EDITORIAL
Facing up to SUDEP
Barbara Dworetzky, MD Epilepsy is a chronic condition that affects approxiStephan U. Schuele, MD, mately 2.3 million people in the United States.1 Approximately one-third of people with epilepsy conMPH tinue to have seizures despite adequate medication trials and adherence to medical recommendations.2 Correspondence to People of all races and backgrounds, young and old, Dr. Dworetzky: are affected by epilepsy from a variety of etiologies, [email protected] and epilepsy carries a high burden of comorbidity including the risk of death. The overwhelming majorNeurology® 2015;84:643–644 ity of the deaths are due to sudden unexpected death in epilepsy (SUDEP), which is closely related to a recent convulsive or tonic-clonic seizure,3 and thus may be a direct result of a seizure. SUDEP preferentially affects young people and carries a public health burden estimated in potential life years lost (1.16 cases per 1,000 patients with epilepsy) second only to stroke.4 The mechanism of SUDEP has been debated: CNS shutdown with impaired autonomic regulation, cardiac causes (arrhythmias), or respiratory etiology (mostly central apneas with hypoventilation) are the top choices, with recent insights from a video-EEG review of recorded SUDEP in the epilepsy monitoring unit.5 Understanding the mechanism of SUDEP may help to prevent it. Increasing research and funding are being devoted to SUDEP to prevent this feared consequence of uncontrolled epilepsy. The rapidly growing literature indicates that uncontrolled and unattended tonic-clonic seizures are likely the strongest risk factor,6 but other important risk factors, such as early onset of epilepsy, longer duration of illness, and prolonged postictal generalized EEG suppression (PGES),7 also correlate with SUDEP. Unfortunately, aside from optimized seizure control, these features are difficult to influence. One potential modifiable risk factor has been identified: being found in bed in the prone position; however, there were no large studies to confirm this.8 In this issue of Neurology®, Liebenthal et al.8 describe their systematic review and meta-analysis of the literature up to 2003 in which they found 25 studies (of 1,106 unique ones): 14 single case studies and 11 case series where body position was documented in relation to the SUDEP. These authors
used the Nashef definition of SUDEP: witnessed or unwitnessed, nontraumatic and nondrowning, excluding status epilepticus or an identifiable cause of death at autopsy9; cases were divided into definite (autopsy-proven), probable (no autopsy), or possible (other cause of death was listed). Assumptions were made about SUDEP occurring during sleep if the person was found dead in bed, and during wakefulness if found outside of the bed or bedroom.8 Of the 253/413 SUDEP cases reviewed in which body position was adequately documented, 73.3% were prone (p , 0.001). Of note, in the 11 cases that had SUDEP documented on video-EEG, 100% were found prone, had had a generalized tonic-clonic seizure, and had PGES.8 A subset analysis by age revealed that patients older than 40 years were less likely to be prone than those younger than 20 years. No difference was found for sex or for sleep/wake state at time of seizure onset. Discovering a possible modifiable risk factor for SUDEP, such as sleeping in the prone position, is clearly important because it implies the possibility of preventing a substantial number of deaths by having patients sleep on their back, as has been done with SIDS (sudden infant death syndrome). Animal models that link SUDEP to a serotonin mechanism (reduced drive to breathe) will be important.10 Furthermore, it will be critical to identify patients at high risk of SUDEP, such as those with PGES during their epilepsy monitoring unit stay, those with intellectual disability and frequent uncontrolled tonic-clonic seizures, or possibly carriers of specific potassium channel genes linked to sudden death in animals. There are several limitations of the study. From a very large number of publications, only 25 studies were used; this small proportion of studies that described a prone or supine position at time of SUDEP may have introduced a reporting bias. There was no control group of final position in patients with tonic-clonic seizures to determine the frequency of patients ending prone without associated SUDEP. The study also cannot answer whether sleeping in a prone position is more prevalent among patients with epilepsy who die of SUDEP, or
See page 703 From Brigham and Women’s Hospital (B.D.), Harvard Medical School, Boston, MA; and Northwestern University (S.U.S.), Feinberg School of Medicine, Chicago, IL. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. © 2015 American Academy of Neurology
643
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
how many patients change body position during or after the terminal seizure. Prone positioning is likely overrepresented in unwitnessed and therefore unattended tonic-clonic seizures, because patients have not been placed in a lateral or supine rescue position. Furthermore, finding someone prone at time of death does not inform mechanism of death, because oxygenation, CO2, and respiratory effort were not available for any of the cases. However, the study underlines that simple measures may have a substantial effect on SUDEP risk and that our efforts to attend to patients and bring them out of a prone position are worthwhile. These cases are rare and it takes persistence and hard work to identify SUDEP and confirm it through autopsy. This is only achievable by joining together as clinicians and researchers to identify and follow high-risk patients prospectively, and use current technology to help prevent the devastating loss of young patients. This approach would truly benefit our patients as current treatments still fall short in stopping all seizures. STUDY FUNDING No targeted funding reported.
