Berg et al. report that complete remission of paediatric epilepsy occurs in about 60% of patients over the course of 20 years. This outcome can be predicted with fair accuracy based on initial clinical factors, and good accuracy based on early seizure outcomes over the first 2–5 years.
Keywords: epidemiology, prognosis, refractory epilepsy, remission, children
Abstract
The ultimate seizure outcome of childhood epilepsy is complete resolution of all seizures without further treatment. How often this happens and how well it can be predicted early in the course of epilepsy could be valuable in helping families understand the nature of childhood epilepsy and what to expect over time. In the Connecticut study of epilepsy, a prospective cohort of 613 children with newly-diagnosed epilepsy (onset age 0–15 years), complete remission, ≥5 years both seizure-free and medication-free, was examined as a proxy of complete seizure resolution. Predictors at initial diagnosis were tested. Information about seizure outcomes within 2 years and from 2–5 years after diagnosis was sequentially added in a proportional hazards model. The predictive value of the models was determined with logistic regression. Five hundred and sixteen subjects were followed ≥10 years. Three hundred and twenty-eight (63%) achieved complete remission; 23 relapsed. The relapse rate was 8.2 per 1000 person-years and decreased over time: 10.7, 6.7, and 0 during first 5 years, the next 5 years, and then >10 years after complete remission (P = 0.06 for trend). Six participants regained complete remission; 311 (60%) were in complete remission at last contact. Baseline factors predicting against complete remission at last contact included onset age ≥10 years (hazard ratio = 0.55, P = 0.0009) and early school or developmental problems (hazard ratio = 0.74, P = 0.01). Factors predicting for complete remission were uncomplicated epilepsy presentation (hazard ratio = 2.23, P < 0.0001), focal self-limited epilepsy syndrome (hazard ratio = 2.13, P < 0.0001), and uncharacterized epilepsy (hazard ratio = 1.61, P = 0.04). Remission (hazard ratio = 1.95, P < 0.0001) and pharmaco-resistance (hazard ratio = 0.33, P < 0.0001) by 2 years respectfully predicted in favour and against complete remission. From 2 to 5 years after diagnosis, relapse (hazard ratio = 0.21, P < 0.0001) and late pharmaco-resistance (hazard ratio = 0.21, P = 0.008) decreased and late remission (hazard ratio = 2.40, P < 0.0001) increased chances of entering complete remission. The overall accuracy of the models increased from 72% (baseline information only), to 77% and 85% with addition of 2-year and 5-year outcomes. Relapses after complete remission are rare making this an acceptable proxy for complete seizure resolution. Complete remission after nearly 20 years is reasonably well predicted within 5 years of initial diagnosis.
Introduction
The ultimate desired seizure outcome of paediatric epilepsy is the complete resolution of seizures without further need for medications. How to know the future by predicting remission based upon early clinical factors and early seizure course is of tremendous interest and has been the focus of considerable research efforts (Sillanpää and Schmidt, 2006, 2009a, b; Camfield and Camfield, 2010, 2014; Geerts et al., 2010; Wirrell et al., 2011). Remission, however, is a relative concept. Inevitably, a variety of different markers of good prognosis have been used ranging from 1 year seizure-free at last contact (Sillanpää and Schmidt, 2009b; Wirrell et al., 2011) to 5 years seizure-free without treatment for some period of time (Geerts et al., 2010).
Recently, The International League Against Epilepsy suggested a definition of ‘resolution’ of epilepsy to include seizure remission for 10 years and at least 5 years off seizure medications (Fisher et al., 2014). This was based, in part, on a definition of complete remission (5 years seizure-free and 5 years medication-free) used in a previous analysis from a subgroup of the Connecticut Study of Epilepsy (Berg et al., 2011). Here we present data regarding the occurrence of complete remission in the full community-based Connecticut cohort and the stability of this outcome up to almost 15 years later. We also develop models of complete remission at the end of the study in which we evaluate the predictive value of clinical variables from initial diagnosis and the additional predictive value of seizure outcomes during the first 5 years after diagnosis.
Materials and methods
The Connecticut Study of Epilepsy invited families of all children with newly diagnosed epilepsy in 1993–97 through the offices of 16 of 17 paediatric neurologists practicing in Connecticut at the time. In the USA, paediatricians are primary care physicians and typically refer to paediatric neurologists when epilepsy is suspected. Details have been previously presented (Berg et al., 1999).
Participants were followed prospectively for up to 20 years. Contact with parents and later young adult participants every 3–4 months and biannual review of the medical records allowed for detailed recording of seizure occurrence and seizure medication usage. Follow-up was concluded over a period of several months, terminating in February 2014.
Complete remission was defined as achieving a 5-year seizure-free and 5-year medication-free period. Any subsequent seizure for any reason was considered a relapse. Complete remission at last contact was defined based on the date of last seizure and date seizure medications were completely stopped. Eight participants achieved complete remission but then several years later began taking seizure medications for other conditions (e.g. migraine). Their follow-up was censored at the time they initiated the medication and their final outcome was designated as complete remission without relapse.
