LETTERS/REPLIES
Testicular Hypofunction and Multiple Sclerosis: Cause or Consequence? Claudio Voci, PhD I read with interest the article by Pakpoor and colleagues investigating the risk of hospital admission for multiple sclerosis (MS) after admission for testicular hypofunction.1 Although interesting, the study is far from proving a causal effect of testicular hypofunction on MS risk. Given that there is a negative age-adjusted correlation with testosterone levels and disability,2 it would be interesting if the authors could show that the patients with admissions for testicular hypofunction and then MS did not have any admissions that could be related to MS prior to the testicular hypofunction admission. Furthermore, it would also be of interest to see the risk for testicular hypofunction admission after being admitted for MS. Depending on the results of these investigations, this would shed further light on a causal or consequential role of testosterone in MS.
Potential Conflicts of Interest Nothing to report.
Department of Epidemiology, University of Bologna, Bologna, Italy
References 1.
2.
Pakpoor J, Goldacre R, Schmierer K, et al. Testicular hypofunction and multiple sclerosis risk: a record-linkage study. Ann Neurol 2014 Aug 18. doi: 10.1002/ana.24250. [Epub ahead of print] Bove R, Musallam A, Healy B, Raghavan K, Glanz B, Bakshi R, et al. Low testosterone is associated with disability in men with multiple sclerosis. Mult Scler 2014 Apr 7. [Epub ahead of print]
DOI: 10.1002/ana.24276
Reply Julia Pakpoor, BA,1 Raph Goldacre, BA,2 Klaus Schmierer, MBBS, PhD, FRCP,3,4 Gavin Giovannoni, MD, PhD, FRCP, FRCPath,3,4 and Michael J. Goldacre, FFPH, FRCP2 We thank Dr Voci for his comments on our article reporting that male subjects with testicular hypofunction (TH) have a 5fold higher rate of subsequent multiple sclerosis (MS). The possibility of reverse causality whereby MS may cause TH is an important consideration. However, in all the cases reported by us, the time lapse between the first episode of day-case care or hospital admission for MS occurred at least 1 year after the first episode of day-case care or hospital admission for TH, making a reverse sequence of events unlikely. Furthermore, using the
same methodology and reference cohort as in our original study, we analyzed the data set for the risk of TH following an admission for MS. The rate ratio was 1.07 (95% confidence interval 5 0.43–2.2, p 5 0.98), based on 7 observed and 6.6 expected cases. Dr Voci also felt it important that we demonstrate that patients admitted with TH who were subsequently admitted for MS did not have any prior admissions that could have been related to MS. We agree with Dr Voci and, in our article, we did this by excluding all subjects from the TH cohort who had any episode of day-case care or admission for MS at the same time as, or before, their first admission for TH. In the data here, on MS before TH, a concurrent or previous admission for TH before MS was excluded, thus ensuring that in considering both analyses (TH before MS, and MS before TH) no one was double-counted. Repeating our study using other diagnoses, symptoms, or signs suggestive of MS prior to TH would be a complex undertaking given the considerable variety of ways in which MS can present. We hope our study of an association between TH and subsequent MS stimulates further work to confirm or refute our findings. We cannot establish causation, which would require a different study design, but our findings are consistent with a hypothesis that supports a role for low testosterone levels in the complex causative cascade underlying MS.
Potential Conflicts of Interest All authors declare no conflicts of interest. JP, RG, and MG report no disclosures. KS has received speaking honoraria from, and/or served on advisory boards for Novartis, Biogen, Teva, Merck-Serono and Merck Inc, and has received support for travelling to the AAN 2014 from Genzyme. KS has been supported by a HEFCE Clinical Senior Lectureship. GG serves on scientific advisory boards for Merck Serono and Biogen Idec and Vertex Pharmaceuticals; served on the editorial board of Multiple Sclerosis; has received speaker honoraria from Bayer Schering Pharma, Merck Serono, Biogen Idec, Pfizer Inc, Teva Pharmaceutical Industries Ltd, Vertex Pharmaceuticals, Genzyme Corporation, Ironwood, and Novartis; has served as a consultant for Bayer Schering Pharma, Biogen Idec, GlaxoSmithKline, Merck Serono, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd., UCB, Vertex Pharmaceuticals, GW Pharma, Novartis, and FivePrime; serves on the speakers bureau for Merck Serono; and has received research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, UCB, Merz Pharmaceuticals, LLC, Teva Pharmaceutical Industries Ltd, GW Pharma, and Ironwood.
