Correspondence
We declare that we have no conflicts of interest.
*Andriy V Samokhvalov, Jürgen Rehm [email protected]
www.thelancet.com Vol 383 February 8, 2014
Centre for Addiction and Mental Health, M5V3R5, Toronto, ON, Canada (AVS, JR); University of Toronto, Toronto, ON, Canada (AVS, JR); and Klinische Psychologie and Psychotherapie, Technische Universität Dresden, Dresden, Germany (JR) 1
2
3
4
5
Fazel S, Wolf A, Långström N, Newton CR, Lichtenstein P. Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study. Lancet 2013; 382: 1646–54. Samokhvalov AV, Irving H, Mohapatra S, Rehm J. Alcohol consumption, unprovoked seizures and epilepsy: a systematic review and meta-analysis. Epilepsia 2010; 51: 1177–84. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224–60. Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 617–27. Rathlev NK, Ulrich AS, Delanty N, D’Onofrio D, D’Onofrio G. Alcohol-related seizures. J Emerg Med 2006; 31: 157–63.
Authors’ reply We agree with Andreas Otte and Dieter Riemann on the potential importance of sleep disturbances for triggering suicide in epilepsy. Our population-based study 1 covering 40 years relied on routinely collected patient data from inpatient and outpatient sources according to the International Classification of Diseases (ICD) diagnoses. This approach would under-report sleep problems that would not meet the diagnostic threshold for sleep disorders and, therefore, we are not able to investigate this issue reliably. Torbjörn Tomson and Dale Hesdorffer suggest that the inclusion of status epilecticus might have overestimated odds of mortality associated with epilepsy. We addressed this potential issue in the Article1 by doing a sensitivity analysis of those receiving two or more diagnoses (including for natural causes of mortality, appendix1) and by investigating the effects by diagnostic category of epilepsy. In addition, the contribution of status epilecticus was likely to be small for external causes of death because deaths directly due to status epilecticus were not included. To test this issue further, we
have examined what proportion of patients had one or more diagnoses of status epilecticus without any other epilepsy diagnoses. We did this for ICD-10 diagnoses because classifications were more precise than ICD-8/9. We found that for 359 (3·0%) patients with only one diagnosis, that diagnosis was status epilecticus. For 108 (0·4%) of those with two or more diagnoses, all those diagnoses were status epilecticus. When we excluded these 467 individuals, the results did not change: the revised adjusted odds ratio (aOR) was 17·1 (95% CI 15·9–18·4) for all-cause mortality and 6·1 (5·2–7·0) for external cause mortality, compared with 17·7 (16·4–19·0) for all-cause mortality and 6·4 (5·5–7·3) for external cause mortality including patients with status epilecticus diagnoses (these odds are higher than those reported in the Article because patients with ICD-10 diagnoses were younger than the overall sample of individuals with ICD-8, 9, and 10 diagnoses). Regarding interactions between substance misuse and epilepsy, we found evidence of negative multiplicative interaction for nonvehicle accidents (p=0·003) but not for external causes of death (p=0·273), suicide (p=0·413), or vehicle accidents (p=0·285). Because statistical interaction does not necessarily reflect biological interaction, we need to be cautious when interpreting these interactions. We note with interest Andriy Samokhvalov and Jürgen Rehm’s comments on the importance of alcohol use disorders in epilepsy. Consistent with their findings, alcohol use disorders were indeed more prevalent than other drug use disorders; among patients with substance misuse, 45% had alcohol use disorders only. However, in patients with substance use disorders, drug misuse disorders are common—23% had drug abuse disorders only and the remaining 33% had both alcohol use disorders and drug misuse disorders.
Tim Beddow/Science Photo Library
Seena Fazel and colleagues1 recently assessed premature mortality in patients with epilepsy. We would like to emphasise the specific effect of alcohol in the development of epilepsy and associated mortality. First, on the basis of data presented by Fazel and colleagues,1 the relative risk of development of epilepsy in people with alcohol misuse is 4·95 (95% CI 4·82–5·07), which corroborates the results of our meta-analysis on alcoholrelated epileptogenesis.2 Second, Fazel and colleagues’ study1 shows the role of comorbid substance use disorders in premature mortality. Substance use disorders were associated with the highest overall risk of premature mortality (adjusted odds ratio [aOR] 22·4, 95% CI 18·3–27·3), the only psychiatric comorbidity associated with increased risk of fatal vehicle accidents (aOR 3·1, 95% CI 1·7–5·5), and associated with an increased risk of suicide similar to that of depression. Although no separate data for alcohol use disorders were presented in Fazel and colleagues’ article, 1 most of the substance use disorderattributable deaths were probably related to alcohol because alcohol use disorders represented the majority of substance use disorder cases (76%), in line with other European data.3 In addition, alcohol use disorders are strongly associated with psychiatric comorbidities4 and negatively affect the course of epilepsy.5 Both of these factors contribute to premature mortality in epilepsy. Further research is needed to better understand the effect of alcohol on both development of epilepsy and associated premature mortality. Proper screening for heavy drinking and suitable interventions including treatment of alcohol use disorders are recommended to reduce premature mortality in people with epilepsy.