Prognostic variables considered included those used in previous analyses of shorter-term seizure outcomes in this cohort (Berg et al., 2001, 2004, 2006, 2009a, 2011) and, as much as possible, those reported in the analyses from other well-known longitudinal paediatric cohorts (Camfield and Camfield, 2003, 2008, 2014; Arts et al., 2004; Sillanpää and Schmidt, 2009b; Geerts et al., 2010, 2012; Dhamija et al., 2011; Wirrell et al., 2011, 2012).
Baseline prognostic variables were factors that were or could have been obtained as part of the initial evaluation (e.g. relevant imaging abnormality). This included grouped age at onset (<5, 5–9, ≥10 years at first seizure), gender, history of febrile seizures, family history of epilepsy, any episode of status epilepticus (seizure ≥30 min) before the diagnosis of epilepsy, initial seizure frequency, slowing on the initial EEG, abnormal initial neurological exam (per the diagnosing physician’s report), and imaging results (abnormal and likely relevant versus normal or incidental/non-causative findings) as previously described (Berg et al., 2009a). Early developmental or school problem was defined as receipt of any school system or similar services before or at the time of epilepsy diagnosis or a Vineland composite score <25%. The Vineland Adaptive Behaviour Scales were administered for preschool-aged children at the time of initial interview for the study. Over half of the participants had research neuropsychological testing 9 years into the study. Based on this and all other information from the medical records and interviews, a determination was made about the diagnosis of intellectual disability (Berg et al., 2008). Types of epilepsy were grouped into non-syndromic with focal features (not fitting any well-defined epilepsy syndromes), encephalopathic (largely consisting of West, Lennox-Gastaut, and Doose syndromes), self-limited-focal (mostly benign epilepsy with central-temporal spikes), genetic generalized (mostly childhood and juvenile absence and juvenile myoclonic epilepsy), and a group of poorly characterized epilepsy not fitting into the above categories. Because some infants and young children develop West or Lennox-Gastaut syndromes as an evolution from a non-syndromic presentation, we did not include those children in the encephalopathic epilepsy group at baseline but did at 2 years. Finally, we designated the overall presentation as uncomplicated if the child had normal neurological and imaging exams, absence of clear intellectual disability, and no identified insult or condition to which the epilepsy might be reasonably attributed. Complicated presentations included the presence of one or more of these factors.
Seizure outcome at 2 years after diagnosis were designated as early remission (in 1-year remission at 2 years), early pharmaco-resistance (failed trials of two appropriate seizure medications by 2 years), and neither in remission or pharmaco-resistant.
We created three additional indicators for the seizure outcomes occurring between 2 and 5 years: relapse after first remission, failure of a second medication (late pharmaco-resistance), and attainment of a first 1-year remission (late remission).
Because the purpose of the analyses is to examine outcomes over an extended period of time, we excluded participants followed <10 years.
Analysis of relapse following complete remission was based on calculating the person-years from attaining complete remission to date of relapse or of last contact if no relapse. Poisson regression was used to determine the rates of relapse during the first 5 years, second 5 years, and >10 years after achieving complete remission. The ‘rule-of-three’ was used to calculate upper confidence limits for 0-numerator results (Hanley and Lippman-Hand, 1983).
Data were analysed in SAS 9.3. Bivariate comparisons were performed with t-tests and chi-square tests as appropriate to the data. Proportional hazards models were used to identify independent predictors of complete remission at last contact. We considered first only those factors that were ascertainable at baseline. The non-syndromic group was used as the comparison against which each other epilepsy type group was tested. We then added 2-year seizure outcomes to that model and reassessed contributions of the original baseline variables. Finally, we added the 5-year seizure outcome variables. Sequential models were created for the full group and separately for participants with complicated and uncomplicated presentations.
We used logistic regression to determine the sensitivity and specificity and overall predictive value of the three sequential models and to determine the area under the curve, a metric of predictive accuracy, for each model.
Finally, because the decision to stop medications may be influenced by the same prognostic factors under study (e.g. family history, early seizure history, etc.), we compared our models of complete remission at last contact to those for 5-year and for 10-year remission at last contact regardless of medication.
Consent was obtained in accordance with the Declaration of Helsinki. Parental written consent and child’s assent (when appropriate) was obtained at initial entry into the study. Young adult consent was obtained upon reaching the age of majority. All procedures were approved by the Institutional Review Boards of all institutions involved in this research.
Results
Of 613 children originally recruited, 14 died before completing 10 years of follow-up. Excluding those who died before 10 years, 516/600 (86%) were followed for ≥10 years. Excluding subjects who died during the first decade after diagnosis, participants followed for <10 versus ≥10 years were highly comparable with respect to demographic features, types of epilepsy, and seizure outcomes in the first 2 years of follow-up (Table 1). In 516 patients followed for ≥10 years, the median length of follow-up was 17 years [interquartile range (IQR) 16–18] for a total of 8856 person-years of follow-up.
Table 1.
