Opinion
EDITORIAL
The Prevention of Epilepsy Mark Agostini, MD
Almost 21 years ago, Dreifuss1 reviewed the state of epilepsy prevention in this journal. He anticipated a quarter century of advances in the understanding of the neurobiological mechanisms and prevention of epileptogenesis. He also identified theoretically preventive strategies such as immunizations, Related article optimizing maternal health, preventing early teenage pregnancies with their increased risk for premature and lowweight infants, increasing the use of helmets for sports and transportation, preventing falls among elderly individuals, and ending boxing in high schools. The focus on prevention is critical given the approximately 30% rate of pharmacoresistance among patients with epilepsy. This is despite at least 16 new antiseizure medications since 1993, some with novel mechanisms of action.2 Failure to control epileptic seizures leads to increased mortality and reduced quality of life.3 From the Presidential Commission for the Control of Epilepsy and its Consequences in 1976 to the 2012 publication of the Institute of Medicine report, “Epilepsy Across The Spectrum: Promoting Health and Understanding,” there has been consistent recognition of the vital importance of acquiring epidemiologic data addressing progress in the prevention of epilepsy.4-6 Neuroscientific advances in the mechanisms of and potential treatments for epileptogenesis have exploded within the last few decades.7,8 Public health measures to prevent head injuries, from car air bags to bicycle helmets, have become commonplace. There has been an understandable sense of optimism that these basic and clinical research advances together with public health safety initiatives would translate to a decline in the rate of epilepsy. We only needed the data to prove this. It is within this atmosphere of great optimism that the article by Sillanpää et al9 comes as a disappointment. Sillanpää and his colleagues9 analyzed the incidence rate of new-onset epilepsy (patients with epilepsy per 100 000 person-years) in Finland from 1973 to 2013.9 They took advantage of a national hospital registry that identifies all patients discharged with a diagnosis of epilepsy. They also benefitted from a national standard of care to hospitalize all patients with epileptic seizures who presented to a hospital emergency department. Coding systems (International Classification of Diseases, Eighth Revision; International Classification of Diseases, Ninth Revision; and International Classification of Diseases, Tenth Revision) as well as the individual codes (345.3-9, 345.4-7, and G40.0-2) changed during this study but the application of an epilepsy diagnosis was consistent for each time interval. The authors’ major finding was that the yearly incidence for new-onset epilepsy was constant for all age groups until 2000, when there was a significant increase. This increase was jamaneurology.com
entirely accounted for by a nearly 5-fold increase in patients older than 65 years. Subgroups, such as children younger than 1 year of age and patients with symptomatic focal epilepsy, also showed an increased incidence over the observation period. For patients with focal epilepsy, the incidence densities increased from 7 per 100 000 person-years in 1978 to 39 per 100 000 person-years in 2013. The strengths of this study included a very long observational period and a strong, consistent method to systematically capture all patients with new-onset epilepsy. However, they noted that in the last 15 years of their study, unpublished data suggested that the diagnoses of new-onset epilepsy doubled if outpatient care was included. It is not clear whether inpatient and outpatient diagnoses represent different types of epilepsy. The latter perhaps might show a different response to 40 years of epilepsy prevention. The authors also raised the concern of an increasingly lower threshold to diagnose epilepsy or perhaps better tools (eg, magnetic resonance imaging and video electroencephalogram) to make a secure diagnosis. This seems unlikely given that the diagnosis of epilepsy remains a predominantly clinical diagnosis, which probably has not changed over the years. The study also used the most conservative definition of epilepsy.10 The authors concluded that not only have we failed to reduce the occurrence of epilepsy over the last 40 years, but there has been a significant 5-fold increase in new-onset epilepsy among the elderly population. The authors discussed the balance of 2 forces that would affect the change in the incidence of new-onset epilepsy. On one hand, over the last 40 years, there have been tremendous and steady advances in neonatal and critical illness care. This has led to enhanced survival of patients with brain injuries likely to precipitate epileptogenesis. Increased survival of those who have had gunshot wounds to the head, military or civilian, or the increased survival of premature infants would be just 2 examples of factors that will contribute to more epilepsy diagnoses. In a sense, an increase in epilepsy is the price paid for the dramatic advances of critical care medicine. Moreover, along with Finland, many nations are experiencing a demographic shift, with a marked increase in the longevity of elderly individuals and their anticipated higher burden of epilepsy risk factors. The forces of public safety measures to prevent brain injuries along with the very few documented medical interventions to prevent epileptogenesis among high-risk patients apparently have not been a sufficient counterbalance.7,8,11 This article has several important implications for the prevention of epilepsy. The first is the importance of welldesigned, long-term, epidemiologic studies to ensure that we have adequate feedback with respect to progress or the lack (Reprinted) JAMA Neurology Published online February 15, 2016
Copyright 2016 American Medical Association. All rights reserved.
