LETTERS AND REPLIES
PRE-MORBID TYPE 2 DIABETES MELLITUS AS A PROGNOSTIC FACTOR IN AMYOTROPHIC LATERAL SCLEROSIS We read the report by Paganoni and colleagues about the prognostic value of pre-morbid diabetes mellitus type 2 (DM2) in amyotrophic lateral sclerosis (ALS)1 with interest, because we previously reported that DM2 is “protective” ALS.2 Their study has several important differences from ours and hence reaches a different conclusion. First, our study had a larger sample size and included all patients with ALS versus only those enrolled in clinical trials. Second, we examined records for glucose laboratory measures/hypoglycemic agents to screen for DM2 (Table 1). Third, we also tested for age of ALS onset, which was delayed 4 years in patients with DM2, suggesting a “protective” effect of DM2 on developing ALS.2 Paganoni et al. did not investigate the effect of DM2 on age of ALS onset, yet reached the conclusion that “Pre-morbid DM2 is not a prognostic factor in ALS.”1 Fourth, Paganoni et al. found that difference in rate of disease progression between patients with and without DM2 to be 20.168 (confidence limits 20.010 to 20.348, P 5 0.07) in the unadjusted analysis and 20.157 (confidence limits 20.018 to 20.332, P 5 0.08) in the analysis adjusted for baseline body mass index (BMI).1 When confidence intervals do not cross 0, the data are typically considered significant. Similarly, the reported P-values of 0.07 and 0.08 are typically considered “trends toward significance.” Confidence limits are also generally agreed to be superior to P-values as they indicate the direction and size of the treatment effect.3 Thus, based on their reported confidence limits, the ALS patients with DM2 would appear to have a slower rate of disease progression in their cohort.1 Similarly, Paganoni and colleagues demonstrated that the prevalence of DM2 in their ALS cohort was half (5.4%) of the expected rate (11.3%), which is in agreement with our finding (7.4%) and supports the suggestion of a “protective” effect of DM2 on ALS.2 They also suggested that diabetics may have been excluded from
their cohort due to DM2-related complications; however, without reporting the number of subjects excluded, the role of sampling bias cannot be ascertained. Moreover, if there was a “selection bias,” it supports a concern about the generalizability of their findings. Finally, the references cited by Paganoni et al. and their interpretations appear to be incomplete,1 including the absence of our study, which was largest on the topic.2 Similarly, the authors indicated that “a recent population based, case–control study from Sweden suggested that pre-morbid diabetes is associated inversely with ALS risk, which is in line with our findings.”1 However, that study showed the risk of ALS was lower in older patients with a history of DM2.4 After considering the methodologic differences, it appears that the Paganoni et al. study1 may actually be in agreement with studies supporting a “protective” effect of DM2 on ALS.2,5,6 Future studies on this important topic should employ stringent statistical analyses, include all ALS patients, and compare their findings to the full body of existing literature on the subject while reaching a conclusion regarding the prognostic value of DM2 in ALS.
Table 1. Methodological differences between studies examining prognostic value of pre-morbid DM2 in ALS. Jawaid et al.1 (2010) Sample size (n) Sites Participants
Screening for pre-morbid DM2
Age of onset
C 2015 Wiley Periodicals, Inc. V
690
Letters to the Editor
2,371 One tertiary care center All patients with possible or probable ALS Review of history, laboratory investigations, and medication records
Delayed 4 years (P < 0.02)
Paganoni et al.2 (2015) 1,322 Multiple centers Selected patients participating in 6 ALS clinical trials Patient interviews, which can be subject to recall bias, could be influenced by cognitive impairment in ALS,2 and may not capture “unlabeled” DM2 Not tested
ALS, amyotrophic lateral sclerosis; DM2, diabetes mellitus type 2.
MUSCLE & NERVE
October 2015
Ali Jawaid, MBBS1 Paul E. Schulz, MD2 1
Brain Research Institute, University of Zurich/Swiss Federal Institute of Technology, Zurich, Switzerland Department of Neurology, University of Texas Health Science Center at Houston, Houston, Texas, USA
2
1. Paganoni S, Hyman T, Shui A, Allred P, Harms M, Liu J. et al. Pre-morbid type 2 diabetes mellitus is not a prognostic factor in ALS. Muscle Nerve (to be published). 2. Jawaid A, Salamone AR, Strutt AM, Murthy SB, Wheaton M, McDowell EJ, et al. ALS disease onset may occur later in patients with pre-morbid diabetes mellitus. Eur J Neurol 2010;17:733–739. 3. Sedgwick P. Confidence intervals, P values, and statistical significance. BMJ 2015;250:h1113. 4. Mariosa D, Kamel F, Bellocco R, Ye W, Fang F. Association between diabetes and amyotrophic lateral sclerosis in Sweden. Eur J Neurol (to be published). 5. Jawaid A, Brown JA, Schulz PE. Diabetes mellitus in amyotrophic lateral sclerosis: Dr Jekyll or Mr Hyde? Eur J Neurol (to be published). 6. Jawaid A, Paganoni S, Hauser C, Schulz PE. Trials of antidiabetic drugs in amyotrophic lateral sclerosis: proceed with caution? Neurodegen Dis 2014;13:205–208.
