Letters
Several limitations of the current study should be considered. First, the sample size was limited (N = 47) and there were fewer carriers than noncarriers, which could contribute to the absence of an association in APOE-ε4– positive individuals. Second, linear regression models were conducted for several predictor variables (TL, telomerase, and telomerase to TL ratio) after partialing out variance attributable to several potential confounders (ie, age, BMI, and years of education), thus constraining the degrees of freedom for each model. Moving forward, it will be critical to extend these findings to a larger cohort to determine the robustness of the model and generalizability. Chronic exposure to inflammatory cytokines, oxidative stress, and glucocorticoids can accelerate telomere shortening and lead to hippocampal atrophy, 7 suggesting common pathways through which markers of telomere maintenance could reflect hippocampal integrity. Examining these pathways in greater depth will advance our understanding of the extent to which alterations in telomerase activity and TL reflect, or perhaps drive, age-related neural deficits.
Permanente), for managerial and analytic support. They did not receive compensation from a funding sponsor. 1. Honig LS, Kang MS, Schupf N, Lee JH, Mayeux R. Association of shorter leukocyte telomere repeat length with dementia and mortality. Arch Neurol. 2012;69(10):1332-1339. 2. Jaskelioff M, Muller FL, Paik JH, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2011;469(7328):102-106. 3. Rasgon NL, Kenna HA, Wroolie TE, et al. Insulin resistance and hippocampal volume in women at risk for Alzheimer’s disease. Neurobiol Aging. 2011;32(11): 1942-1948. 4. Jacobs EG, Kroenke C, Lin J, et al. Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use. PLoS One. 2013;8(2):e54713. 5. Lin J, Kroenke CH, Epel E, et al. Greater endogenous estrogen exposure is associated with longer telomeres in postmenopausal women at risk for cognitive decline. Brain Res. 2011;1379:224-231. 6. Beery AK, Lin J, Biddle JS, Francis DD, Blackburn EH, Epel ES. Chronic stress elevates telomerase activity in rats. Biol Lett. 2012;8(6):1063-1066. 7. Wolkowitz OM, Epel ES, Reus VI, Mellon SH. Depression gets old fast: do stress and depression accelerate cell aging? Depress Anxiety. 2010;27(4):327-338.
COMMENT & RESPONSE
Features of Neuromyelitis Optica Spectrum Disorders With Aquaporin-4 and MyelinOligodendrocyte Glycoprotein Antibodies
Emily G. Jacobs, PhD Elissa S. Epel, PhD Jue Lin, PhD Elizabeth H. Blackburn, PhD Natalie L. Rasgon, MD, PhD Author Affiliations: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (Jacobs); Department of Psychiatry, University of California, San Francisco (Epel); Department of Biochemistry and Biophysics, University of California, San Francisco (Lin, Blackburn); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California (Rasgon). Corresponding Author: Emily G. Jacobs, PhD, Department of Psychiatry, Harvard Medical School and Brigham and Women’s Hospital, 1 Brigham Circle, 3-034 Boston, MA 02120 ([email protected]). Author Contributions: Dr Rasgon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Jacobs, Epel, Rasgon. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Jacobs. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Jacobs. Obtained funding: Jacobs, Rasgon. Administrative, technical, or material support: Epel, Lin, Rasgon. Study supervision: Epel, Blackburn, Rasgon. Conflict of Interest Disclosures: Drs Epel, Lin, and Blackburn were cofounders of Telome Health Inc, a telomere length measurement company. No other disclosures were reported. Funding/Support: This study was funded by grant R01 AG22008 from the National Institute on Aging (Dr Rasgon) and grant M01 RR-00070 from the National Center for Research Resources, National Institutes of Health. This study also received support from the Robert Wood Johnson Foundation Health and Society Scholars program (Dr Jacobs).
