Letters
Corresponding Author: Hongliang Zhang, MD, PhD, Department of Neurology, The First Hospital of Jilin University, Jilin University, Xinmin St 71, 130021 Changchun, China ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by grants from the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry; the National Natural Science Foundation of China (grant 81241147); and The First Hospital of Jilin University. Role of the Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. 1. Kitley J, Waters P, Woodhall M, et al. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol. 2014;71(3):276-283. 2. Weinshenker BG. Neuromyelitis optica is distinct from multiple sclerosis. Arch Neurol. 2007;64(6):899-901. 3. Papadopoulos MC, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol. 2012;11(6):535-544. 4. Kim W, Kim SH, Huh SY, Kim HJ. Brain abnormalities in neuromyelitis optica spectrum disorder [published online December 3, 2012]. Mult Scler Int. doi:10.1155/2012/735486. 5. Jarius S, Wandinger KP, Borowski K, Stoecker W, Wildemann B. Antibodies to CV2/CRMP5 in neuromyelitis optica-like disease: case report and review of the literature. Clin Neurol Neurosurg. 2012;114(4):331-335.
In Reply We thank Gao and colleagues for their comments regarding our article.1 We agree that the spectrum of neuromyelitis optica (NMO) is much wider than originally thought and that it is now recognized that the term NMO is not synonymous with aquaporin-4 antibody (AQP4-Ab) disease. In our experience, the presence of AQP4-Ab indicates a generally severe, frequently relapsing central nervous system inflammatory disease and we manage AQP4-Ab–positive patients with early and long-term immunosuppression regardless of the clinical phenotype. Conversely, patients referred to our UK AQP4-Ab assay service and those seen within our specialist clinical NMO service are a heterogeneous group, despite many having features considered typical of NMO such as longitudinally extensive transverse myelitis or severe/bilateral optic neuritis. We consider AQP4Ab–negative patients separately from those with AQP4-Ab, even if fulfilling diagnostic criteria for NMO. In general, we treat such patients less aggressively but their management is difficult because of the clinical heterogeneity. Myelinoligodendrocyte glycoprotein Abs appear to offer an alternative biomarker in patients presenting with features of NMO and its spectrum who are negative for AQP4-Ab and this biomarker appears to be helpful in making decisions regarding patient management and prognosis. We agree that the current NMO diagnostic criteria need updating to reflect the fact that AQP4-Ab–negative NMO/NMO spectrum disorder is not a clear entity and that such patients should be considered separately from those with AQP4-Ab disease. Joanna Kitley, BMBS Patrick Waters, PhD Angela Vincent, FRS Jacqueline Palace, DM Author Affiliations: Nuffield Department of Clinical Neurosciences, Oxford University Hospitals NHS Trust, University of Oxford, Oxford, England. 924
Corresponding Author: Jacqueline Palace, DM, Nuffield Department of Clinical Neurosciences, Level 3 West Wing, Oxford University Hospitals NHS Trust, University of Oxford, Headley Way, Oxford OX3 9DU, England (jacqueline [email protected]). Conflict of Interest Disclosures: None reported. 1. Kitley J, Waters P, Woodhall M, et al. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol. 2014;71(3):276-283.
Moving to Fingolimod From Natalizumab in Multiple Sclerosis: The ENIGM Is Not Solved To the Editor Cohen et al1 reported the efficacy and safety results of switching from natalizumab to fingolimod in patients with multiple sclerosis in a real-practice setting in the ENIGM (Enquête Nationale sur I’Introduction du Fingolimod en Relais au Natalizumab) study. We read the article with great interest; however, we are afraid that some of the presented results may not be conclusively supported by the analyses that were performed. First, a washout period of fewer than 3 months was in multivariate analysis an independent predictor of relapse during the washout period. Why did the authors not compare patients based on the duration of the washout (3 months) rather than just on the presence or absence of relapse? This would clarify whether the risk for relapse during fingolimod therapy is lower for shorter durations of washout, as suggested by the study of de Seze and colleagues.2 Second, the authors concluded that multiple sclerosis disease activity in a subgroup of patients was greater during the washout period but not after fingolimod initiation. As reported by the authors, the analysis was conducted after a period of treatment with fingolimod of only 6 months, and for as much as 31% of patients (103 of 333), there were no data on relapse during fingolimod treatment. Nevertheless, the proportion of patients with relapse while taking fingolimod (20%) was calculated including the 103 patients whose data were not available. And Table 3 of their article1 did not declare the number of cases that made up the groups of relapsing and nonrelapsing patients on which the statistical analysis was made. Moreover, the impact of multiple recurrences in the same patient or the time to first recurrence were not analyzed. Although we believe there is indeed a causal relationship between washout period and increased risk for relapse, on the basis of the data presented, it cannot be excluded that the duration of washout has no impact on the risk for relapse during treatment with fingolimod. In fact, natalizumab is detectable in the serum of patients for up to 8 weeks after the last intravenous infusion,3 while plasma concentrations of fingolimod reach steady state about 2 months after starting therapy.4 A shorter, or even absent, washout period could have a positive impact not only on the risk for relapse during the washout period, but also during fingolimod treatment. This question could be finally resolved only by a randomized intervention study comparing 2 different durations of the washout period in terms of both efficacy and safety. Assunta Bianco, MD Paolo Maria Rossini, MD Massimiliano Mirabella, PhD
JAMA Neurology July 2014 Volume 71, Number 7
Copyright 2014 American Medical Association. All rights reserved.