511
We declare that we have no conflicts of interest.
*Andriy V Samokhvalov, Jürgen Rehm [email protected]
www.thelancet.com Vol 383 February 8, 2014
Centre for Addiction and Mental Health, M5V3R5, Toronto, ON, Canada (AVS, JR); University of Toronto, Toronto, ON, Canada (AVS, JR); and Klinische Psychologie and Psychotherapie, Technische Universität Dresden, Dresden, Germany (JR) 1
2
3
4
5
Fazel S, Wolf A, Långström N, Newton CR, Lichtenstein P. Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study. Lancet 2013; 382: 1646–54. Samokhvalov AV, Irving H, Mohapatra S, Rehm J. Alcohol consumption, unprovoked seizures and epilepsy: a systematic review and meta-analysis. Epilepsia 2010; 51: 1177–84. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224–60. Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 617–27. Rathlev NK, Ulrich AS, Delanty N, D’Onofrio D, D’Onofrio G. Alcohol-related seizures. J Emerg Med 2006; 31: 157–63.
Authors’ reply We agree with Andreas Otte and Dieter Riemann on the potential importance of sleep disturbances for triggering suicide in epilepsy. Our population-based study 1 covering 40 years relied on routinely collected patient data from inpatient and outpatient sources according to the International Classification of Diseases (ICD) diagnoses. This approach would under-report sleep problems that would not meet the diagnostic threshold for sleep disorders and, therefore, we are not able to investigate this issue reliably. Torbjörn Tomson and Dale Hesdorffer suggest that the inclusion of status epilecticus might have overestimated odds of mortality associated with epilepsy. We addressed this potential issue in the Article1 by doing a sensitivity analysis of those receiving two or more diagnoses (including for natural causes of mortality, appendix1) and by investigating the effects by diagnostic category of epilepsy. In addition, the contribution of status epilecticus was likely to be small for external causes of death because deaths directly due to status epilecticus were not included. To test this issue further, we
have examined what proportion of patients had one or more diagnoses of status epilecticus without any other epilepsy diagnoses. We did this for ICD-10 diagnoses because classifications were more precise than ICD-8/9. We found that for 359 (3·0%) patients with only one diagnosis, that diagnosis was status epilecticus. For 108 (0·4%) of those with two or more diagnoses, all those diagnoses were status epilecticus. When we excluded these 467 individuals, the results did not change: the revised adjusted odds ratio (aOR) was 17·1 (95% CI 15·9–18·4) for all-cause mortality and 6·1 (5·2–7·0) for external cause mortality, compared with 17·7 (16·4–19·0) for all-cause mortality and 6·4 (5·5–7·3) for external cause mortality including patients with status epilecticus diagnoses (these odds are higher than those reported in the Article because patients with ICD-10 diagnoses were younger than the overall sample of individuals with ICD-8, 9, and 10 diagnoses). Regarding interactions between substance misuse and epilepsy, we found evidence of negative multiplicative interaction for nonvehicle accidents (p=0·003) but not for external causes of death (p=0·273), suicide (p=0·413), or vehicle accidents (p=0·285). Because statistical interaction does not necessarily reflect biological interaction, we need to be cautious when interpreting these interactions. We note with interest Andriy Samokhvalov and Jürgen Rehm’s comments on the importance of alcohol use disorders in epilepsy. Consistent with their findings, alcohol use disorders were indeed more prevalent than other drug use disorders; among patients with substance misuse, 45% had alcohol use disorders only. However, in patients with substance use disorders, drug misuse disorders are common—23% had drug abuse disorders only and the remaining 33% had both alcohol use disorders and drug misuse disorders.
Tim Beddow/Science Photo Library
Seena Fazel and colleagues1 recently assessed premature mortality in patients with epilepsy. We would like to emphasise the specific effect of alcohol in the development of epilepsy and associated mortality. First, on the basis of data presented by Fazel and colleagues,1 the relative risk of development of epilepsy in people with alcohol misuse is 4·95 (95% CI 4·82–5·07), which corroborates the results of our meta-analysis on alcoholrelated epileptogenesis.2 Second, Fazel and colleagues’ study1 shows the role of comorbid substance use disorders in premature mortality. Substance use disorders were associated with the highest overall risk of premature mortality (adjusted odds ratio [aOR] 22·4, 95% CI 18·3–27·3), the only psychiatric comorbidity associated with increased risk of fatal vehicle accidents (aOR 3·1, 95% CI 1·7–5·5), and associated with an increased risk of suicide similar to that of depression. Although no separate data for alcohol use disorders were presented in Fazel and colleagues’ article, 1 most of the substance use disorderattributable deaths were probably related to alcohol because alcohol use disorders represented the majority of substance use disorder cases (76%), in line with other European data.3 In addition, alcohol use disorders are strongly associated with psychiatric comorbidities4 and negatively affect the course of epilepsy.5 Both of these factors contribute to premature mortality in epilepsy. Further research is needed to better understand the effect of alcohol on both development of epilepsy and associated premature mortality. Proper screening for heavy drinking and suitable interventions including treatment of alcohol use disorders are recommended to reduce premature mortality in people with epilepsy.
511