Comparison of survivors followed for <10 years versus those followed for ≥10 years
| Feature | Followed <10 years | Followed ≥10 years | P-value |
|---|---|---|---|
| n = 83 | n = 516 | ||
| Gender | |||
| Female | 44 (53%) | 248 (48%) | |
| Male | 39 (47%) | 268 (52%) | 0.40 |
| Age at onset of epilepsy | |||
| <5 years | 32 (39%) | 237 (46%) | 0.42 |
| 5–10 years | 34 (41%) | 191 (37%) | |
| >10 years | 17 (20%) | 88 (17%) | |
| Early seizure outcome at 2 years after diagnosis* | |||
| 1-year remission by 2 years post diagnosis | 34 (48%) | 283 (54%) | 0.63 |
| Pharmaco-resistant by 2 years post diagnosis | 9 (13%) | 59 (11%) | |
| Unclear, neither pharmaco-resistant or in remission | 28 (39%) | 174 (33%) | |
| Type of epilepsy | |||
| Encephalopathic | 6 (7%) | 46 (9%) | 0.78 |
| Non-syndromic with focal features | 42 (51%) | 261 (51%) | |
| Self-limited epilepsy with focal features | 9 (11%) | 62 (12%) | |
| Generalized genetic epilepsy | 18 (22%) | 113 (22%) | |
| Unclear, not categorized | 8 (10%) | 31 (6%) | |
| Presence of presumed cause or abnormal neurological exam | |||
| None | 67 (81%) | 404 (78%) | 0.65 |
| Present | 16 (19%) | 112 (22%) | |
*12 children lost to follow-up before 2 years are excluded from these counts.
Complete remission and relapse rates
A total of 328 participants achieved complete remission. The average duration of follow-up after achieving complete remission was 8.6 years (standard deviation 3.7). Of the 328, 265 were followed for ≥5 years and 138 participants were followed for ≥10 years after attaining complete remission. Twenty-three (7.0%) individuals experienced relapse for an overall relapse rate of 8.2 (4.8, 11.5) per 1000 person-years of follow-up. This rate was slightly higher in the first 5 years than in the second 5 years after complete remission, 10.7 [95% confidence interval (CI) 5.5–15.9] versus 6.7 (95% CI 1.7–11.6). No relapse occurred more than 10 years after attaining complete remission. We can be 95% confident that the rate of relapse after 10 years is ≤11.2/1000 person-years (Hanley and Lippman-Hand, 1983). These data suggested a decreasing risk of relapse over time since achieving complete remission (P = 0.06 for trend, Table 2). For 18 of 23 individuals who relapsed, the relapse seemed to be spontaneous (with no apparent explanation). Of these, 12 had more than one spontaneous seizure whereas the others had only one seizure and no others during the remainder of the follow-up. Three individuals acknowledged use of illicit drugs in proximity to their seizure relapse, and two others had acute provoking factors (eclampsia and shunt malfunction).
Table 2.
Rate of relapse after attaining complete remission (5 years seizure-free and 5 years drug-free) overall and by 5-year epochs
| Time period since achieving complete remission | Number contributing person-years to the time epoch | Relapse, n | Person years | Rate/1000 person-years | 95% CI |
|---|---|---|---|---|---|
| Overall | 327 | 23 | 2813.5 | 8.2 | 4.8–11.5 |
| 0–5 years | 327 | 16 | 1496.6 | 10.7 | 5.5–15.9 |
| 5–10 years | 265 | 7 | 1048.7 | 6.7 | 1.7–11.6 |
| >10 years | 138 | 0 | 268.1 | 0 | 0–11.2 |
P = 0.06 for the trend in decreasing rate from one time epoch to the next.
Six individuals who relapsed after achieving complete remission experienced a second complete remission episode. Only one went on to experience pharmaco-resistance (Kwan et al., 2010). At the end of the study, 311 (60.3%) of those followed for ≥10 years were in complete remission. The median time to complete remission at last contact was 8.1 years (IQR 6.9–9.7). At the end of the study, 374 (72.5%) and 303 (58.7%) were in 5- and 10-year remission regardless of treatment.
Most of the individual baseline prognostic factors that we examined had strong bivariate associations with complete remission at last contact, as did all of the 2- and 5-year seizure outcomes (Table 3).
Table 3.