Published online 3 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24758
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REPLY We thank Drs. Jawaid and Schulz for their interest in our study, and we are pleased that the role of metabolism is an area of great interest in the field of amyotrophic lateral scleorsis (ALS). While the primary goal of our study was to analyze the effect of pre-morbid diabetes mellitus type 2 (DM2) on ALS prognosis, we also found a lower-than-expected prevalence of DM2 in our study population. This was true not only in our clinical trials cohorts (where one might argue that the low prevalence of DM2 is secondary to exclusion criteria that may indirectly affect enrollment of diabetics), but also in our clinic-based cohorts. Thus, we postulated a protective effect of DM2 on ALS risk and concluded that, “the low DM2 prevalence rate should be examined in a large, prospective study to determine whether DM2 affects ALS risk”—that is, in studies that are designed to answer questions related to risk of disease. Interestingly, in line with our findings, recent, large, population-based Swedish and American studies1,2 suggested that DM2 is indeed a protective factor for ALS risk. This growing body of literature is in agreement with Drs. Jawaid and Schulz’s earlier studies, as well as with our study. We apologize for not referencing their study on DM2 and ALS.3 Their work analyzed primarily the impact of DM2 on age of onset of ALS, which was not the focus of our study. They observed a P-value of 0.09 for a delay in the rate of progression of motor symptoms. If we pool that with our P-value of 0.08 the result would be significant and indicate a modest decrease in the rate of progression for patients with DM, but this conclusion should not replace a careful meta-analysis of these and other data on this issue. In response to other comments, we would like to clarify that we did not select a subpopulation of particiLetters to the Editor
pants in the 6 clinical trials. All participants in the trials were included. Their Table 1 also suggests the possibility of recall bias in our population. Although this is possible, a detailed interview and chart review is customary at screening for clinical trial enrollment, which should help mitigate recall bias. As noted above, our findings of lower-than-expected prevalence of DM2 in ALS are consistent with recent population-based studies. In conclusion, our study is in agreement with a growing body of evidence which suggests there is a protective effect of DM2 on ALS risk. Sabrina Paganoni, MD, PhD1 David Schoenfeld, PhD2 Amy Shui, MA2 Merit Cudkowicz, MD, MSc1 Timothy M. Miller, MD, PhD3 1
Harvard Medical School, Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, Massachusetts, USA 2 Massachusetts General Hospital Biostatistics Center, Boston, Massachusetts, USA 3 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA 1. Mariosa D, Kamel F, Bellocco R, Ye W, Fang F. Association between diabetes and amyotrophic lateral sclerosis in Sweden. Eur J Neurol (to be published). 2. Kioumourtzoglou MA, Rotem RS, Seals RM, Gredal O, Hansen J, Weisskopf MG. Diabetes mellitus, obesity, and diagnosis of amyotrophic lateral sclerosis: a population-based study. JAMA Neurol (to be published). 3. Jawaid A, Salamone AR, Strutt AM, Murthy SB, Wheaton M, McDowell EJ, et al. ALS disease onset may occur later in patients with pre-morbid diabetes mellitus. Eur J Neurol 2010;17:733–739.
