure was based on review of the referring and treating neurologists’ records. A drug was not considered a failure unless it had been pushed to maximum tolerable levels without adequate seizure control. Drugs stopped only because of side effects were not considered therapeutic failures. In addition, lack of seizure control due to noncompliance was not considered a drug failure. All of the patients in this study had been referred to one of the surgical centers for a surgical evaluation because their treating neurologist had determined that their epilepsy was not responsive to drug therapy. We also considered the time between the first unprovoked seizure and failure of the second drug; however, we did not use this as the primary outcome because several individuals had a prolonged interval (⬎1 year) between the first two seizures, and we were interested in events from the point at which patients would formally be considered to have epilepsy and in most cases would have been treated.9 Age at onset, however, was still considered the age at the initial seizure as this is the age at which the disorder first became apparent, and we are not in a position to know the extent to which age at onset might modify the time between the first and second seizure in this population. Remission was based on a self-reported history of having had at least a 1-year period seizure-free between the second unprovoked seizure and the presentation for surgery. The duration of reported remission and the occurrence of more than one period of remission were recorded. The factors whose association with the early course of epilepsy we were most interested in examining were the type of surgery (anterior temporal lobe resection vs all other), a history of febrile seizures, mesial temporal sclerosis, and age at onset. The presence of hippocampal atrophy on the MRI scan was used as a measure of mesial temporal sclerosis. All scans were read by a single neuroradiologist under a standard protocol and were therefore more uniform and complete than were the pathology reports. Age at first and second seizures and a history of febrile seizures were abstracted from the medical records and through interview. Discrepancies were resolved through re-interview of participants, rereview of records, and, when necessary, discussion with the neurologist. Data were analyzed with standard bivariate methods. Because of the skewed distribution of the latency time variable, we used nonparametric t-tests and one-way analysis of variance for bivariate comparisons. 2 Tests were used for dichotomous outcomes (remission). Multiple linear regression was used to determine which factors independently contributed to the time to failure of the second drug (intractability). A log transformation of latency time was used in these analyses. Multiple logistic regression was used to identify factors associated with having a 1-year remission. All analyses were done for the entire surgical group as well as just in those patients who had undergone anterior temporal lobe resections.
Table 1 Descriptive statistics for full sample (N ⫽ 333) Characteristic
n (%)
Age at first unprovoked seizure, y* ⬍5
74 (22.2)
5–9
58 (17.4)
10–14
62 (18.6)
15–19
51 (15.3)
20–29
44 (13.2)
30–39
29 (8.7)
40⫹
15 (4.5)
Duration of epilepsy at time of surgical evaluation, y† ⬍5
23 (6.9)
5–9
38 (11.4)
10–14
42 (12.6)
15–19
50 (15.0)
20⫹
180 (54.1)
Age at surgical evaluation, y‡ 12–19
24 (7.2)
20–29
63 (18.9)
30–39
117 (35.1)
40–49
89 (26.7)
50⫹
40 (12.0)
Sex Male
145 (46.3)
Female
179 (53.7)
History of febrile seizures No
238 (71.5)
Yes
95 (28.5)
Hippocampal atrophy (MRI) No
118 (35.4)
Yes
215 (64.6)
Site of resection Anterior temporal
294 (88.3)
Other
39 (11.7)
* Mean 14.6, SD 11.7. † Mean 22.1, SD 12.5. ‡ Mean 36.7, SD 11.0.
Results. A total of 788 potentially eligible patients were identified by the study, 223 of whom, after preliminary evaluation, either were found to be ineligible for the study or were excluded for reasons related to inadequate information available to comply with the multicenter protocol. Of the other 565, 169 chose not to have surgery after undergoing a full evaluation or were determined not to be good surgical candidates. A total of 396 patients had resective surgery. Of those who have had surgery, 333 are included in this analysis. Reasons for exclusion of surgical patients from the analysis include missing information about early seizure history (specifically age at onset or history of febrile seizures); original MRI films have not been obtainable; or a combination of these reasons. In addition, participants missing information for both outcomes (latency time and previous remission) were excluded. Those with information for at least one outcome were retained in the analysis as long as the other data were complete. January (2 of 2) 2003
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effects of both age at onset (p ⫽ 0.0005) and history of febrile seizures (p ⬍ 0.0001) were found, suggesting that each independently contributes to the finding of hippocampal atrophy.