Bivariate associations for complete remission at last contact and baseline, 2-year, and 5-year variables
| Factor (n, %) | Total of 516 | Not in complete remission (n = 205, 39.7%) | In complete remission (n = 311, 60.3%) | P-value | Bivariate hazard ratio (95% CI) | P-value |
|---|---|---|---|---|---|---|
| Age at onset | ||||||
| <5 years | 237 (46%) | 93 (39.2%) | 144 (60.8%) | <0.0001 | 1.0 | |
| 5–10 years | 191 (37.0%) | 60 (31.4%) | 131 (68.6%) | 1.24 (0.97–1.57) | 0.08 | |
| >10 years | 88 (17.1%) | 52 (59.1%) | 36 (40.9%) | 0.56 (0.39–0.81) | 0.002 | |
| Gender | ||||||
| Female | 248 (48.1%) | 106 (42.7%) | 142 (57.3%) | 0.18 | 1.09 (0.87–1.37) | 0.44 |
| Male | 268 (51.9%) | 99 (36.9%) | 169 (63.1%) | |||
| Presentation | ||||||
| Complicated | 112 (21.7%) | 74 (66.1%) | 38 (33.9%) | <0.0001 | 1.0 | |
| Uncomplicated | 404 (78.3%) | 131 (32.4%) | 272 (67.6%) | 2.84 (2.02–4.00) | <0.0001 | |
| Neurological exam | ||||||
| Normal | 453 (87.8%) | 161 (35.5%) | 292 (64.5%) | <0.0001 | 1.0 | |
| Abnormal | 63 (12.2%) | 44 (69.8%) | 19 (30.2%) | 0.34 (0.21–0.54) | <0.0001 | |
| Neuroimaging | ||||||
| Normal/incidental | 414 (80.2%) | 147 (35.5%) | 267 (64.5%) | <0.0001 | 1.0 | |
| Abnormal/relevant | 64 (12.4%) | 47 (73.4%) | 17 (26.6%) | 0.29 (0.18–0.47) | <0.0001 | |
| No imaging | 38 (7.4%) | 11 (28.9%) | 27 (71.1%) | |||
| Intellectual disability | ||||||
| Absent | 438 (84.9%) | 147 (33.6%) | 291 (66.4%) | <0.0001 | 1.0 | |
| Present | 78 (15.1%) | 58 (74.4%) | 20 (25.6%) | 0.27 (0.17–0.42) | <0.0001 | |
| Early school/developmental problem | ||||||
| Absent | 277 (53.7%) | 88 (31.8%) | 189 (68.2%) | <0.0001 | 1.0 | |
| Present | 239 (46.3%) | 117 (49.0%) | 122 (51%) | 0.59 (0.47–0.74) | <0.0001 | |
| Family history of epilepsy, first degree relative | ||||||
| Absent | 464 (89.9%) | 180 (38.8%) | 284 (61.2%) | 0.23 | 1.0 | |
| Present | 46 (8.9%) | 22 (47.8%) | 24 (52.2%) | 0.72 (0.48–1.10) | 0.13 | |
| Unknown | 6 (1.2%) | 3 (50%) | 3 (50%) | |||
| Any family history of epilepsy | ||||||
| Absent | 286 (55.4%) | 107 (37.4%) | 179 (62.6%) | 0.25 | 1.0 | |
| Present | 224 (43.4%) | 95 (42.4%) | 129 (57.6%) | 0.83 (0.66–1.04) | 0.10 | |
| Unknown | 6 (1.1%) | 3 (50%) | 3 (50%) | |||
| History of febrile seizures | ||||||
| Absent | 450 (87.2%) | 179 (39.8%) | 271 (60.2%) | 0.87 | 1.0 | |
| Present | 62 (12.0%) | 24 (38.7%) | 38 (61.3%) | 0.95 (0.68–1.34) | 0.79 | |
| Unknown | 2 (50%) | 2 (50%) | ||||
| Status Epilepticus by the time of diagnosis | ||||||
| Absent | 472 (91.5%) | 182 (38.6%) | 290 (61.4%) | 0.07 | 1.0 | |
| Present | 44 (8.5%) | 23 (52.3%) | 21 (47.7%) | 0.62 (0.40–0.96) | 0.03 | |
| Initial seizure frequency | ||||||
| <1/month | 101 (19.6%) | 37 (36.6%) | 64 (63.4%) | 0.10 | 1.0 (1.0–1.0) | 0.21 |
| 1- | 234 (45.4%) | 91 (38.9%) | 143 (61.1%) | |||
| 10- | 84 (16.3%) | 32 (38.1%) | 52 (61.9%) | |||
| 50- | 31 (6.0%) | 12 (38.7%) | 19 (61.3%) | |||
| 100 | 29 (5.6%) | 15 (51.7%) | 14 (48.3%) | |||
| ≥200/month | 37 (7.2%) | 18 (48.7%) | 19 (51.4%) | |||
| Type of epilepsy | ||||||
| Non-syndromic – focal | 264 (51.2%) | 117 (44.3%) | 147 (55.7%) | <0.0001 | 1.0 | |
| Encephalopathic | 46 (8.9%) | 27 (58.7%) | 19 (41.3%) | 0.70 (0.43–1.13) | 0.14 | |
| Self-limited – focal | 62 (12.0%) | 3 (4.8%) | 59 (95.2%) | 2.79 (2.01–3.80) | <0.0001 | |
| Genetic generalized | 113 (21.9%) | 48 (42.5%) | 65 (57.5%) | 1.06 (0.79–1.42) | 0.70 | |
| Not further specified | 31 (6.0%) | 10 (32.3%) | 21 (67.7%) | 1.64 (1.04–2.59) | 0.03 | |
| Any EEG slowing | ||||||
| Absent | 424 (82.2%) | 154 (36.3%) | 270 (63.7%) | 0.0007 | 1.0 | |
| Present | 92 (17.8%) | 51 (55.4%) | 41 (44.6%) | 0.61 (−0.43–0.84) | 0.003 | |
| Focal slowing | ||||||
| Absent | 469 (90.9%) | 181 (38.6%) | 288 (61.4%) | 0.10 | 1.0 | |