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Letters
Author Affiliations: Institute of Neurology, Catholic University, Rome, Italy. Corresponding Author: Assunta Bianco, MD, Institute of Neurology, Department of Geriatrics, Neurosciences and Orthopaedics, Catholic University, School of Medicine A. Gemelli, Largo Agostino Gemelli 8, 00168 Rome, Italy ([email protected]). Conflict of Interest Disclosures: None reported. 1. Cohen M, Maillart E, Tourbah A, et al; Club Francophone de la Sclérose en Plaques Investigators. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436-441. 2. de Seze J, Ongagna JC, Collongues N, et al; Alsacep Network. Reduction of the washout time between natalizumab and fingolimod. Mult Scler. 2013;19(9): 1248. 3. Stüve O, Cravens PD, Frohman EM, et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology. 2009;72 (5):396-401. 4. Kahan BD, Karlix JL, Ferguson RM, et al. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation. 2003;76(7):1079-1084.
In Reply We read with attention comments from Bianco et al regarding the ENIGM (Enquête Nationale sur I’Introduction du Fingolimod en Relais au Natalizumab) study. In our statistical analysis, the main outcome was the presence of clinical disease reactivation (occurrence of at least 1 relapse) during the switching period. We first analyzed the washout then the fingolimod initiation period during a 6-month follow-up.1 Regarding washout, our results revealed an important reduction of disease reactivation rates for patients with washout duration shorter than 3 months (odds ratio, 0.23; P < .01). This result seems highly significant both in univariate and multivariate analyses. Regarding initiation of fingolimod, 230 patients reached the 6-month follow-up end point when the analysis was conducted. However, among patients who had not reached this end point, some had already relapsed and that is why the result (20%) was reported among the whole cohort. Furthermore, statistical analysis for this period was conducted comparing all patients who experienced at least 1 relapse while taking fingolimod compared with the patients who reached 6-month follow-up without any relapse. We did not collect either data about multiple recurrences nor the precise time to first relapse in our study. Finally, Bianco et al suggested that a randomized intervention study could give more relevant results about the safety and efficacy of switching from natalizumab to fingolimod. We would like to underline the results of the TOFINGO Study2 that were presented at the 2013 European Committee for Treatment and Research in Multiple Sclerosis Annual Meeting. The TOFINGO Study was a rater- and patient-blind, randomized study that compared the safety and efficacy of 3 different washout durations (8, 12, or 16 weeks) in a cohort of 142 patients. The main outcome was the presence of radiologic signs of disease reactivation and follow-up duration during fingolimod treatment of 32 weeks. The results showed that the patients in the 16-week washout group had a significantly higher risk for disease reactivation compared with the 2 other groups. No statistical difference was found
between 8-week and 12-week washout regimens either in efficacy or toxicity. Those results, which were not available at the time of submission of our article, are fairly similar to our findings in the ENIGM study. Mikael Cohen, MD Christine Lebrun, MD, PhD Author Affiliations: Department of Neurology, University Hospital of Nice, Nice, France. Corresponding Author: Mikael Cohen, MD, Department of Neurology, University Hospital of Nice, 30 Voie Romaine, 06000 Nice, France (cohen.m @chu-nice.fr). Conflict of Interest Disclosures: None reported. 1. Cohen M, Maillart E, Tourbah A, et al; Club Francophone de la Sclérose en Plaques Investigators. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436-441. 2. Kappos L, Radue EW, Comi G, et al. Disease control and safety in relapsing-remitting multiple sclerosis (RRMS) patients switching from natalizumab to fingolimod: a 32-week, rater- and patient-blind, randomized, parallel-group study (TOFINGO). Abstract No. 167. Paper presented at the 2013 European Committee for Treatment and Research in Multiple Sclerosis Annual Meeting; October 2-5, 2013; Copenhagen, Denmark.