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E1
Opinion Editorial
thereof. While it is likely that Finland’s epidemiologic data are representative of many developed countries, this may not apply to less well-developed nations. The challenge is for every country to initiate epidemiologic surveillance for patients with new-onset and chronic epilepsy. Second, efforts toward identifying patients at high risk for developing epilepsy and initiating clinical treatments to prevent epileptogenesis have never been more important if we are ever to balance the increasing survival of brain-injured patients and aging populations. For exARTICLE INFORMATION Author Affiliation: Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas. Corresponding Author: Mark Agostini, MD, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 753908508 ([email protected]). Published Online: February 15, 2016. doi:10.1001/jamaneurol.2015.4780. Conflict of Interest Disclosures: None reported. REFERENCES 1. Dreifuss FE. Prevention as it pertains to epilepsy. Arch Neurol. 1995;52(4):363-366. 2. Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011;365(10):919-926. 3. Theodore WH, Spencer SS, Wiebe S, et al. Epilepsy in North America: a report prepared under
E2
ample, the European Forum on Epilepsy research proposed a specific “roadmap for translational research,” including a recommendation to establish both preclinical and clinical European consortiums for antiepileptogenesis studies.12 Finally, there may still be public health measures that could further reduce the incidence of severe brain injuries (eg, reductions in gun violence and in sports- and traffic-related head trauma). Sillanpää and colleagues9 have provided essential feedback that more work has to be done.
the auspices of the global campaign against epilepsy, the International Bureau for Epilepsy, the International League Against Epilepsy, and the World Health Organization. Epilepsia. 2006;47(10): 1700-1722. 4. Hesdorffer DC, Beck V, Begley CE, et al. Research implications of the Institute of Medicine report, Epilepsy Across the Spectrum: Promoting Health and Understanding. Epilepsia. 2013;54(2): 207-216. 5. Hesdorffer DC, Begley CE. Surveillance of epilepsy and prevention of epilepsy and its sequelae: lessons from the Institute of Medicine report. Curr Opin Neurol. 2013;26(2):168-173. 6. Institute of Medicine. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academics Press; 2012. 7. Giblin KA, Blumenfeld H. Is epilepsy a preventable disorder? new evidence from animal models. Neuroscientist. 2010;16(3):253-275.
8. Pitkänen A, Engel J Jr. Past and present definitions of epileptogenesis and its biomarkers. Neurotherapeutics. 2014;11(2):231-241. 9. Sillanpää M, Gissler M, Schmidt D. Efforts in epilepsy prevention in the last 40 years: lessons from a large nationwide study [published online February 15, 2016]. JAMA Neurol. doi:10.1001 /jamaneurol.2015.4515. 10. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475-482. 11. Guo J, Guo J, Li J, et al. Statin treatment reduces the risk of poststroke seizures. Neurology. 2015;85 (8):701-707. 12. Baulac M, de Boer H, Elger C, et al. Epilepsy priorities in Europe: a report of the ILAE-IBE Epilepsy Advocacy Europe Task Force. Epilepsia. 2015;56(11):1687-1695.