| Present | 47 (9.1%) | 24 (51.1%) | 23 (48.9%) | 0.74 (0.49–1.14) | 0.17 | |
| Other slowing | ||||||
| Absent | 468 (90.7%) | 175 (37.4%) | 293 (62.6%) | 0.0007 | 1.0 | |
| Present | 48 (9.3%) | 30 (62.5%) | 18 (37.5%) | 0.49 (0.30–0.79) | 0.003 | |
| Appearance of West or Lennox-Gastaut syndrome or other encephalopathy | ||||||
| At onset | 46 (8.9%) | 27 (58.7%) | 19 (41.3%) | 0.005 | ||
| By ∼2 years | 8 (1.6%) | 6 (75%) | 2 (25%) | |||
| None | 462 (89.5%) | 172 (37.2%) | 290 (62.8%) | |||
| Seizure outcome at 2-years | ||||||
| In 1+ year remission | 283 (54.8%) | 80 (28.3%) | 203 (71.7%) | <0.0001 | 1.96 (1.55–2.49) | <0.0001 |
| Pharmaco-resistant | 59 (11.4%) | 48 (81.4%) | 11 (18.6%) | 0.29 (0.16–0.57) | <0.0001 | |
| Uncertain | 174 (33.7%) | 77 (44.3%) | 97 (55.8%) | 1.0 | ||
| Relapse between 2 and 5 years* | ||||||
| None | 374 (76.3%) | 101 (27.0%) | 273 (73.0%) | <0.0001 | 1.0 | |
| Present | 116 (23.7%) | 78 (67.2%) | 38 (32.8%) | 0.31 (0.22–0.44) | <0.0001 | |
| Failure of a second AED between 2 and 5 years | ||||||
| Absent | 492 (95.4%) | 184 (37.4%) | 308 (62.6%) | <0.0001 | 1.0 | 0.0005 |
| Present | 24 (4.7%) | 21 (87.5%) | 3 (12.5%) | 0.13 (0.04–0.41) | ||
Bivariate hazards ratios with 95% CI from a Cox proportional hazards models are provided.
AED = anti-epileptic drug.
Nineteen of 20 participants who underwent surgery for treatment of epilepsy or removal of a brain tumour were followed for ≥10 years. Six, all of whom had undergone tumour resection, were in complete remission. Two others were seizure-free for 5 years but on medications, and the remaining 11 were seizure-free for <5 years at last contact. Details of the surgeries were previously reported (Berg et al., 2009).
Multivariable analyses
Sequential multivariable model starting with baseline information and then adding 2- and 5-year seizure outcomes were created for the overall, uncomplicated, and complicated presentation groups (Table 4).
Table 4.
Multivariable Cox proportional hazards models and area under the curve for sequential models to predict complete remission at last contact
| Models and terms | Hazard ratio (95% CI) | P-value | Area under the curve (%) |
|---|---|---|---|
| A. Overall (n = 516) | |||
| Baseline variables | |||
| Age at onset ≥10 years | 0.55 (0.39–0.79) | 0.0009 | 72 (68, 76) |
| Focal self-limited epilepsy syndrome | 2.13 (1.58–2.87) | <0.0001 | |
| Uncharacterized epilepsy | 1.62 (1.03–2.53) | 0.04 | |
| Uncomplicated epilepsy presentation | 2.22 (1.55–3.21) | <0.0001 | |
| Early school problem or low Vineland | 0.74 (0.58–0.94) | 0.01 | |
| With addition of seizure outcomes at 2 years | |||
| Age at onset ≥10 years | 0.52 (0.36–0.73) | 0.0002 | 77 (73, 81) |
| Focal self-limited epilepsy syndrome | 2.07 (1.53–2.80) | <0.0001 | |
| Uncharacterized epilepsy | 1.59 (1.01–2.49) | 0.04 | |
| Uncomplicated epilepsy presentation | 2.03 (1.43–2.88) | <0.0001 | |
| Early remission | 1.97 (1.55–2.50) | <0.0001 | |
| Early pharmaco-resistance | 0.33 (0.20–0.57) | <0.0001 | |
| With addition of seizure outcomes from 2–5 years | |||
| Age at onset ≥10 years | 0.59 (0.41–0.83) | 0.003 | 85 (82, 89) |
| Focal self-limited epilepsy syndrome | 1.60 (1.19–2.16) | 0.002 | |
| Uncomplicated epilepsy presentation | 1.68 (1.18–2.38) | 0.004 | |
| Early remission | 3.99 (2.82–5.64) | <0.0001 | |
| Early pharmaco-resistance | 0.32 (0.19–0.54) | <0.0001 | |
| Late remission | 2.35 (1.59–3.48) | <0.0001 | |
| Relapse between 2 and 5 years | 0.21 (0.15–0.30) | <0.0001 | |
| Late pharmaco-resistance | 0.21 (0.07–0.67) | 0.008 | |
| B. Uncomplicated initial presentation (n = 411) | |||
| Baseline variables | |||
| Age ≥10 at onset | 0.63 (0.44–0.91) | 0.01 | 69 (64, 74) |