Tau, S-100 Calcium-Binding Protein B, and NeuronSpecific Enolase as Biomarkers of Concussion To the Editor That the Quanterix platform was able to detect elevated levels of tau at subfentamole concentrations after sports-related concussion is indeed an exciting development in the article by Shahim and colleagues.1 However, the conclusion made by Shahim et al,1 and by the accompanying editorial,2 that S-100 calcium-binding protein B (S-100B) and neuron-specific enolase (NSE) lack use as diagnostic markers is flawed for several reasons. Shahim et al1 compared postconcussion marker concentrations in 1 subset of athletes with preinjury concentrations in an independent subset from the same ice hockey league, preventing the authors from uncovering significant subjectspecific marker differences. High variation in normal brain structure and function can obscure small but significant changes when groups, rather than individuals, are analyzed. This realization has led to the discovery of concussionrelated changes in cognitive function, cortical activation, and white matter integrity.3 Indeed, Kiechle et al4 previously demonstrated the markedly enhanced diagnostic value of S-100B when postinjury values were compared with baseline values for each athlete. Additionally, there is no biologic rationale for combining marker values from the 4 postinjury time intervals studied (1, 12, 36, and 144 hours). The axonal injury events reflected by changes in the levels of tau, S-100B, and NSE vary from hour to hour postinjury. The lack of a statistical increase in this temporally aggregated postinjury metric was used in the accompanying editorial to cast “serious doubt” on the usefulness of S-100B and an NSE as concussion biomarkers.2 In fact, Shahim et al1 reported that both S-100B and tau were significantly elevated acutely after concussion, which is arguably the most important time for making diagnostic decisions in prehospital, emergency department, playing field, and battlefield settings.
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JAMA Neurology July 2014 Volume 71, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Birmingham User on 06/04/2015
925
Corresponding Author: Hongliang Zhang, MD, PhD, Department of Neurology, The First Hospital of Jilin University, Jilin University, Xinmin St 71, 130021 Changchun, China ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by grants from the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry; the National Natural Science Foundation of China (grant 81241147); and The First Hospital of Jilin University. Role of the Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. 1. Kitley J, Waters P, Woodhall M, et al. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol. 2014;71(3):276-283. 2. Weinshenker BG. Neuromyelitis optica is distinct from multiple sclerosis. Arch Neurol. 2007;64(6):899-901. 3. Papadopoulos MC, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol. 2012;11(6):535-544. 4. Kim W, Kim SH, Huh SY, Kim HJ. Brain abnormalities in neuromyelitis optica spectrum disorder [published online December 3, 2012]. Mult Scler Int. doi:10.1155/2012/735486. 5. Jarius S, Wandinger KP, Borowski K, Stoecker W, Wildemann B. Antibodies to CV2/CRMP5 in neuromyelitis optica-like disease: case report and review of the literature. Clin Neurol Neurosurg. 2012;114(4):331-335.
In Reply We thank Gao and colleagues for their comments regarding our article.1 We agree that the spectrum of neuromyelitis optica (NMO) is much wider than originally thought and that it is now recognized that the term NMO is not synonymous with aquaporin-4 antibody (AQP4-Ab) disease. In our experience, the presence of AQP4-Ab indicates a generally severe, frequently relapsing central nervous system inflammatory disease and we manage AQP4-Ab–positive patients with early and long-term immunosuppression regardless of the clinical phenotype. Conversely, patients referred to our UK AQP4-Ab assay service and those seen within our specialist clinical NMO service are a heterogeneous group, despite many having features considered typical of NMO such as longitudinally extensive transverse myelitis or severe/bilateral optic neuritis. We consider AQP4Ab–negative patients separately from those with AQP4-Ab, even if fulfilling diagnostic criteria for NMO. In general, we treat such patients less aggressively but their management is difficult because of the clinical heterogeneity. Myelinoligodendrocyte glycoprotein Abs appear to offer an alternative biomarker in patients presenting with features of NMO and its spectrum who are negative for AQP4-Ab and this biomarker appears to be helpful in making decisions regarding patient management and prognosis. We agree that the current NMO diagnostic criteria need updating to reflect the fact that AQP4-Ab–negative NMO/NMO spectrum disorder is not a clear entity and that such patients should be considered separately from those with AQP4-Ab disease. Joanna Kitley, BMBS Patrick Waters, PhD Angela Vincent, FRS Jacqueline Palace, DM Author Affiliations: Nuffield Department of Clinical Neurosciences, Oxford University Hospitals NHS Trust, University of Oxford, Oxford, England. 924
Corresponding Author: Jacqueline Palace, DM, Nuffield Department of Clinical Neurosciences, Level 3 West Wing, Oxford University Hospitals NHS Trust, University of Oxford, Headley Way, Oxford OX3 9DU, England (jacqueline [email protected]). Conflict of Interest Disclosures: None reported. 1. Kitley J, Waters P, Woodhall M, et al. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol. 2014;71(3):276-283.