Figure. Distribution of time from second unprovoked seizure to failure of second medication (intractability) in 333 surgical patients. Univariate descriptive statistics of the sample are provided in table 1. The average age at the time of the first unprovoked seizure (onset of epilepsy) was 14.6 years. The average age at presentation for evaluation for surgery was 36.7 years. Time to intractability—latency time. In the 282 patients for whom the information was available, the average time to failure of the second drug (latency time) was 9.1 years (median, 5 years; range, 0 to 46 years; figure). In bivariate analysis, the latency time varied substantially as a function of age at onset, febrile seizures, hippocampal atrophy, and type of surgery (table 2). In a multiple linear regression analysis that included febrile seizures, hippocampal atrophy, and type of surgery, age at onset was independently and significantly associated with log of latency time; the younger the age at onset the longer the latency time (p ⬍ 0.0001). After adjustment for age at onset, the difference in latency time between those who had an anterior temporal procedure vs other procedures was reduced (relative to the unadjusted association seen in table 2) to 2.3 years (p ⬍ 0.01). After adjustment for these factors, febrile seizure had an associated p value of 0.09, and hippocampal atrophy did not approach statistical significance. Restriction of the analysis to patients with anterior temporal lobectomies produced nearly identical results, with only age at onset being significantly associated with latency time. History of a previous remission. Of 284 surgical patients who responded to this question, 74 (26%) indicated that they had experienced a period of at least 1 year seizure-free since the onset of their epilepsy (not including a prolonged period between the first and second unprovoked seizure). Of those, 19 indicated having had more than one such remission period. The duration of the remission lasted from 1 to 28 years; the median was 2 years. A remission of ⱖ5 years was reported in 24 patients, which represents 8.5% of the total who responded to the question. A 1-year remission was substantially more common in those with a young age (⬍5 years) at onset (table 3). Febrile seizures, hippocampal atrophy, and type of surgery were not significantly associated with reported episodes of previous remission. Multivariable analysis with logistic regression did not alter the assessment of the associations appreciated in the bivariate analysis. Relation between age at onset, febrile seizures, and hippocampal atrophy. Although age at onset, febrile seizures, and hippocampal atrophy were all associated with latency time, multivariable analysis suggested that age at onset had the greatest explanatory value. This indicated intercorrelations between these three variables. In fact, the proportion with both febrile seizures and hippocampal atrophy was greater the younger the age at onset, and, as expected, febrile seizures and hippocampal atrophy were closely associated (table 4). As hippocampal atrophy is a hallmark of temporal lobe epilepsy, we used logistic regression to determine whether age at onset or history of febrile seizures or both were independently associated with it. Strong independent 188
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Discussion. In this study of mostly adult surgical patients, we note that more than half of the participants had their initial onset of epilepsy during childhood and early adolescence and that most had epilepsy of many (⬎20) years’ duration. This finding is entirely consistent with the observations of several other investigators5,10-17 and begs the question of why there is a long delay between onset and surgery. Our results suggest that, in many cases, the need for surgery may not be immediately apparent. The average time to second drug failure is 9 years, and a quarter of those asked reported having had significant periods of remission prior to having their surgical evaluation. In fact, others have also pointed out that prolonged seizure-free intervals may occur after the onset of epilepsy but before an individual considers surgery5 or even after having been deemed to have intractable disease.6,18 The relapsing-remitting aspect of this disorder has been previously noted.4 The latency time and the proportion reporting remission are greatest in those with the youngest age at onset (⬍5 years). This is the same age group most likely to have a history of febrile seizures and hippocampal atrophy, two factors that are strongly intercorrelated and for which, in the past, a causal link was assumed. Although a previous study suggested that age at onset and not history of febrile seizures was the primary factor related to hippocampal atrophy, our findings suggest that both play a role.19 Table 2 Relationship between characteristics of epilepsy and latency time to intractability (based on N ⫽ 264) Characteristic
Latency time, Median latency y, mean (SD) time, y p Value*
Age at onset, y ⬍5
15.2 (12.2)
15.0
5–9
9.9 (9.3)
7.5
10–14
8.6 (10.9)
3.0
15–19
7.2 (6.9)
5.5
20–29
7.5 (7.1)
7.0
30–39
3.6 (4.1)
2.0
40⫹
3.2 (3.5)
1.0
No
8.1 (9.4)
5.0
Yes
11.5 (10.4)
9.0
Absent
6.4 (7.8)
3.0
Present
10.6 (10.4)
8.0
Anterior temporal
9.7 (10.0)
6.5
Other
4.2 (5.3)
2.0
⬍0.0001
Febrile seizure 0.002
Hippocampal atrophy ⬍0.001
Surgery 0.003
* Nonparametric t-test or nonparametric analysis of variance.