JAMA Neurology Published online February 15, 2016 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a GAZI UNIVERSITESI User on 02/17/2016
jamaneurology.com
EDITORIAL
The Prevention of Epilepsy Mark Agostini, MD
Almost 21 years ago, Dreifuss1 reviewed the state of epilepsy prevention in this journal. He anticipated a quarter century of advances in the understanding of the neurobiological mechanisms and prevention of epileptogenesis. He also identified theoretically preventive strategies such as immunizations, Related article optimizing maternal health, preventing early teenage pregnancies with their increased risk for premature and lowweight infants, increasing the use of helmets for sports and transportation, preventing falls among elderly individuals, and ending boxing in high schools. The focus on prevention is critical given the approximately 30% rate of pharmacoresistance among patients with epilepsy. This is despite at least 16 new antiseizure medications since 1993, some with novel mechanisms of action.2 Failure to control epileptic seizures leads to increased mortality and reduced quality of life.3 From the Presidential Commission for the Control of Epilepsy and its Consequences in 1976 to the 2012 publication of the Institute of Medicine report, “Epilepsy Across The Spectrum: Promoting Health and Understanding,” there has been consistent recognition of the vital importance of acquiring epidemiologic data addressing progress in the prevention of epilepsy.4-6 Neuroscientific advances in the mechanisms of and potential treatments for epileptogenesis have exploded within the last few decades.7,8 Public health measures to prevent head injuries, from car air bags to bicycle helmets, have become commonplace. There has been an understandable sense of optimism that these basic and clinical research advances together with public health safety initiatives would translate to a decline in the rate of epilepsy. We only needed the data to prove this. It is within this atmosphere of great optimism that the article by Sillanpää et al9 comes as a disappointment. Sillanpää and his colleagues9 analyzed the incidence rate of new-onset epilepsy (patients with epilepsy per 100 000 person-years) in Finland from 1973 to 2013.9 They took advantage of a national hospital registry that identifies all patients discharged with a diagnosis of epilepsy. They also benefitted from a national standard of care to hospitalize all patients with epileptic seizures who presented to a hospital emergency department. Coding systems (International Classification of Diseases, Eighth Revision; International Classification of Diseases, Ninth Revision; and International Classification of Diseases, Tenth Revision) as well as the individual codes (345.3-9, 345.4-7, and G40.0-2) changed during this study but the application of an epilepsy diagnosis was consistent for each time interval. The authors’ major finding was that the yearly incidence for new-onset epilepsy was constant for all age groups until 2000, when there was a significant increase. This increase was jamaneurology.com
entirely accounted for by a nearly 5-fold increase in patients older than 65 years. Subgroups, such as children younger than 1 year of age and patients with symptomatic focal epilepsy, also showed an increased incidence over the observation period. For patients with focal epilepsy, the incidence densities increased from 7 per 100 000 person-years in 1978 to 39 per 100 000 person-years in 2013. The strengths of this study included a very long observational period and a strong, consistent method to systematically capture all patients with new-onset epilepsy. However, they noted that in the last 15 years of their study, unpublished data suggested that the diagnoses of new-onset epilepsy doubled if outpatient care was included. It is not clear whether inpatient and outpatient diagnoses represent different types of epilepsy. The latter perhaps might show a different response to 40 years of epilepsy prevention. The authors also raised the concern of an increasingly lower threshold to diagnose epilepsy or perhaps better tools (eg, magnetic resonance imaging and video electroencephalogram) to make a secure diagnosis. This seems unlikely given that the diagnosis of epilepsy remains a predominantly clinical diagnosis, which probably has not changed over the years. The study also used the most conservative definition of epilepsy.10 The authors concluded that not only have we failed to reduce the occurrence of epilepsy over the last 40 years, but there has been a significant 5-fold increase in new-onset epilepsy among the elderly population. The authors discussed the balance of 2 forces that would affect the change in the incidence of new-onset epilepsy. On one hand, over the last 