Moving to Fingolimod From Natalizumab in Multiple Sclerosis: The ENIGM Is Not Solved To the Editor Cohen et al1 reported the efficacy and safety results of switching from natalizumab to fingolimod in patients with multiple sclerosis in a real-practice setting in the ENIGM (Enquête Nationale sur I’Introduction du Fingolimod en Relais au Natalizumab) study. We read the article with great interest; however, we are afraid that some of the presented results may not be conclusively supported by the analyses that were performed. First, a washout period of fewer than 3 months was in multivariate analysis an independent predictor of relapse during the washout period. Why did the authors not compare patients based on the duration of the washout (3 months) rather than just on the presence or absence of relapse? This would clarify whether the risk for relapse during fingolimod therapy is lower for shorter durations of washout, as suggested by the study of de Seze and colleagues.2 Second, the authors concluded that multiple sclerosis disease activity in a subgroup of patients was greater during the washout period but not after fingolimod initiation. As reported by the authors, the analysis was conducted after a period of treatment with fingolimod of only 6 months, and for as much as 31% of patients (103 of 333), there were no data on relapse during fingolimod treatment. Nevertheless, the proportion of patients with relapse while taking fingolimod (20%) was calculated including the 103 patients whose data were not available. And Table 3 of their article1 did not declare the number of cases that made up the groups of relapsing and nonrelapsing patients on which the statistical analysis was made. Moreover, the impact of multiple recurrences in the same patient or the time to first recurrence were not analyzed. Although we believe there is indeed a causal relationship between washout period and increased risk for relapse, on the basis of the data presented, it cannot be excluded that the duration of washout has no impact on the risk for relapse during treatment with fingolimod. In fact, natalizumab is detectable in the serum of patients for up to 8 weeks after the last intravenous infusion,3 while plasma concentrations of fingolimod reach steady state about 2 months after starting therapy.4 A shorter, or even absent, washout period could have a positive impact not only on the risk for relapse during the washout period, but also during fingolimod treatment. This question could be finally resolved only by a randomized intervention study comparing 2 different durations of the washout period in terms of both efficacy and safety. Assunta Bianco, MD Paolo Maria Rossini, MD Massimiliano Mirabella, PhD
JAMA Neurology July 2014 Volume 71, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Birmingham User on 06/04/2015
jamaneurology.com
Letters
Author Affiliations: Institute of Neurology, Catholic University, Rome, Italy. Corresponding Author: Assunta Bianco, MD, Institute of Neurology, Department of Geriatrics, Neurosciences and Orthopaedics, Catholic University, School of Medicine A. Gemelli, Largo Agostino Gemelli 8, 00168 Rome, Italy ([email protected]). Conflict of Interest Disclosures: None reported. 1. Cohen M, Maillart E, Tourbah A, et al; Club Francophone de la Sclérose en Plaques Investigators. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436-441. 2. de Seze J, Ongagna JC, Collongues N, et al; Alsacep Network. Reduction of the washout time between natalizumab and fingolimod. Mult Scler. 2013;19(9): 1248. 3. Stüve O, Cravens PD, Frohman EM, et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology. 2009;72 (5):396-401. 4. Kahan BD, Karlix JL, Ferguson RM, et al. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation. 2003;76(7):1079-1084.
