NEWS & VIEWS EPILEPSY
Long-term rates of childhood-onset epilepsy remission confirmed Matti Sillanpää and Dieter Schmidt
Approximately 60% of people diagnosed with childhood-onset epilepsy are known to be in 5-year remission and off medication, or in complete remission. A new report confirms and consolidates these findings and gives further evidence of the long-term stability of remission in epilepsy. A future risk of relapse is suggested, which might be an overestimate. Sillanpää, M. & Schmidt, D. Nat. Rev. Neurol. advance online publication 27 January 2015; doi:10.1038/nrneurol.2014.262
An estimated 65 million people world wide have epilepsy,1 making it one of the most common chronic neurological dis orders. Therefore, any improvement in our understanding of epileptogenesis—the development and progress of epilepsy—is invaluable. Such information might enable more-effective treatment and, ultimately, seizure resolution without a need for further treatment. The recently published Connecticut Study of Epilepsy 2 consolidates our understanding of the long-term course and outcome of epilepsy in standard care. In a prospective cohort study, 516 children aged 0–15 years with newly diagnosed epi lepsy were followed up for ≥10 years. 328 patients (64%) entered complete remission (defined as seizure remission without use of antiepileptic drugs [AEDs] for ≥5 years) and 23 patients (7%) relapsed, six of whom regained complete remission. A total of 311 patients (60%) were in complete remission at last contact. Patients with an onset age ≥10 years, early school or developmental problems or drug-resistant epilepsy had a significantly worse than average prognosis at last contact. Uncomplicated epilepsy at presentation, focal self-limited epilepsy syn drome, uncharacterized epilepsy and remis sion at 2 years were all associated with higher than average rates of complete remission.2 Better knowledge of epileptogenesis and resolution of seizures is particularly impor tant when advising families of children with epilepsy: these children often (but not always) have a good prognosis. This need for more knowledge explains why long-term outcome studies of childhoodonset epilepsy after stopping AEDs have,
‘‘
…the risk of relapse still exists for more than 10 years after entering complete seizure remission
’’
deservedly, received great attention.3–7 The course and seizure outcomes of childhoodonset epilepsy are hard to anticipate. During long-term follow-up, a marked fluctuation between remissions and relapses often takes place, 3,6,8 and even remissions of several decades might be interrupted by a relapse.3 Consequently, any estimates of the propor tion of patients with a complete seizure resolution are, to some extent, dependent on the cut-off point and length of follow-up period of a particular study. Longitudinal cohort studies of the prog nosis of new-onset epilepsy after cessa tion of drug treatment in patients who are seizure-free have transformed our under standing of epilepsy prognosis. In a Finnish prospective follow-up study of 148 children aged 0–15 years, patients were followed up for almost 40 years,3 90 patients (63%) were off medication at last contact, and 58 patients (37%) remained on medication. Symptomatic aetiology, pretreatment and early treatment seizure frequency, and early drug resistance were all found to predict the long-term clinical outcome.3 In a prospective Dutch study, 413 children aged 0–16 years with childhood-onset epilepsy were fol lowed up for 15 years; 62% were in 5-year terminal remission and off m edication at the end of the follow-up period.6 Although the study designs are not fully comparable, broadly similar percentages
NATURE REVIEWS | NEUROLOGY
of patients achieved complete seizure remission, as pointed out by Berg et al. 2 Furthermore, the reported risk factors for epilepsy were largely the same in this diverse range of studies. 3–7 This concur rence in findings suggests that the current evidence on risk factors is sufficient to accurately advise patients and their families regarding risks. The study by Berg and colleagues2 had a median follow-up period of 17 years. The relapse rate after the first 5 years of followup in patients who achieved complete remission was 10.7/1,000 person-years, and 6.7/1,000 person-years for a further 5-year follow-up period. 2 In compari son, on reanalysis of the Finnish data,3 84 patients (58%) with incident epilepsy fol lowed-up for ≥10 years were in remission and off medication for a period of ≥5 years after ≥10 years of follow-up (M. Saarinen, unpublished analysis). In the Finnish study, relapse after achieved remission occurred in four patients (4.8%) after the first 5 years of follow-up (9.6/1,000 person years) and in one patient (0.7%) after a further 5 years of follow-up (2.4/1,000 person-years). Berg et al. 2 reported no incidences of relapse ≥10 years after complete seizure remis sion. Berg and co-authors concluded that relapses after complete remission are rare, making remission lasting 5 years or more an acceptable proxy for complete seizure resolution. Cautious estimates suggest, however, a residual risk of approximately 1% per year; this estimate was derived from an upper 95% confidence level of 11.2/1,000 person-years reported to relapse ≥10 years after complete seizure remission, and the authors also suggested that the ≤20 years