Published online 3 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24760
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STIMULATED JITTER IN INFANT BOTULISM A word of caution is warranted regarding interpretation of the study by Verma and colleagues.1 The normative values cited in their study were obtained from adults, using recording parameters different from those used by the authors.2 Normative jitter values are not available for infants, and published reports have shown that neuromuscular transmission in neonates and infants is significantly different from that of adults.3,4 Thus, jitter in infants and young children should be considered abnormal only if the mean jitter is markedly increased, and it is more convincing if there is blocking in at least 10% of potentials. In an earlier study of 4 patients with infant botulism, jitter measured with SFEMG electrodes in a hand muscle during stimulation exceeded 90 ls in all fibers reported,5 whereas the mean jitter in the orbicularis oculi in the patient reported by Verma et al. was 42 ls, with blocking in only 7% of potentials. Finally, if jitter is measured with concentric needle electrodes, it is recommended that the electrode with the smallest recording surface be used, and with the high-pass filter set at 1,000 HZ, so that signal quality can be assessed to assure that jitter is measured only from visibly demonstrable apparent single muscle fiber action potentials.6,7 MUSCLE & NERVE
October 2015
691
PRE-MORBID TYPE 2 DIABETES MELLITUS AS A PROGNOSTIC FACTOR IN AMYOTROPHIC LATERAL SCLEROSIS We read the report by Paganoni and colleagues about the prognostic value of pre-morbid diabetes mellitus type 2 (DM2) in amyotrophic lateral sclerosis (ALS)1 with interest, because we previously reported that DM2 is “protective” ALS.2 Their study has several important differences from ours and hence reaches a different conclusion. First, our study had a larger sample size and included all patients with ALS versus only those enrolled in clinical trials. Second, we examined records for glucose laboratory measures/hypoglycemic agents to screen for DM2 (Table 1). Third, we also tested for age of ALS onset, which was delayed 4 years in patients with DM2, suggesting a “protective” effect of DM2 on developing ALS.2 Paganoni et al. did not investigate the effect of DM2 on age of ALS onset, yet reached the conclusion that “Pre-morbid DM2 is not a prognostic factor in ALS.”1 Fourth, Paganoni et al. found that difference in rate of disease progression between patients with and without DM2 to be 20.168 (confidence limits 20.010 to 20.348, P 5 0.07) in the unadjusted analysis and 20.157 (confidence limits 20.018 to 20.332, P 5 0.08) in the analysis adjusted for baseline body mass index (BMI).1 When confidence intervals do not cross 0, the data are typically considered significant. Similarly, the reported P-values of 0.07 and 0.08 are typically considered “trends toward significance.” Confidence limits are also generally agreed to be superior to P-values as they indicate the direction and size of the treatment effect.3 Thus, based on their reported confidence limits, the ALS patients with DM2 would appear to have a slower rate of disease progression in their cohort.1 Similarly, Paganoni and colleagues demonstrated that the prevalence of DM2 in their ALS cohort was half (5.4%) of the expected rate (11.3%), which is in agreement with our finding (7.4%) and supports the suggestion of a “protective” effect of DM2 on ALS.2 They also suggested that diabetics may have been excluded from
their cohort due to DM2-related complications; however, without reporting the number of subjects excluded, the role of sampling bias cannot be ascertained. Moreover, if there was a “selection bias,” it supports a concern about the generalizability of their findings. Finally, the references cited by Paganoni et al. and their interpretations appear to be incomplete,1 including the absence of our study, which was largest on the topic.2 Similarly, the authors indicated that “a recent population based, case–control study from Sweden suggested that pre-morbid diabetes is associated inversely with ALS risk, which is in line with our findings.”1 However, that study showed the risk of ALS was lower in older patients with a history of DM2.4 After considering the methodologic differences, it appears that the Paganoni et al. study1 may actually be in agreement with studies supporting a “protective” effect of DM2 on ALS.2,5,6 Future studies on this important topic should employ stringent statistical analyses, include all ALS patients, and compare their findings to the full body of existing literature on the subject while reaching a conclusion regarding the prognostic value of DM2 in ALS.
Table 1. Methodological differences between studies examining prognostic value of pre-morbid DM2 in ALS. Jawaid et al.1 (2010) Sample size (n) Sites Participants
Screening for pre-morbid DM2
Age of onset
C 2015 Wiley Periodicals, Inc. V
690
Letters to the Editor
2,371 One tertiary care center All patients with possible or probable ALS Review of history, laboratory investigations, and medication records
Delayed 4 years (P < 0.02)
Paganoni et al.2 (2015) 1,322 Multiple centers Selected patients participating in 6 ALS clinical trials Patient interviews, which can be subject to recall bias, could be influenced by cognitive impairment in ALS,2 and may not capture “unlabeled” DM2 Not tested
ALS, amyotrophic lateral sclerosis; DM2, diabetes mellitus type 2.
MUSCLE & NERVE
October 2015
Ali Jawaid, MBBS1 Paul E. Schulz, MD2 1
Brain Research Institute, University of Zurich/Swiss Federal Institute of Technology, Zurich, Switzerland Department of Neurology, University of Texas Health Science Center at Houston, Houston, Texas, USA
2
1. Paganoni S, Hyman T, Shui A, Allred P, Harms M, Liu J. et al. Pre-morbid type 2 diabetes mellitus is not a prognostic factor in ALS. Muscle Nerve (to be published). 2. Jawaid A, Salamone AR, Strutt AM, Murthy SB, Wheaton M, McDowell EJ, et al. ALS disease onset may occur later in patients with pre-morbid diabetes mellitus. Eur J Neurol 2010;17:733–739. 3. Sedgwick P. Confidence intervals, P values, and statistical significance. BMJ 2015;250:h1113. 4. Mariosa D, Kamel F, Bellocco R, Ye W, Fang F. Association between diabetes and amyotrophic lateral sclerosis in Sweden. Eur J Neurol (to be published). 5. Jawaid A, Brown JA, Schulz PE. Diabetes mellitus in amyotrophic lateral sclerosis: Dr Jekyll or Mr Hyde? Eur J Neurol (to be published). 6. Jawaid A, Paganoni S, Hauser C, Schulz PE. Trials of antidiabetic drugs in amyotrophic lateral sclerosis: proceed with caution? Neurodegen Dis 2014;13:205–208.