40 years, there have been tremendous and steady advances in neonatal and critical illness care. This has led to enhanced survival of patients with brain injuries likely to precipitate epileptogenesis. Increased survival of those who have had gunshot wounds to the head, military or civilian, or the increased survival of premature infants would be just 2 examples of factors that will contribute to more epilepsy diagnoses. In a sense, an increase in epilepsy is the price paid for the dramatic advances of critical care medicine. Moreover, along with Finland, many nations are experiencing a demographic shift, with a marked increase in the longevity of elderly individuals and their anticipated higher burden of epilepsy risk factors. The forces of public safety measures to prevent brain injuries along with the very few documented medical interventions to prevent epileptogenesis among high-risk patients apparently have not been a sufficient counterbalance.7,8,11 This article has several important implications for the prevention of epilepsy. The first is the importance of welldesigned, long-term, epidemiologic studies to ensure that we have adequate feedback with respect to progress or the lack (Reprinted) JAMA Neurology Published online February 15, 2016
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a GAZI UNIVERSITESI User on 02/17/2016
E1
Opinion Editorial
thereof. While it is likely that Finland’s epidemiologic data are representative of many developed countries, this may not apply to less well-developed nations. The challenge is for every country to initiate epidemiologic surveillance for patients with new-onset and chronic epilepsy. Second, efforts toward identifying patients at high risk for developing epilepsy and initiating clinical treatments to prevent epileptogenesis have never been more important if we are ever to balance the increasing survival of brain-injured patients and aging populations. For exARTICLE INFORMATION Author Affiliation: Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas. Corresponding Author: Mark Agostini, MD, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 753908508 ([email protected]). Published Online: February 15, 2016. doi:10.1001/jamaneurol.2015.4780. Conflict of Interest Disclosures: None reported. REFERENCES 1. Dreifuss FE. Prevention as it pertains to epilepsy. Arch Neurol. 1995;52(4):363-366. 2. Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011;365(10):919-926. 3. Theodore WH, Spencer SS, Wiebe S, et al. Epilepsy in North America: a report prepared under
E2
ample, the European Forum on Epilepsy research proposed a specific “roadmap for translational research,” including a recommendation to establish both preclinical and clinical European consortiums for antiepileptogenesis studies.12 Finally, there may still be public health measures that could further reduce the incidence of severe brain injuries (eg, reductions in gun violence and in sports- and traffic-related head trauma). Sillanpää and colleagues9 have provided essential feedback that more work has to be done.
the auspices of the global campaign against epilepsy, the International Bureau for Epilepsy, the International League Against Epilepsy, and the World Health Organization. Epilepsia. 2006;47(10): 1700-1722. 4. Hesdorffer DC, Beck V, Begley CE, et al. Research implications of the Institute of Medicine report, Epilepsy Across the Spectrum: Promoting Health and Understanding. Epilepsia. 2013;54(2): 207-216. 5. Hesdorffer DC, Begley CE. Surveillance of epilepsy and prevention of epilepsy and its sequelae: lessons from the Institute of Medicine report. Curr Opin Neurol. 2013;26(2):168-173. 6. Institute of Medicine. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academics Press; 2012. 7. Giblin KA, Blumenfeld H. Is epilepsy a preventable disorder? new evidence from animal models. Neuroscientist. 2010;16(3):253-275.
8. Pitkänen A, Engel J Jr. Past and present definitions of epileptogenesis and its biomarkers. Neurotherapeutics. 2014;11(2):231-241. 9. Sillanpää M, Gissler M, Schmidt D. Efforts in epilepsy prevention in the last 40 years: lessons from a large nationwide study [published online February 15, 2016]. JAMA Neurol. doi:10.1001 /jamaneurol.2015.4515. 10. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475-482. 11. Guo J, Guo J, Li J, et al. Statin treatment reduces the risk of poststroke seizures. Neurology. 2015;85 (8):701-707. 12. Baulac M, de Boer H, Elger C, et al. Epilepsy priorities in Europe: a report of the ILAE-IBE Epilepsy Advocacy Europe Task Force. Epilepsia. 2015;56(11):1687-1695.
JAMA Neurology Published online February 15, 2016 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a GAZI UNIVERSITESI User on 02/17/2016
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