Mark Strozier/iStock/Thinkstock
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NEWS & VIEWS of follow-up might have been too short. A reanalysis of the Finnish data3 revealed relapse in three (2.1%) of 84 patients at 18, 23 and 26 years during a median follow-up of 33 years after achieving complete remis sion, and a relapse rate of 1.7/1,000 personyears during ≥10-year follow-up with a confidence interval of 0.56–5.37 per 1,000 person-years. This indicates a substan tially lower risk than the upper limit of 11.2 per 1,000 person-years calculated by Berg et al.2 Nevertheless, the risk of relapse still exists for more than 10 years after entering complete seizure remission. In summary, the study by Berg and colleagues. 2 is carefully designed, well described and appropriately analyzed. Con firmation and consolidation of the previous data on complete seizure remission repre sents the main value of this study. However, an important barrier to implementation of findings from this and other studies cur rently exists. In 2014, The International League Against Epilepsy (ILAE) suggested a definition of ‘resolution’ of epilepsy to include seizure remission for 10 years and at least 5 years’ cessation of seizure medi cations. 9 The ILAE definition has been criticized for being arbitrary and lacking an evidential basis.10 Whatever the defini tion, an insurmountable bias exists, both in
the study by Berg et al.2 and in virtually any other study: remission without medication requires that medication is discontinued. Despite a good prognosis in most patients with childhood-onset epilepsy, it should be noted that even when medical indications for drug discontinuation are clearly present, other reasons for continuing medication might exist. These reasons can include anxiety of the patient or the physician regarding the possibility of a relapse upon medication withdrawal, or other reason able motivations such as not endangering the patient’s job or driver’s licence. Such reasons exist in many patients, regardless of the chances of remaining seizure-free without medication. Reported remission frequencies are in line with this trend, given that 14% of patients who achieved seizure remission for at least 5 years elected not to discontinue therapy.3 Department of Child Neurology, 20014 University of Turku, Turku, Finland (M.S.). Epilepsy Research Group, Goethestrasse 5, D‑14163 Berlin, Germany (D.S.). Correspondence to: M.S. [email protected] Acknowledgements We thank Maiju Saarinen for statistical work-up and assistance in the preparation of the manuscript.
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Competing interests The authors declare no competing interests. 1.
Moshé, S. L., Perucca, E., Ryvlin, P. & Tomson, T. Epilepsy: new advances. Lancet http://dx.doi.org/10.1016/S0140– 6736(14)60456–6. 2. Berg, T. A., Rychlik, K., Levy, S. R. & Testa, F. M. Complete remission of childhood-onset epilepsy: stability and prediction over two decades. Brain 137, 3213–3222 (2014). 3. Sillanpää, M. & Schmidt, D. Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients: a long-term population-based study of childhood-onset epilepsy. Epilepsy Behav. 8, 713–719 (2006). 4. Sillanpää, M. & Schmidt, D. Early seizure frequency and aetiology predict long-term medical outcome in childhood-onset epilepsy. Brain 132, 989–998 (2009). 5. Sillanpää, M., Saarinen, M. & Schmidt, D. Long-term risks following first remission in childhood-onset epilepsy. A population-based study. Epilepsy Behav. 25, 145–152 (2012). 6. Geerts, A. et al. Course and outcome of childhood epilepsy: a 15-year follow-up of the Dutch Study of Epilepsy in Childhood. Epilepsia 51, 1189–1197 (2010). 7. Camfield C. S. & Camfield, P. R. Rolandic epilepsy has little effect on adult life 30 years later: a population-based study. Neurology 82, 1162–1166 (2014). 8. Berg, A. T. et al. How long does it take for epilepsy to become intractable? A prospective investigation. Ann. Neurol. 60, 73–79 (2006). 9. Fisher, R. A. et al. ILAE Official Report: a practical clinical definition of epilepsy. Epilepsia 55, 475–482 (2014). 10. Hauser W. Commentary: ILAE definition of epilepsy. Epilepsia 55, 488–490 (2014).