In Reply We read with attention comments from Bianco et al regarding the ENIGM (Enquête Nationale sur I’Introduction du Fingolimod en Relais au Natalizumab) study. In our statistical analysis, the main outcome was the presence of clinical disease reactivation (occurrence of at least 1 relapse) during the switching period. We first analyzed the washout then the fingolimod initiation period during a 6-month follow-up.1 Regarding washout, our results revealed an important reduction of disease reactivation rates for patients with washout duration shorter than 3 months (odds ratio, 0.23; P < .01). This result seems highly significant both in univariate and multivariate analyses. Regarding initiation of fingolimod, 230 patients reached the 6-month follow-up end point when the analysis was conducted. However, among patients who had not reached this end point, some had already relapsed and that is why the result (20%) was reported among the whole cohort. Furthermore, statistical analysis for this period was conducted comparing all patients who experienced at least 1 relapse while taking fingolimod compared with the patients who reached 6-month follow-up without any relapse. We did not collect either data about multiple recurrences nor the precise time to first relapse in our study. Finally, Bianco et al suggested that a randomized intervention study could give more relevant results about the safety and efficacy of switching from natalizumab to fingolimod. We would like to underline the results of the TOFINGO Study2 that were presented at the 2013 European Committee for Treatment and Research in Multiple Sclerosis Annual Meeting. The TOFINGO Study was a rater- and patient-blind, randomized study that compared the safety and efficacy of 3 different washout durations (8, 12, or 16 weeks) in a cohort of 142 patients. The main outcome was the presence of radiologic signs of disease reactivation and follow-up duration during fingolimod treatment of 32 weeks. The results showed that the patients in the 16-week washout group had a significantly higher risk for disease reactivation compared with the 2 other groups. No statistical difference was found
between 8-week and 12-week washout regimens either in efficacy or toxicity. Those results, which were not available at the time of submission of our article, are fairly similar to our findings in the ENIGM study. Mikael Cohen, MD Christine Lebrun, MD, PhD Author Affiliations: Department of Neurology, University Hospital of Nice, Nice, France. Corresponding Author: Mikael Cohen, MD, Department of Neurology, University Hospital of Nice, 30 Voie Romaine, 06000 Nice, France (cohen.m @chu-nice.fr). Conflict of Interest Disclosures: None reported. 1. Cohen M, Maillart E, Tourbah A, et al; Club Francophone de la Sclérose en Plaques Investigators. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436-441. 2. Kappos L, Radue EW, Comi G, et al. Disease control and safety in relapsing-remitting multiple sclerosis (RRMS) patients switching from natalizumab to fingolimod: a 32-week, rater- and patient-blind, randomized, parallel-group study (TOFINGO). Abstract No. 167. Paper presented at the 2013 European Committee for Treatment and Research in Multiple Sclerosis Annual Meeting; October 2-5, 2013; Copenhagen, Denmark.
Tau, S-100 Calcium-Binding Protein B, and NeuronSpecific Enolase as Biomarkers of Concussion To the Editor That the Quanterix platform was able to detect elevated levels of tau at subfentamole concentrations after sports-related concussion is indeed an exciting development in the article by Shahim and colleagues.1 However, the conclusion made by Shahim et al,1 and by the accompanying editorial,2 that S-100 calcium-binding protein B (S-100B) and neuron-specific enolase (NSE) lack use as diagnostic markers is flawed for several reasons. Shahim et al1 compared postconcussion marker concentrations in 1 subset of athletes with preinjury concentrations in an independent subset from the same ice hockey league, preventing the authors from uncovering significant subjectspecific marker differences. High variation in normal brain structure and function can obscure small but significant changes when groups, rather than individuals, are analyzed. This realization has led to the discovery of concussionrelated changes in cognitive function, cortical activation, and white matter integrity.3 Indeed, Kiechle et al4 previously demonstrated the markedly enhanced diagnostic value of S-100B when postinjury values were compared with baseline values for each athlete. Additionally, there is no biologic rationale for combining marker values from the 4 postinjury time intervals studied (1, 12, 36, and 144 hours). The axonal injury events reflected by changes in the levels of tau, S-100B, and NSE vary from hour to hour postinjury. The lack of a statistical increase in this temporally aggregated postinjury metric was used in the accompanying editorial to cast “serious doubt” on the usefulness of S-100B and an NSE as concussion biomarkers.2 In fact, Shahim et al1 reported that both S-100B and tau were significantly elevated acutely after concussion, which is arguably the most important time for making diagnostic decisions in prehospital, emergency department, playing field, and battlefield settings.
jamaneurology.com
JAMA Neurology July 2014 Volume 71, Number 7
Copyright 2014 American Medical Association. All rights reserved.
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925