C 2014 American Neurological Association V 765
ANNALS
of Neurology
1
Oxford University Medical School, John Radcliffe Hospital, Oxford, 2Unit of Health-Care Epidemiology, Nuffield Department of Population Health, University of Oxford, Oxford, 3 Blizard Institute, Queen Mary University of London, Barts and London School of Medicine and Dentistry, London, 4Department of Neurology, Royal London Hospital, Barts Health National Health Service Trust, London, United Kingdom
DOI: 10.1002/ana.24275
Short-Term Risk of Stroke after Dizziness Presentation Li Yang, MD, PhD,1 Harrison X. Bai, MD,2 Xin Zhao, MD,1 Yanqiao Xiao, MD,1 and Liming Tan, MD1 We read with interest a paper published by Kerber et al on the risk of stroke after emergency department presentation of dizziness, vertigo, or imbalance.1 With a median follow-up of 347 days, the authors found that the risk of stroke was low (1.2%, 15 of 1,245), although the majority of the stroke events occurred within 2 days. The design of the study features multiple case capture methods and stroke events identified by merging prospective population-based surveillance studies. We would like to point out that there may be some blurring between cases excluded due to stroke as the cause of index presentation versus those that had a stroke event within 1 to 2 days after the initial dizziness presentation. When a patient initially presented with dizziness that was designated as “nonstroke,” it is highly possible that (1) neurological deficits
in addition to dizziness were too subtle to be recognized; (2) it may be too early for stroke to show up on imaging; and (3) posterior circulation strokes can present as transient isolated brainstem symptoms and are even harder to appreciate on magnetic resonance imaging (MRI).2 Of note, all 6 cases of subsequent stroke events captured within 1 or 2 days in this study were proven by MRI. In contrast, among the 9 cases that occurred later, only 3 showed acute infarction on MRI, so the remaining cases must have been diagnosed by symptoms alone. This indicates that the stroke event may have already existed when the patient initially presented to the emergency department (ED) with dizziness, or some patients may have been missed or misclassified into the exclusion category because only MRI evidence of stroke could be confidently called stroke when the duration between the initial dizziness presentation and the stroke event was so short. This would also explain why vascular stratification was insufficient to identify these cases, although it has been shown to have a high sensitivity in distinguishing cerebrovascular causes of dizziness from other etiologies.3,4 In this article, the authors referred to 2 previous large population-based studies that concurred with the current study on a large proportion of the stroke risk occurring within a short period after initial presentation (Table).5,6 Although Kim et al demonstrated that the incidence of stroke was highest in the first month, the peak was at 15 days.5 In the study by Lee et al, the incidence of subsequent stroke events in patients who presented to the ED with dizziness or vertigo was only slightly higher in the first 6 months than in the second 6 months (1 vs 0.8%).6 In a separate study of hospitalized patients with isolated vertigo, the incidence of stroke was 35%
TABLE 1. Large Studies of Subsequent Stroke Risk of Patients Who Present with Dizziness Symptoms
Study
Setting
Age, yr Chief Complaint
Case Capture
Number of Length of Stroke Timing Patients Follow-up Risk
Kerber ED et al.1
>45
Dizziness, vertigo, or imbalance
Symptom-based 1,245 and ICD-9
347 days
1.20% Most 90-day stroke risk occurred within 2 days
Kim ED et al.5
>18
Dizziness or vertigo
ICD-9
31,159
180 days
0.63% Incidence highest during the first month
Lee Hospitalized All et al.7
Acute isolated ICD-9 vertigo
3,021
4 years
6.10% 35% in the first year and 62% within 2 years
Lee ED et al.6
>18
Dizziness or vertigo
ICD-9
1,118
3 years
3.30% Incidence highest during the first year
Hospitalized >15
Dizziness or vertigo
Diagnosis-based 883 and ICD-9
2 years
1.90%
Our study
ED 5 emergency department; ICD-9 5 International Classification of Disease, 9th Edition.