www.nature.com/nrneurol © 2015 Macmillan Publishers Limited. All rights reserved
Long-term rates of childhood-onset epilepsy remission confirmed Matti Sillanpää and Dieter Schmidt
Approximately 60% of people diagnosed with childhood-onset epilepsy are known to be in 5-year remission and off medication, or in complete remission. A new report confirms and consolidates these findings and gives further evidence of the long-term stability of remission in epilepsy. A future risk of relapse is suggested, which might be an overestimate. Sillanpää, M. & Schmidt, D. Nat. Rev. Neurol. advance online publication 27 January 2015; doi:10.1038/nrneurol.2014.262
An estimated 65 million people world wide have epilepsy,1 making it one of the most common chronic neurological dis orders. Therefore, any improvement in our understanding of epileptogenesis—the development and progress of epilepsy—is invaluable. Such information might enable more-effective treatment and, ultimately, seizure resolution without a need for further treatment. The recently published Connecticut Study of Epilepsy 2 consolidates our understanding of the long-term course and outcome of epilepsy in standard care. In a prospective cohort study, 516 children aged 0–15 years with newly diagnosed epi lepsy were followed up for ≥10 years. 328 patients (64%) entered complete remission (defined as seizure remission without use of antiepileptic drugs [AEDs] for ≥5 years) and 23 patients (7%) relapsed, six of whom regained complete remission. A total of 311 patients (60%) were in complete remission at last contact. Patients with an onset age ≥10 years, early school or developmental problems or drug-resistant epilepsy had a significantly worse than average prognosis at last contact. Uncomplicated epilepsy at presentation, focal self-limited epilepsy syn drome, uncharacterized epilepsy and remis sion at 2 years were all associated with higher than average rates of complete remission.2 Better knowledge of epileptogenesis and resolution of seizures is particularly impor tant when advising families of children with epilepsy: these children often (but not always) have a good prognosis. This need for more knowledge explains why long-term outcome studies of childhoodonset epilepsy after stopping AEDs have,
‘‘
…the risk of relapse still exists for more than 10 years after entering complete seizure remission
’’
deservedly, received great attention.3–7 The course and seizure outcomes of childhoodonset epilepsy are hard to anticipate. During long-term follow-up, a marked fluctuation between remissions and relapses often takes place, 3,6,8 and even remissions of several decades might be interrupted by a relapse.3 Consequently, any estimates of the propor tion of patients with a complete seizure resolution are, to some extent, dependent on the cut-off point and length of follow-up period of a particular study. Longitudinal cohort studies of the prog nosis of new-onset epilepsy after cessa tion of drug treatment in patients who are seizure-free have transformed our under standing of epilepsy prognosis. In a Finnish prospective follow-up study of 148 children aged 0–15 years, patients were followed up for almost 40 years,3 90 patients (63%) were off medication at last contact, and 58 patients (37%) remained on medication. Symptomatic aetiology, pretreatment and early treatment seizure frequency, and early drug resistance were all found to predict the long-term clinical outcome.3 In a prospective Dutch study, 413 children aged 0–16 years with childhood-onset epilepsy were fol lowed up for 15 years; 62% were in 5-year terminal remission and off m edication at the end of the follow-up period.6 Although the study designs are not fully comparable, broadly similar percentages
NATURE REVIEWS | NEUROLOGY
of patients achieved complete seizure remission, as pointed out by Berg et al. 2 Furthermore, the reported risk factors for epilepsy were largely the same in this diverse range of studies. 3–7 This concur rence in findings suggests that the current evidence on risk factors is sufficient to accurately advise patients and their families regarding risks. The study by Berg and colleagues2 had a median follow-up period of 17 years. The relapse rate after the first 5 years of followup in patients who achieved complete remission was 10.7/1,000 person-years, and 6.7/1,000 person-years for a further 5-year follow-up period. 2 In compari son, on reanalysis of the Finnish data,3 84 patients (58%) with incident epilepsy fol lowed-up for ≥10 years were in remission and off medication for a period of ≥5 years after ≥10 years of follow-up (M. Saarinen, unpublished analysis). In the Finnish study, relapse after achieved remission occurred in four patients (4.8%) after the first 5 years of follow-up (9.6/1,000 person years) and in one patient (0.7%) after a further 5 years of follow-up (2.4/1,000 person-years). Berg et al. 2 reported no incidences of relapse ≥10 years after complete seizure remis sion. Berg and co-authors concluded that relapses after complete remission are rare, making remission lasting 5 years or more an acceptable proxy for complete seizure resolution. Cautious estimates suggest, however, a residual risk of approximately 1% per year; this estimate was derived from an upper 95% confidence level of 11.2/1,000 person-years reported to relapse ≥10 years after complete seizure remission, and the authors also suggested that the ≤20 years