To the Editor In their article, Kitley and colleagues1 characterized the features of patients with neuromyelitis optica (NMO)/ NMO spectrum disorders (NMOSDs) with myelin-oligodendrocyte glycoprotein antibodies (Abs) and compared them with patients with aquaporin-4 antibody (AQP4-Ab)–positive NMO/ NMOSD. They found that patients with myelin-oligodendrocyte glycoprotein Abs who fulfilled the diagnostic criteria for NMO were different from those with AQP4-Abs in terms of sex preponderance, age distribution, and involvement of conus and deep gray matter structures on imaging, as well as outcomes.1 Neuromyelitis optica spectrum disorder refers to cases in which patients are seropositive for AQP4-Ab but have not fully met the clinical criteria for NMO.2 Although still controversial, it is more commonly accepted that NMOSD should be defined by AQP4-Ab seropositivity.3 Some patients with NMOSD may present with brain symptoms as their first manifestation and develop recurrent brain symptoms without optic neuritis or myelitis.4 If NMOSD could be diagnosed without seropositivity of anti–APQ4-Abs, another clinical entity—namely paraneoplastic neurological syndrome that may involve optic nerves and spinal cord—while without APQ4-Abs, could also be categorized as NMOSD.5 However, a great number of regional inflammatory disorders may, consequently, also be included in NMOSD. However, this may lead to failure to establish diagnostic criteria of NMOSD, both for clinical use and for scientific research.
Role of the Sponsor: The funding agencies had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript, but not the decision to submit the manuscript for publication.
Jiguo Gao, MD Wei Pan, MD Hongliang Zhang, MD, PhD
Additional Contributions: We thank Allan Reiss, MD (Stanford University), for overseeing brain imaging acquisition and volumetric analyses; Ryan Kelley, BS (Stanford University), for help with volumetric analyses; Joachim Hallmayer, MD (Stanford University), for overseeing apolipoprotein E genotyping; and Heather Kenna, MA (Stanford University), and Candyce Kroenke, MPH, ScD (Kaiser
Author Affiliations: Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Changchun, China (Gao, Zhang); Department of Neurology, The Second Part, The First Hospital of Jilin University, Changchun, China (Gao); School of Public Health, Jilin University, Changchun, China (Pan).
jamaneurology.com
JAMA Neurology July 2014 Volume 71, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Nanyang Technological University User on 06/01/2015
923
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.
Downloaded From: http://archneur.jamanetwork.com/ by a Nanyang Technological University User on 06/01/2015
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Several limitations of the current study should be considered. First, the sample size was limited (N = 47) and there were fewer carriers than noncarriers, which could contribute to the absence of an association in APOE-ε4– positive individuals. Second, linear regression models were conducted for several predictor variables (TL, telomerase, and telomerase to TL ratio) after partialing out variance attributable to several potential confounders (ie, age, BMI, and years of education), thus constraining the degrees of freedom for each model. Moving forward, it will be critical to extend these findings to a larger cohort to determine the robustness of the model and generalizability. Chronic exposure to inflammatory cytokines, oxidative stress, and glucocorticoids can accelerate telomere shortening and lead to hippocampal atrophy, 7 suggesting common pathways through which markers of telomere maintenance could reflect hippocampal integrity. Examining these pathways in greater depth will advance our understanding of the extent to which alterations in telomerase activity and TL reflect, or perhaps drive, age-related neural deficits.
Permanente), for managerial and analytic support. They did not receive compensation from a funding sponsor. 1. Honig LS, Kang MS, Schupf N, Lee JH, Mayeux R. Association of shorter leukocyte telomere repeat length with dementia and mortality. Arch Neurol. 2012;69(10):1332-1339. 2. Jaskelioff M, Muller FL, Paik JH, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2011;469(7328):102-106. 3. Rasgon NL, Kenna HA, Wroolie TE, et al. Insulin resistance and hippocampal volume in women at risk for Alzheimer’s disease. Neurobiol Aging. 2011;32(11): 1942-1948. 4. Jacobs EG, Kroenke C, Lin J, et al. Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use. PLoS One. 2013;8(2):e54713. 5. Lin J, Kroenke CH, Epel E, et al. Greater endogenous estrogen exposure is associated with longer telomeres in postmenopausal women at risk for cognitive decline. Brain Res. 2011;1379:224-231. 6. Beery AK, Lin J, Biddle JS, Francis DD, Blackburn EH, Epel ES. Chronic stress elevates telomerase activity in rats. Biol Lett. 2012;8(6):1063-1066. 7. Wolkowitz OM, Epel ES, Reus VI, Mellon SH. Depression gets old fast: do stress and depression accelerate cell aging? Depress Anxiety. 2010;27(4):327-338.