| Self-limited focal epilepsy | 2.21 (1.63–3.00) | <0.0001 | |
| Uncharacterized epilepsy | 1.71 (1.08–2.72) | 0.02 | |
| Early developmental or school problem | 0.73 (0.56–0.94) | 0.01 | |
| Any family history of epilepsy | 0.69 (0.54–0.88) | 0.003 | |
| At 2 years | |||
| Age ≥10 at onset | 0.57 (0.40–0.83) | 0.003 | 75 (70, 80) |
| Self-limited focal epilepsy | 2.13 (1.57–2.89) | <0.0001 | |
| Uncharacterized epilepsy | 1.66 (1.04–2.64) | 0.03 | |
| Any family history of epilepsy | 0.74 (0.58–0.94) | 0.01 | |
| Early remission | 1.87 (1.45–2.42) | <0.0001 | |
| Early pharmaco-resistance | 0.29 (0.15–0.57) | 0.0003 | |
| At 5 years | |||
| Age ≥10 at onset | 0.66 (0.45–0.95) | 0.02 | 84 (80, 88) |
| Self-limited focal epilepsy | 1.76 (1.29–2.39) | 0.0003 | |
| Uncharacterized epilepsy | 1.74 (1.09–2.78) | 0.02 | |
| Any family history of epilepsy | 0.68 (0.53–0.86) | 0.002 | |
| Early remission | 3.53 (2.45–5.08) | <0.0001 | |
| Early pharmaco-resistance | 0.26 (0.13–0.51) | <0.0001 | |
| Late remission | 2.14 (1.41–3.26) | 0.0004 | |
| Relapse between 2 and 5 years | 0.20 (0.13–0.29) | <0.0001 | |
| Failure of second AED between 2 and 5 years | 0.29 (0.09–0.91) | 0.03 | |
| C. Complicated presentation (n = 112) | 74 (65, 83) | ||
| Age ≥10 years | 0.22 (0.05–0.94) | 0.04 | |
| Intellectual disability | 0.39 (0.21–0.75) | 0.005 | |
| Relevant imaging abnormality | 0.49 (0.26–0.94) | 0.03 | |
| At 2 years | 78 (69, 88) | ||
| Age ≥10 years | 0.24 (0.06–1.03) | 0.06 | |
| Intellectual disability | 0.46 (0.24–0.88) | 0.02 | |
| Relevant imaging abnormality* | 0.63 (0.32–1.24) | 0.18 | |
| Early remission | 2.53 (1.28–5.02) | 0.008 | |
| At 5 years | 87 (81, 94) | ||
| Age ≥10 years* | 0.30 (0.07–1.27) | 0.10 | |
| Intellectual disability | 0.37 (0.18–0.73) | 0.004 | |
| Relevant imaging abnormality | 0.41 (0.21–0.81) | 0.01 | |
| Early remission | 14.35 (5.11–40.22) | <0.0001 | |
| Relapse or late pharmaco-resistance | 0.11 (0.05–0.27) | <0.0001 | |
| Late remission | 7.46 (2.51–22.22) | 0.0003 | |
*Kept in model for parsimony because it was retained in preceding and following models.
Overall
In the first proportional hazards model of baseline clinical factors, focal self-limited epilepsy syndromes [hazard ratio (HR) = 2.13, P < 0.0001], uncharacterized epilepsies (HR = 1.61, P = 0.04), and an uncomplicated epilepsy presentation (HR = 2.23, P < 0.0001) were independently associated with an increased chance of attaining complete remission, whereas age at onset ≥10 years (HR = 0.55, P = 0.0009) and early school or developmental problems (HR = 0.74, P = 0.01) were associated with a lower chance.
Early remission by 2 years was associated with an increased chance of complete remission (HR = 1.95, P < 0.0001), while early pharmaco-resistance (HR = 0.33, P < 0.0001) predicted against. Finally, both late relapse (HR = 0.21, P < 0.0001) and late pharmaco-resistance (HR = 0.21, P = 0.005) weighed against complete remission. Late remission (HR = 2.40, P < 0.0001), however, weighed in favour of complete remission.
The reasons associated with relapses occurring between 2 and 5 years were not differentially associated with attaining complete remission: 11/37 (29.7%) for a spontaneous relapse with good medication adherence; 4/5 (80%) in patients who had never taken seizure medication; 2/6 (33%) for relapses following non-adherence of treatment; 4/9 (44.4%) for relapses during medication tapering; 14/46 (30.4%) for relapses that occurred after completely stopping medications; 1/4 (25%) for relapses in the context of a significant illness such as the flu; and 2/7 (28.6%) for relapses associated with other factors (e.g. outgrowing medication dosage, severe sleep deprivation, or excessive stress).