DISCLOSURE B. Dworetzky has consulted for SleepMed (interpreting ambulatory EEGs). S. Schuele serves on the speakers bureau for Sunovion and GSK and has been a medical consultant for Supernus. Go to Neurology.org for full disclosures.
644
Neurology 84
REFERENCES 1. Centers for Disease Control and Prevention (CDC). Comorbidity in adults with epilepsy—United States, 2010. MMWR Morb Mortal Wkly Rep 2013;62: 849–853. 2. Kwon P, Brodie M. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–319. 3. Ryvlin P, Nashef L, Tomson T. Prevention of SUDEP: a realistic goal? Epilepsia 2013;(54 suppl 2):23–28. 4. Thurman DJ, Hesdorffer DC, French JA. SUDEP: assessing the public health burden. Epilepsia 2014;55: 1479–1485. 5. Ryvlin P, Nashef L, Lhatoo SD, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 2013;12:966–977. 6. Nilsson L, Farahmond BY, Persson PG, Thiblin I, Tomson T. Risk factors for sudden unexpected death in epilepsy: a case control study. Lancet 1999;353: 888–893. 7. Lhatoo SD, Faulkner HJ, Dembny K, Thippick K, Johnson C, Bird JM. An electroclinical case-control of sudden unexpected death in epilepsy. Ann Neurol 2010; 68:787–796. 8. Liebenthal JA, Wu S, Rose S, Ebersole JS, Tao JX. Association of prone position with sudden unexpected death in epilepsy. Neurology 2015;84:703–709. 9. Nashef L. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia 1997;38(11 suppl): S6–S8. 10. Richerson GB. Serotonin: the Anti-SuddenDeathAmine? Epilepsy Curr 2013;13:241–244.
February 17, 2015
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Facing up to SUDEP Barbara Dworetzky and Stephan U. Schuele Neurology 2015;84;643-644 Published Online before print January 21, 2015 DOI 10.1212/WNL.0000000000001274 This information is current as of January 21, 2015 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/84/7/643.full.html
References
This article cites 9 articles, 0 of which you can access for free at: http://www.neurology.org/content/84/7/643.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Sleep Disorders http://www.neurology.org//cgi/collection/all_sleep_disorders EEG http://www.neurology.org//cgi/collection/eeg_ Epilepsy monitoring http://www.neurology.org//cgi/collection/epilepsy_monitoring_ Generalized seizures http://www.neurology.org//cgi/collection/generalized_seizures
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Facing up to SUDEP
Barbara Dworetzky, MD Epilepsy is a chronic condition that affects approxiStephan U. Schuele, MD, mately 2.3 million people in the United States.1 Approximately one-third of people with epilepsy conMPH tinue to have seizures despite adequate medication trials and adherence to medical recommendations.2 Correspondence to People of all races and backgrounds, young and old, Dr. Dworetzky: are affected by epilepsy from a variety of etiologies, [email protected] and epilepsy carries a high burden of comorbidity including the risk of death. The overwhelming majorNeurology® 2015;84:643–644 ity of the deaths are due to sudden unexpected death in epilepsy (SUDEP), which is closely related to a recent convulsive or tonic-clonic seizure,3 and thus may be a direct result of a seizure. SUDEP preferentially affects young people and carries a public health burden estimated in potential life years lost (1.16 cases per 1,000 patients with epilepsy) second only to stroke.4 The mechanism of SUDEP has been debated: CNS shutdown with impaired autonomic regulation, cardiac causes (arrhythmias), or respiratory etiology (mostly central apneas with hypoventilation) are the top choices, with recent insights from a video-EEG review of recorded SUDEP in the epilepsy monitoring unit.5 Understanding the mechanism of SUDEP may help to prevent it. Increasing research and funding are being devoted to SUDEP to prevent this feared consequence of uncontrolled epilepsy. The rapidly growing literature indicates that uncontrolled and unattended tonic-clonic seizures are likely the strongest risk factor,6 but other important risk factors, such as early onset of epilepsy, longer duration of illness, and prolonged postictal generalized EEG suppression (PGES),7 also correlate with SUDEP. Unfortunately, aside from optimized seizure control, these features are difficult to influence. One potential modifiable risk factor has been identified: being found in bed in the prone position; however, there were no large studies to confirm this.8 In this issue of Neurology®, Liebenthal et al.8 describe their systematic review and meta-analysis of the literature up to 2003 in which they found 25 studies (of 1,106 unique ones): 14 single case studies and 11 case series where body position was documented in relation to the SUDEP. These authors