Table 3 Association between characteristics of epilepsy and previous 1-year remission prior to surgical evaluation (based on N ⫽ 284) No. of patients
One-year remission, n (%)
⬍5
61
29 (47.5)
5–9
50
14 (28.0)
10–14
55
12 (21.8)
15–19
45
7 (15.6)
20–29
36
5 (13.9)
30–39
24
6 (25.0)
40⫹
13
1 (7.7)
Factor
p Value*
Age at onset, y ⬍0.0001 (For trend on 1 df)
Febrile seizure No
201
50 (24.9)
Yes
83
24 (28.9)
Absent
106
23 (21.7)
Present
178
51 (28.7)
250
66 (26.4)
34
8 (23.5)
0.48
Hippocampal atrophy 0.20
Surgery Anterior–temporal Other
0.72
These observations made in retrospect in adult surgical patients with intractable epilepsy may help explain why prospective studies of children followed from onset of epilepsy fail to find much if any association between febrile seizures, intractable temporal lobe epilepsy, hippocampal atrophy, or the prognosis of epilepsy over the first several years.1,6,20-22 We also note that, although the use of neurosurgery for treating epilepsy in children has greatly increased in recent years, relatively little surgery is done in children for mesial temporal sclerosis.23,24 In
a community-based study, there was very little hippocampal atrophy in children at the time of initial diagnosis of epilepsy.25 Further, when it is present in a young surgical patient, it tends to have a different appearance than in adults.24 Combined, these observations strongly suggest that the syndrome seen in adults with intractable temporal lobe epilepsy with early onset of seizures (a substantial proportion of adult surgery patients) has a course of development previously not widely appreciated, although at least some have recognized this phenomenon previously.4,5 In particular, for some individuals, it may take a long time before the seizures become intractable. A caution in interpreting our data is that one of the criteria for entry into the surgery study was age ⱖ12 years. Thus, to have had early-childhood-onset epilepsy, a person would also have to have had epilepsy for at least several years. It could be argued that all of the early-onset epilepsy that had become intractable had already gone to surgery. This is unlikely because of the findings from other studies reviewed here. Another cautionary note is that our information was collected historically, going back over many years and even several decades. This is universally the case in studies of surgical series, which, to date, have not prospectively followed patients from the onset of epilepsy to the point of surgery. Conversely, for most historical information, including time to second drug failure, we relied heavily on the accumulated medical history that had been documented over the years and was not based on the patient’s recollection of his or her history as obtained at one time point. The criterion of two drug failures also deserves comment. There is no standard definition of intractability. We required failure of two appropriate drugs for partial epilepsy. The choices of drugs available when the individuals in our study first developed epilepsy were largely limited to carbamazepine, phenyt-
Table 4 Associations between age at onset, hippocampal atrophy, and febrile seizures Variable
No. of patients
Hippocampal atrophy, n (%)
Febrile seizures, n (%)
⬍5
74
62 (83.8)
30 (40.5)
5–9
58
44 (75.9)
23 (39.7)
10–15
62
39 (62.9)
20 (32.3)
15–19
51
25 (49.0)
12 (23.5)
20–29
44
23 (52.3)
5 (11.4)
30–39
29
15 (51.7)
2 (6.9)
40⫹
15
7 (46.7)
3 (20.0)
Age at onset, y
p ⬍ 0.0001 (for trend)
p ⬍ 0.001 (for trend)
Febrile seizures No
238
134 (56.3)
Yes
95
81 (85.3) p ⬍ 0.0001 January (2 of 2) 2003
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oin, phenobarbital, and primidone. Recent prospective studies, including a randomized trial of surgery, selected two drug failures as the drug criterion for intractability.3,6,26 Furthermore, two studies have recently suggested that failure of just one drug is a strong predictor of medically refractory epilepsy.2,3 Finally, all of the members of the clinical teams who evaluated these patients for surgery thought that, for clinical purposes, this was an appropriate criterion. Undoubtedly, there are many patients whose epilepsy is clearly intractable from the start. Information about those who develop intractable seizures early in the course of the disorder is becoming available.6 It also appears, however, that there are those in whom the first several years are characterized by remission or very infrequent seizures who only years later develop sufficiently intractable seizures to warrant surgery. Recent prospective studies are attempting to follow large representative cohorts of people with newly diagnosed epilepsy for prolonged periods in order to obtain detailed information about seizure outcomes and the factors associated with them and may be able to address these questions in the future.1,3,6,27 If, as our results suggest, there are some in whom epilepsy appears relatively benign at first and who only years later experience significant deterioration in seizure control, this could have important implications for the conduct of prospective studies both for the follow-up period needed to assess outcomes and for the manner in which outcomes are construed. The findings from the current surgical series provide valuable information for planning such prospective studies to examine these associations in a more definitive manner. The possibility that an early benign course does not necessarily ensure a good long-term outcome is sobering news, if true. However, if it is true, then we may also be able to learn to identify early those patients who will later develop intractable temporal lobe epilepsy regardless of a relatively benign initial course. This raises the possibility of identifying the mechanisms involved in this progression and could eventually open the door to therapeutic approaches that might prevent some forms of epilepsy from becoming intractable. References 1. Arts WFM, Geerts AT, Brouwer OF, Peters ACB, Stroink H, van Donselaar CA. The early prognosis of epilepsy in childhood: the prediction of a poor outcome. The Dutch study of epilepsy in childhood. Epilepsia 1999;40:726 –734.
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