Uncomplicated presentation
In the uncomplicated group, age at onset ≥10 years (HR = 0.63, P = 0.01), early school or developmental problems (HR = 0.73, P = 0.01), and family history of epilepsy (HR = 0.69, P = 0.003) independently weighed against complete remission. Self-limited epilepsy syndromes (HR = 2.21, P < 0.0001) and uncharacterized forms of epilepsy (HR = 1.71, P = 0.02) were associated with an increased chance of a good outcome. These factors remained in the predictive model with the addition of early remission, which weighed in favour (HR = 1.87, P < 0.0001), and early pharmaco-resistance (HR = 0.29, P = 0.0004), which weighed against complete remission. With the exception of early school or developmental problems, all of the above factors remained in the model once late remission (HR = 2.14, P = 0.0004), relapse by 5 years (HR = 0.2, P < 0.0001), and late pharmaco-resistance (HR = 0.29, P = 0.03) were added.
Complicated presentation
Older age at onset (HR = 0.22, P = 0.04), intellectual disability (HR = 0.39, P = 0.005), and a relevant imaging abnormality (HR = 0.49, P = 0.03) were independently associated with lower rates of attaining complete remission. At 2 years, early remission (HR = 2.53, P = 0.008) favoured attaining complete remission. We combined late pharmaco-resistance and relapse between 2 and 5 years as they were too intercorrelated to test separately. Together, they strongly weighed against attaining complete remission (HR = 0.11, P < 0.0001). Late remission, however, strongly weighed in favour of a good outcome (HR = 7.43, P = 0.0003).
Predictive values of the proportional hazards models
The areas under the curve for the overall group were 72%, 77%, and 85% at baseline, 2, and 5 years, respectively. The comparable figures were 69%, 75%, and 84% for the uncomplicated group and 74%, 78%, and 87% for the complicated group, respectively. Most of these changes from baseline to 2–5 years represented significant incremental improvements in the accuracy of the models (Figure 1).
Figure 1.
Receiver operator curves for predication of complete remission at last contact based on initial clinical information, with addition of 2-year seizure outcomes, and with addition of 5-year seizure outcomes: (A) Overall (n = 516), (B) uncomplicated epilepsy presentation (n = 404), and (C) complicated epilepsy presentation (n = 112).
Remission regardless of medication
To explore whether factors such as family history of epilepsy or early school/developmental problems might be associated with use of medication rather than remission itself, we re-ran all analyses with 5- and 10-year remission as outcomes, regardless of seizure medication use. Only uncharacterized epilepsy syndrome and early school/developmental problem were no longer associated with 5-year remission, overall and in the uncomplicated group. Models for the complicated group were not substantially altered. These patterns were mirrored in analyses of 10-year remission (Supplementary Table 1).
Discussion
Over the course of nearly two decades, almost two-thirds of children with newly diagnosed epilepsy achieve complete remission. Our findings suggest that this is a meaningful proxy for the resolution of epilepsy. Although there is a small residual risk of relapse (<1% per year), this is the strongest marker of enduring remission that we are aware of to date. The proportion in remission is comparable to what has been reported in other cohorts followed for longer periods of time but based on varying and less stringent definitions of remission (Sillanpää et al., 1998, 2012; Geerts et al., 2010; Wirrell et al., 2011; Camfield and Camfield, 2014). Complete remission, as we have defined it, has a low risk of later relapse and as such is an excellent marker of seizure resolution. While no relapses were recorded >10 years after attaining complete remission, our data cannot rule out a residual relapse rate of ∼1% per year, ∼10 times the population rate for new incident seizures (Olafsson et al., 2005).
In terms of anticipatory guidance and prognostication, our findings confirm the unique position of benign epilepsy with central-temporal spikes and related epilepsies in determining long-term resolution of seizures (Loiseau et al., 1983, 1988; Bouma et al., 1997). They also highlight the importance of a clear neurological insult or related condition and of early seizure outcomes in predicting later outcomes (Sillanpää et al., 1998, 2012; Camfield and Camfield, 2003, 2008, 2010; Geelhoed et al., 2005; Sillanpää and Schmidt, 2009a, b; Geerts et al., 2010, 2012; Dhamija et al., 2011; Wirrell et al., 2011). Area under the curve is a common metric used to summarize the trade-off between sensitivity and specificity in predictive models (Eng, 2005). According to some recommended interpretations of area under the curve, the overall predictive accuracy based on the initial clinical variables was only fair (70–80%) (Kaiser-Permanente, 2009). With seizure outcomes through 5 years, predictive accuracy was good (80–90%) but not excellent (>90%). Excellent prediction of seizure outcome is elusive. For example, Geelhoed et al. (2005) reported only slightly less predictive accuracy in models of 2-year seizure outcome and also noted the importance of early (6-month) outcomes relative to initial clinical (baseline) information. Given the types of information available in a large-scale study, this may be the best that can be expected, especially in an ‘omnibus’ analysis that includes such heterogeneous epilepsies. Analyses limited to more homogeneous patient subgroups might provide more precise information, although limited and relevant to the subgroup only.