used the Nashef definition of SUDEP: witnessed or unwitnessed, nontraumatic and nondrowning, excluding status epilepticus or an identifiable cause of death at autopsy9; cases were divided into definite (autopsy-proven), probable (no autopsy), or possible (other cause of death was listed). Assumptions were made about SUDEP occurring during sleep if the person was found dead in bed, and during wakefulness if found outside of the bed or bedroom.8 Of the 253/413 SUDEP cases reviewed in which body position was adequately documented, 73.3% were prone (p , 0.001). Of note, in the 11 cases that had SUDEP documented on video-EEG, 100% were found prone, had had a generalized tonic-clonic seizure, and had PGES.8 A subset analysis by age revealed that patients older than 40 years were less likely to be prone than those younger than 20 years. No difference was found for sex or for sleep/wake state at time of seizure onset. Discovering a possible modifiable risk factor for SUDEP, such as sleeping in the prone position, is clearly important because it implies the possibility of preventing a substantial number of deaths by having patients sleep on their back, as has been done with SIDS (sudden infant death syndrome). Animal models that link SUDEP to a serotonin mechanism (reduced drive to breathe) will be important.10 Furthermore, it will be critical to identify patients at high risk of SUDEP, such as those with PGES during their epilepsy monitoring unit stay, those with intellectual disability and frequent uncontrolled tonic-clonic seizures, or possibly carriers of specific potassium channel genes linked to sudden death in animals. There are several limitations of the study. From a very large number of publications, only 25 studies were used; this small proportion of studies that described a prone or supine position at time of SUDEP may have introduced a reporting bias. There was no control group of final position in patients with tonic-clonic seizures to determine the frequency of patients ending prone without associated SUDEP. The study also cannot answer whether sleeping in a prone position is more prevalent among patients with epilepsy who die of SUDEP, or
See page 703 From Brigham and Women’s Hospital (B.D.), Harvard Medical School, Boston, MA; and Northwestern University (S.U.S.), Feinberg School of Medicine, Chicago, IL. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. © 2015 American Academy of Neurology
643
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
how many patients change body position during or after the terminal seizure. Prone positioning is likely overrepresented in unwitnessed and therefore unattended tonic-clonic seizures, because patients have not been placed in a lateral or supine rescue position. Furthermore, finding someone prone at time of death does not inform mechanism of death, because oxygenation, CO2, and respiratory effort were not available for any of the cases. However, the study underlines that simple measures may have a substantial effect on SUDEP risk and that our efforts to attend to patients and bring them out of a prone position are worthwhile. These cases are rare and it takes persistence and hard work to identify SUDEP and confirm it through autopsy. This is only achievable by joining together as clinicians and researchers to identify and follow high-risk patients prospectively, and use current technology to help prevent the devastating loss of young patients. This approach would truly benefit our patients as current treatments still fall short in stopping all seizures. STUDY FUNDING No targeted funding reported.
DISCLOSURE B. Dworetzky has consulted for SleepMed (interpreting ambulatory EEGs). S. Schuele serves on the speakers bureau for Sunovion and GSK and has been a medical consultant for Supernus. Go to Neurology.org for full disclosures.
644
Neurology 84
REFERENCES 1. Centers for Disease Control and Prevention (CDC). Comorbidity in adults with epilepsy—United States, 2010. MMWR Morb Mortal Wkly Rep 2013;62: 849–853. 2. Kwon P, Brodie M. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–319. 3. Ryvlin P, Nashef L, Tomson T. Prevention of SUDEP: a realistic goal? Epilepsia 2013;(54 suppl 2):23–28. 4. Thurman DJ, Hesdorffer DC, French JA. SUDEP: assessing the public health burden. Epilepsia 2014;55: 1479–1485. 5. Ryvlin P, Nashef L, Lhatoo SD, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 2013;12:966–977. 6. Nilsson L, Farahmond BY, Persson PG, Thiblin I, Tomson T. Risk factors for sudden unexpected death in epilepsy: a case control study. Lancet 1999;353: 888–893. 7. Lhatoo SD, Faulkner HJ, Dembny K, Thippick K, Johnson C, Bird JM. An electroclinical case-control of sudden unexpected death in epilepsy. Ann Neurol 2010; 68:787–796. 8. Liebenthal JA, Wu S, Rose S, Ebersole JS, Tao JX. Association of prone position with sudden unexpected death in epilepsy. Neurology 2015;84:703–709. 9. Nashef L. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia 1997;38(11 suppl): S6–S8. 10. Richerson GB. Serotonin: the Anti-SuddenDeathAmine? Epilepsy Curr 2013;13:241–244.
February 17, 2015
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Facing up to SUDEP Barbara Dworetzky and Stephan U. Schuele Neurology 2015;84;643-644 Published Online before print January 21, 2015 DOI 10.1212/WNL.0000000000001274 This information is current as of January 21, 2015 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/84/7/643.full.html
References
This article cites 9 articles, 0 of which you can access for free at: http://www.neurology.org/content/84/7/643.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Sleep Disorders http://www.neurology.org//cgi/collection/all_sleep_disorders EEG http://www.neurology.org//cgi/collection/eeg_ Epilepsy monitoring http://www.neurology.org//cgi/collection/epilepsy_monitoring_ Generalized seizures http://www.neurology.org//cgi/collection/generalized_seizures
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