Published online 3 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24758
---------------------------------------------------------
REPLY We thank Drs. Jawaid and Schulz for their interest in our study, and we are pleased that the role of metabolism is an area of great interest in the field of amyotrophic lateral scleorsis (ALS). While the primary goal of our study was to analyze the effect of pre-morbid diabetes mellitus type 2 (DM2) on ALS prognosis, we also found a lower-than-expected prevalence of DM2 in our study population. This was true not only in our clinical trials cohorts (where one might argue that the low prevalence of DM2 is secondary to exclusion criteria that may indirectly affect enrollment of diabetics), but also in our clinic-based cohorts. Thus, we postulated a protective effect of DM2 on ALS risk and concluded that, “the low DM2 prevalence rate should be examined in a large, prospective study to determine whether DM2 affects ALS risk”—that is, in studies that are designed to answer questions related to risk of disease. Interestingly, in line with our findings, recent, large, population-based Swedish and American studies1,2 suggested that DM2 is indeed a protective factor for ALS risk. This growing body of literature is in agreement with Drs. Jawaid and Schulz’s earlier studies, as well as with our study. We apologize for not referencing their study on DM2 and ALS.3 Their work analyzed primarily the impact of DM2 on age of onset of ALS, which was not the focus of our study. They observed a P-value of 0.09 for a delay in the rate of progression of motor symptoms. If we pool that with our P-value of 0.08 the result would be significant and indicate a modest decrease in the rate of progression for patients with DM, but this conclusion should not replace a careful meta-analysis of these and other data on this issue. In response to other comments, we would like to clarify that we did not select a subpopulation of particiLetters to the Editor
pants in the 6 clinical trials. All participants in the trials were included. Their Table 1 also suggests the possibility of recall bias in our population. Although this is possible, a detailed interview and chart review is customary at screening for clinical trial enrollment, which should help mitigate recall bias. As noted above, our findings of lower-than-expected prevalence of DM2 in ALS are consistent with recent population-based studies. In conclusion, our study is in agreement with a growing body of evidence which suggests there is a protective effect of DM2 on ALS risk. Sabrina Paganoni, MD, PhD1 David Schoenfeld, PhD2 Amy Shui, MA2 Merit Cudkowicz, MD, MSc1 Timothy M. Miller, MD, PhD3 1
Harvard Medical School, Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, Massachusetts, USA 2 Massachusetts General Hospital Biostatistics Center, Boston, Massachusetts, USA 3 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA 1. Mariosa D, Kamel F, Bellocco R, Ye W, Fang F. Association between diabetes and amyotrophic lateral sclerosis in Sweden. Eur J Neurol (to be published). 2. Kioumourtzoglou MA, Rotem RS, Seals RM, Gredal O, Hansen J, Weisskopf MG. Diabetes mellitus, obesity, and diagnosis of amyotrophic lateral sclerosis: a population-based study. JAMA Neurol (to be published). 3. Jawaid A, Salamone AR, Strutt AM, Murthy SB, Wheaton M, McDowell EJ, et al. ALS disease onset may occur later in patients with pre-morbid diabetes mellitus. Eur J Neurol 2010;17:733–739.
Published online 3 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24760
---------------------------------------------------------
STIMULATED JITTER IN INFANT BOTULISM A word of caution is warranted regarding interpretation of the study by Verma and colleagues.1 The normative values cited in their study were obtained from adults, using recording parameters different from those used by the authors.2 Normative jitter values are not available for infants, and published reports have shown that neuromuscular transmission in neonates and infants is significantly different from that of adults.3,4 Thus, jitter in infants and young children should be considered abnormal only if the mean jitter is markedly increased, and it is more convincing if there is blocking in at least 10% of potentials. In an earlier study of 4 patients with infant botulism, jitter measured with SFEMG electrodes in a hand muscle during stimulation exceeded 90 ls in all fibers reported,5 whereas the mean jitter in the orbicularis oculi in the patient reported by Verma et al. was 42 ls, with blocking in only 7% of potentials. Finally, if jitter is measured with concentric needle electrodes, it is recommended that the electrode with the smallest recording surface be used, and with the high-pass filter set at 1,000 HZ, so that signal quality can be assessed to assure that jitter is measured only from visibly demonstrable apparent single muscle fiber action potentials.6,7 MUSCLE & NERVE
October 2015
691