Mark Strozier/iStock/Thinkstock
ADVANCE ONLINE PUBLICATION | 1 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS of follow-up might have been too short. A reanalysis of the Finnish data3 revealed relapse in three (2.1%) of 84 patients at 18, 23 and 26 years during a median follow-up of 33 years after achieving complete remis sion, and a relapse rate of 1.7/1,000 personyears during ≥10-year follow-up with a confidence interval of 0.56–5.37 per 1,000 person-years. This indicates a substan tially lower risk than the upper limit of 11.2 per 1,000 person-years calculated by Berg et al.2 Nevertheless, the risk of relapse still exists for more than 10 years after entering complete seizure remission. In summary, the study by Berg and colleagues. 2 is carefully designed, well described and appropriately analyzed. Con firmation and consolidation of the previous data on complete seizure remission repre sents the main value of this study. However, an important barrier to implementation of findings from this and other studies cur rently exists. In 2014, The International League Against Epilepsy (ILAE) suggested a definition of ‘resolution’ of epilepsy to include seizure remission for 10 years and at least 5 years’ cessation of seizure medi cations. 9 The ILAE definition has been criticized for being arbitrary and lacking an evidential basis.10 Whatever the defini tion, an insurmountable bias exists, both in
the study by Berg et al.2 and in virtually any other study: remission without medication requires that medication is discontinued. Despite a good prognosis in most patients with childhood-onset epilepsy, it should be noted that even when medical indications for drug discontinuation are clearly present, other reasons for continuing medication might exist. These reasons can include anxiety of the patient or the physician regarding the possibility of a relapse upon medication withdrawal, or other reason able motivations such as not endangering the patient’s job or driver’s licence. Such reasons exist in many patients, regardless of the chances of remaining seizure-free without medication. Reported remission frequencies are in line with this trend, given that 14% of patients who achieved seizure remission for at least 5 years elected not to discontinue therapy.3 Department of Child Neurology, 20014 University of Turku, Turku, Finland (M.S.). Epilepsy Research Group, Goethestrasse 5, D‑14163 Berlin, Germany (D.S.). Correspondence to: M.S. [email protected] Acknowledgements We thank Maiju Saarinen for statistical work-up and assistance in the preparation of the manuscript.
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Competing interests The authors declare no competing interests. 1.
Moshé, S. L., Perucca, E., Ryvlin, P. & Tomson, T. Epilepsy: new advances. Lancet http://dx.doi.org/10.1016/S0140– 6736(14)60456–6. 2. Berg, T. A., Rychlik, K., Levy, S. R. & Testa, F. M. Complete remission of childhood-onset epilepsy: stability and prediction over two decades. Brain 137, 3213–3222 (2014). 3. Sillanpää, M. & Schmidt, D. Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients: a long-term population-based study of childhood-onset epilepsy. Epilepsy Behav. 8, 713–719 (2006). 4. Sillanpää, M. & Schmidt, D. Early seizure frequency and aetiology predict long-term medical outcome in childhood-onset epilepsy. Brain 132, 989–998 (2009). 5. Sillanpää, M., Saarinen, M. & Schmidt, D. Long-term risks following first remission in childhood-onset epilepsy. A population-based study. Epilepsy Behav. 25, 145–152 (2012). 6. Geerts, A. et al. Course and outcome of childhood epilepsy: a 15-year follow-up of the Dutch Study of Epilepsy in Childhood. Epilepsia 51, 1189–1197 (2010). 7. Camfield C. S. & Camfield, P. R. Rolandic epilepsy has little effect on adult life 30 years later: a population-based study. Neurology 82, 1162–1166 (2014). 8. Berg, A. T. et al. How long does it take for epilepsy to become intractable? A prospective investigation. Ann. Neurol. 60, 73–79 (2006). 9. Fisher, R. A. et al. ILAE Official Report: a practical clinical definition of epilepsy. Epilepsia 55, 475–482 (2014). 10. Hauser W. Commentary: ILAE definition of epilepsy. Epilepsia 55, 488–490 (2014).
www.nature.com/nrneurol © 2015 Macmillan Publishers Limited. All rights reserved