766
Volume 76, No. 5
Testicular Hypofunction and Multiple Sclerosis: Cause or Consequence? Claudio Voci, PhD I read with interest the article by Pakpoor and colleagues investigating the risk of hospital admission for multiple sclerosis (MS) after admission for testicular hypofunction.1 Although interesting, the study is far from proving a causal effect of testicular hypofunction on MS risk. Given that there is a negative age-adjusted correlation with testosterone levels and disability,2 it would be interesting if the authors could show that the patients with admissions for testicular hypofunction and then MS did not have any admissions that could be related to MS prior to the testicular hypofunction admission. Furthermore, it would also be of interest to see the risk for testicular hypofunction admission after being admitted for MS. Depending on the results of these investigations, this would shed further light on a causal or consequential role of testosterone in MS.
Potential Conflicts of Interest Nothing to report.
Department of Epidemiology, University of Bologna, Bologna, Italy
References 1.
2.
Pakpoor J, Goldacre R, Schmierer K, et al. Testicular hypofunction and multiple sclerosis risk: a record-linkage study. Ann Neurol 2014 Aug 18. doi: 10.1002/ana.24250. [Epub ahead of print] Bove R, Musallam A, Healy B, Raghavan K, Glanz B, Bakshi R, et al. Low testosterone is associated with disability in men with multiple sclerosis. Mult Scler 2014 Apr 7. [Epub ahead of print]
DOI: 10.1002/ana.24276
Reply Julia Pakpoor, BA,1 Raph Goldacre, BA,2 Klaus Schmierer, MBBS, PhD, FRCP,3,4 Gavin Giovannoni, MD, PhD, FRCP, FRCPath,3,4 and Michael J. Goldacre, FFPH, FRCP2 We thank Dr Voci for his comments on our article reporting that male subjects with testicular hypofunction (TH) have a 5fold higher rate of subsequent multiple sclerosis (MS). The possibility of reverse causality whereby MS may cause TH is an important consideration. However, in all the cases reported by us, the time lapse between the first episode of day-case care or hospital admission for MS occurred at least 1 year after the first episode of day-case care or hospital admission for TH, making a reverse sequence of events unlikely. Furthermore, using the
same methodology and reference cohort as in our original study, we analyzed the data set for the risk of TH following an admission for MS. The rate ratio was 1.07 (95% confidence interval 5 0.43–2.2, p 5 0.98), based on 7 observed and 6.6 expected cases. Dr Voci also felt it important that we demonstrate that patients admitted with TH who were subsequently admitted for MS did not have any prior admissions that could have been related to MS. We agree with Dr Voci and, in our article, we did this by excluding all subjects from the TH cohort who had any episode of day-case care or admission for MS at the same time as, or before, their first admission for TH. In the data here, on MS before TH, a concurrent or previous admission for TH before MS was excluded, thus ensuring that in considering both analyses (TH before MS, and MS before TH) no one was double-counted. Repeating our study using other diagnoses, symptoms, or signs suggestive of MS prior to TH would be a complex undertaking given the considerable variety of ways in which MS can present. We hope our study of an association between TH and subsequent MS stimulates further work to confirm or refute our findings. We cannot establish causation, which would require a different study design, but our findings are consistent with a hypothesis that supports a role for low testosterone levels in the complex causative cascade underlying MS.
Potential Conflicts of Interest All authors declare no conflicts of interest. JP, RG, and MG report no disclosures. KS has received speaking honoraria from, and/or served on advisory boards for Novartis, Biogen, Teva, Merck-Serono and Merck Inc, and has received support for travelling to the AAN 2014 from Genzyme. KS has been supported by a HEFCE Clinical Senior Lectureship. GG serves on scientific advisory boards for Merck Serono and Biogen Idec and Vertex Pharmaceuticals; served on the editorial board of Multiple Sclerosis; has received speaker honoraria from Bayer Schering Pharma, Merck Serono, Biogen Idec, Pfizer Inc, Teva Pharmaceutical Industries Ltd, Vertex Pharmaceuticals, Genzyme Corporation, Ironwood, and Novartis; has served as a consultant for Bayer Schering Pharma, Biogen Idec, GlaxoSmithKline, Merck Serono, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd., UCB, Vertex Pharmaceuticals, GW Pharma, Novartis, and FivePrime; serves on the speakers bureau for Merck Serono; and has received research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, UCB, Merz Pharmaceuticals, LLC, Teva Pharmaceutical Industries Ltd, GW Pharma, and Ironwood.