Of particular interest was the dramatic decrease in attaining complete remission if any relapse occurred after remission in the first 5 years. The factors associated with relapse (e.g. planned discontinuation of medication or non-adherence versus spontaneous remissions) did not seem to influence complete remission. While our data cannot definitively support the notion that maximizing efforts to limit relapses early will improve long-term outcomes, they are certainly consistent with the observations and the interpretations presented by Modi and colleagues (2014) who found that poor early adherence to medication schedules heralded a poorer chance of seizure control several years later. Although about a third who relapsed in our cohort still achieved complete remission, this is substantially less than the overall average, and it is information that needs to be communicated carefully to families.
There is the insurmountable problem, in this and virtually any study; remission without medication requires that medications be stopped. The reasons for continuing medication may not necessarily be related to the patient’s chances of remaining seizure-free off medication and thus could, potentially, seem to be negatively predictive of remission without medication. Our finding that most factors, especially early seizure outcomes, that predicted complete remission at last contact also predicts 5- and 10-year remission (regardless of medications) suggests that the factors we identified are indeed predictive of seizure resolution.
Over the last several years, many seizure medications have been found useful in the treatment of a variety of other disorders. In fact, we deliberately censored follow-up for a handful of patients in whom complete remission was ‘broken’ because medications used to treat seizures were initiated for non-seizure indications (e.g. migraine, other pain, psychiatric and behavioural indications). Whether resolution of seizures without treatment realistically can be studied today given the multiple purposes for which seizure medications are used is another concern and creates questions that might be better addressed in other settings.
There has, in the past, been debate, especially among epidemiologists, about the value of recognizing epilepsy syndromes (Olafsson et al., 2005). At this point in time, there can be no doubt that these syndromes are of considerable value, although not just for predicting outcome. They are critical for pursuing causes, genetic counselling, selecting treatment, management, and anticipatory guidance. Each tends to occur in a small number of children. The individual contributions of each syndrome to understanding complete remission in a heterogeneous cohort such as ours and those published by others cannot be reasonably studied in a single cohort-wide analysis. By combining into broad groups (e.g. encephalopathic, generalized genetic, etc.), we are able to consider only the most dramatic impacts with respect to complete remission, particularly that of benign epilepsy with central-temporal spikes. Furthermore, we have considered only one outcome, complete remission of epilepsy. Of those who do not attain this outcome, there is a range of outcomes from well-controlled, to moderately controlled, to relentlessly refractory seizures. To understand fully the contribution of individual syndromes to seizure prognosis requires a detailed analysis within sufficiently large homogeneous samples and consideration of this broader range of outcomes.
All studies have limitations and the greatest concern with ours is that two decades of follow-up may not be adequate to reveal the longer-term prognosis of childhood epilepsies. While that may be true for some purposes, it is not clear that a longer follow-up would provide more precise information. Treatment options have expanded tremendously since the mid-1990s when the Connecticut cohort was recruited. Diagnostic technologies have also changed. In our cohort, 85% of participants had an MRI for either clinical or research purposes; however, this was mostly with 1.5 T machines. Whether today’s advanced imaging technologies and genetic testing could provide more precise prognostic information is a question of great interest.
There are many seizure outcomes that are studied, usually for different purposes. The choice should be determined by the question under investigation and the time scale of the study. For example, treatment trials of infantile spasms might reasonably target a 1-week spasm-free period as a meaningful marker of therapeutic success (Elterman et al., 2001). A randomized trial of AEDs for newly diagnosed epilepsy might target 1-year seizure freedom (First Seizure Trial Group, 1993; Marson et al., 2005, 2007a, b). Such trials are informative about the impact of the treatment on seizures. They provide limited insight, however, into the long-term likelihood that epilepsy will fully resolve, be a life-long, chronic disorder (managed to a greater or lesser extent), or be relentlessly intractable. For long-term studies, perhaps complete resolution of seizures would be of greatest interest. To advance our understanding of the long-term, perhaps life-long, prognosis of epilepsy with regard to seizure resolution, better prediction of shorter-term outcomes that reliably predict longer-term outcomes may be the most efficient way to move forward.
Acknowledgements
We thank the paediatric neurologists of Connecticut who contributed to this study. We extend a special recognition to Eugene Shapiro and Shlomo Shinnar for their contributions, to Barry Russman who opened doors and made the study possible right from the very beginning, and to the research associates, Christina Rios, Charles Hurst, and Maria Consolatore as well as Susan Smith and Barbara Beckerman whose dedication was an essential ingredient for success. The families who generously gave their time and energy to this study made this all possible and worthwhile.
Funding
This study was fully funded by a grant from the National Institutes of Health – the National Institute of Neurological Disorders and Stroke–R37-NS31146.
Supplementary material
Supplementary material is available at Brain online.
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