COMMENT & RESPONSE
Features of Neuromyelitis Optica Spectrum Disorders With Aquaporin-4 and MyelinOligodendrocyte Glycoprotein Antibodies
Emily G. Jacobs, PhD Elissa S. Epel, PhD Jue Lin, PhD Elizabeth H. Blackburn, PhD Natalie L. Rasgon, MD, PhD Author Affiliations: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (Jacobs); Department of Psychiatry, University of California, San Francisco (Epel); Department of Biochemistry and Biophysics, University of California, San Francisco (Lin, Blackburn); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California (Rasgon). Corresponding Author: Emily G. Jacobs, PhD, Department of Psychiatry, Harvard Medical School and Brigham and Women’s Hospital, 1 Brigham Circle, 3-034 Boston, MA 02120 ([email protected]). Author Contributions: Dr Rasgon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Jacobs, Epel, Rasgon. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Jacobs. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Jacobs. Obtained funding: Jacobs, Rasgon. Administrative, technical, or material support: Epel, Lin, Rasgon. Study supervision: Epel, Blackburn, Rasgon. Conflict of Interest Disclosures: Drs Epel, Lin, and Blackburn were cofounders of Telome Health Inc, a telomere length measurement company. No other disclosures were reported. Funding/Support: This study was funded by grant R01 AG22008 from the National Institute on Aging (Dr Rasgon) and grant M01 RR-00070 from the National Center for Research Resources, National Institutes of Health. This study also received support from the Robert Wood Johnson Foundation Health and Society Scholars program (Dr Jacobs).
To the Editor In their article, Kitley and colleagues1 characterized the features of patients with neuromyelitis optica (NMO)/ NMO spectrum disorders (NMOSDs) with myelin-oligodendrocyte glycoprotein antibodies (Abs) and compared them with patients with aquaporin-4 antibody (AQP4-Ab)–positive NMO/ NMOSD. They found that patients with myelin-oligodendrocyte glycoprotein Abs who fulfilled the diagnostic criteria for NMO were different from those with AQP4-Abs in terms of sex preponderance, age distribution, and involvement of conus and deep gray matter structures on imaging, as well as outcomes.1 Neuromyelitis optica spectrum disorder refers to cases in which patients are seropositive for AQP4-Ab but have not fully met the clinical criteria for NMO.2 Although still controversial, it is more commonly accepted that NMOSD should be defined by AQP4-Ab seropositivity.3 Some patients with NMOSD may present with brain symptoms as their first manifestation and develop recurrent brain symptoms without optic neuritis or myelitis.4 If NMOSD could be diagnosed without seropositivity of anti–APQ4-Abs, another clinical entity—namely paraneoplastic neurological syndrome that may involve optic nerves and spinal cord—while without APQ4-Abs, could also be categorized as NMOSD.5 However, a great number of regional inflammatory disorders may, consequently, also be included in NMOSD. However, this may lead to failure to establish diagnostic criteria of NMOSD, both for clinical use and for scientific research.
Role of the Sponsor: The funding agencies had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript, but not the decision to submit the manuscript for publication.
Jiguo Gao, MD Wei Pan, MD Hongliang Zhang, MD, PhD
Additional Contributions: We thank Allan Reiss, MD (Stanford University), for overseeing brain imaging acquisition and volumetric analyses; Ryan Kelley, BS (Stanford University), for help with volumetric analyses; Joachim Hallmayer, MD (Stanford University), for overseeing apolipoprotein E genotyping; and Heather Kenna, MA (Stanford University), and Candyce Kroenke, MPH, ScD (Kaiser
Author Affiliations: Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Changchun, China (Gao, Zhang); Department of Neurology, The Second Part, The First Hospital of Jilin University, Changchun, China (Gao); School of Public Health, Jilin University, Changchun, China (Pan).
jamaneurology.com
JAMA Neurology July 2014 Volume 71, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Nanyang Technological University User on 06/01/2015
923
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.
Downloaded From: http://archneur.jamanetwork.com/ by a Nanyang Technological University User on 06/01/2015
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