C 2014 American Neurological Association V 765
ANNALS
of Neurology
1
Oxford University Medical School, John Radcliffe Hospital, Oxford, 2Unit of Health-Care Epidemiology, Nuffield Department of Population Health, University of Oxford, Oxford, 3 Blizard Institute, Queen Mary University of London, Barts and London School of Medicine and Dentistry, London, 4Department of Neurology, Royal London Hospital, Barts Health National Health Service Trust, London, United Kingdom
DOI: 10.1002/ana.24275
Short-Term Risk of Stroke after Dizziness Presentation Li Yang, MD, PhD,1 Harrison X. Bai, MD,2 Xin Zhao, MD,1 Yanqiao Xiao, MD,1 and Liming Tan, MD1 We read with interest a paper published by Kerber et al on the risk of stroke after emergency department presentation of dizziness, vertigo, or imbalance.1 With a median follow-up of 347 days, the authors found that the risk of stroke was low (1.2%, 15 of 1,245), although the majority of the stroke events occurred within 2 days. The design of the study features multiple case capture methods and stroke events identified by merging prospective population-based surveillance studies. We would like to point out that there may be some blurring between cases excluded due to stroke as the cause of index presentation versus those that had a stroke event within 1 to 2 days after the initial dizziness presentation. When a patient initially presented with dizziness that was designated as “nonstroke,” it is highly possible that (1) neurological deficits
in addition to dizziness were too subtle to be recognized; (2) it may be too early for stroke to show up on imaging; and (3) posterior circulation strokes can present as transient isolated brainstem symptoms and are even harder to appreciate on magnetic resonance imaging (MRI).2 Of note, all 6 cases of subsequent stroke events captured within 1 or 2 days in this study were proven by MRI. In contrast, among the 9 cases that occurred later, only 3 showed acute infarction on MRI, so the remaining cases must have been diagnosed by symptoms alone. This indicates that the stroke event may have already existed when the patient initially presented to the emergency department (ED) with dizziness, or some patients may have been missed or misclassified into the exclusion category because only MRI evidence of stroke could be confidently called stroke when the duration between the initial dizziness presentation and the stroke event was so short. This would also explain why vascular stratification was insufficient to identify these cases, although it has been shown to have a high sensitivity in distinguishing cerebrovascular causes of dizziness from other etiologies.3,4 In this article, the authors referred to 2 previous large population-based studies that concurred with the current study on a large proportion of the stroke risk occurring within a short period after initial presentation (Table).5,6 Although Kim et al demonstrated that the incidence of stroke was highest in the first month, the peak was at 15 days.5 In the study by Lee et al, the incidence of subsequent stroke events in patients who presented to the ED with dizziness or vertigo was only slightly higher in the first 6 months than in the second 6 months (1 vs 0.8%).6 In a separate study of hospitalized patients with isolated vertigo, the incidence of stroke was 35%
TABLE 1. Large Studies of Subsequent Stroke Risk of Patients Who Present with Dizziness Symptoms
Study
Setting
Age, yr Chief Complaint
Case Capture
Number of Length of Stroke Timing Patients Follow-up Risk
Kerber ED et al.1
>45
Dizziness, vertigo, or imbalance
Symptom-based 1,245 and ICD-9
347 days
1.20% Most 90-day stroke risk occurred within 2 days
Kim ED et al.5
>18
Dizziness or vertigo
ICD-9
31,159
180 days
0.63% Incidence highest during the first month
Lee Hospitalized All et al.7
Acute isolated ICD-9 vertigo
3,021
4 years
6.10% 35% in the first year and 62% within 2 years
Lee ED et al.6
>18
Dizziness or vertigo
ICD-9
1,118
3 years
3.30% Incidence highest during the first year
Hospitalized >15
Dizziness or vertigo
Diagnosis-based 883 and ICD-9
2 years
1.90%
Our study
ED 5 emergency department; ICD-9 5 International Classification of Disease, 9th Edition.
766
Volume 76, No. 5
