Multiplehttp://msj.sagepub.com/ Sclerosis Journal
The onset location of neuromyelitis optica spectrum disorder predicts the location of subsequent relapses Manuella Edler Zandoná, Su-Hyun Kim, Jae-Won Hyun, Boram Park, Jungnam Joo and Ho Jin Kim Mult Scler published online 31 March 2014 DOI: 10.1177/1352458514528763 The online version of this article can be found at: http://msj.sagepub.com/content/early/2014/03/31/1352458514528763 A more recent version of this article was published on - Apr 2, 2014
Published by: http://www.sagepublications.com
On behalf of: European Committee for Treatment and Research in Multiple Sclerosis
Americas Committee for Treatment and Research in Multiple Sclerosis
Pan-Asian Committee for Treatment and Research in Multiple Sclerosis
Latin American Committee on Treatment and Research of Multiple Sclerosis
Additional services and information for Multiple Sclerosis Journal can be found at: Email Alerts: http://msj.sagepub.com/cgi/alerts Subscriptions: http://msj.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Downloaded from msj.sagepub.com at University of Hong Kong Libraries on October 9, 2014
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528763
research-article2014
MSJ0010.1177/1352458514528763Multiple Sclerosis JournalZandoná
MULTIPLE SCLEROSIS MSJ JOURNAL
Short Report
The onset location of neuromyelitis optica spectrum disorder predicts the location of subsequent relapses
Multiple Sclerosis Journal 1–4 DOI: 10.1177/ 1352458514528763 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Manuella Edler Zandoná, Su-Hyun Kim, Jae-Won Hyun, Boram Park, Jungnam Joo and Ho Jin Kim
Abstract: We evaluated whether the location of the initial attack predicted the locations of subsequent events in neuromyelitis optica spectrum disorder (NMOSD). In the retrospective analysis from 164 patients with NMOSD, increased odds of a second attack occurring in the initial event location were seen in all locations (odds ratio [OR] brain: 16.00; brainstem: 4.42; optic nerve: 4.08; and spinal cord: 4.59), as was a positive linear trend when evaluating the number of previous events in the same location as the third event location (OR brain: 62.52; brainstem: 44.55; optic nerve: 6.48; and spinal cord: 2.98). This study suggests early clinical events of NMOSD tend to recur in the same anatomical location within the central nervous system (CNS).
Keywords: Neuromyelitis optica, neuromyelitis optica spectrum disorder, aquaporin-4, onset location Date received: 24 November 2013; revised: 21 February 2014; accepted: 26 February 2014 Background Neuromyelitis optica (NMO) was originally defined as a disease confined to the optic nerve and spinal cord. However, after the identification of a disease-specific autoantibody against aquaporin-4 (AQP4), NMO is now recognized as a spectrum disease that affects other regions of the central nervous system (CNS) and includes more diverse clinical presentations.1–4 It has often been observed that some patients with the AQP4 antibody experience clinical relapses in a specific location of the CNS and a limited form of NMO remains long after disease onset. Such a pattern of localized clinical relapses has been demonstrated in patients with relapsing–remitting multiple sclerosis.5 In this study, we evaluated whether the location of the initial attack predicted the location of future clinical events. Methods The Institutional Review Board at the National Cancer Center, Korea, approved the protocol and waived the need for informed consent. In total, 164 patients with NMO and NMO spectrum disorder (NMOSP) who had at least two previous clinical events were selected from the NMO database at the National Cancer Center.
All patients were positive for AQP4 antibody and seronegative NMO was excluded. Those presenting with polyregional attacks were also excluded to preserve the quality of the statistical evaluation. The 131 remaining patients were then enrolled and analyzed retrospectively. Attacks were defined as objective worsening of new neurological symptoms that lasted at least 24 h and were preceded by stability for at least 1 month. They were divided by their location into four groups: brain, brainstem, optic nerve, and spinal cord. We analyzed whether the location of the first clinical event predicted subsequent events and also whether having neither, one, or both of the first two events in the same location showed a positive linear trend for having a third event in that location. Age, gender, disease duration, recovery from each attack, presence of other autoimmune disease or autoantibodies, and interferon-beta or immunosuppressive treatments during clinical symptoms were considered as important variables in this analysis.6, 7 A patient was considered as being on a given therapy if he/she had at least three months of continuous treatment before the subsequent relapse. Statistical significance was determined by logistic regression, performed using the SAS software. A p-value < 0.05 was considered to indicate statistical significance.
Correspondence to: Ho Jin Kim Department of Neurology, Research Institute and Hospital of the National Cancer Center, 323 Ilsan Street, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, Korea. [email protected] Su-Hyun Kim Jae-Won Hyun Department of Neurology, Research Institute and Hospital of National Cancer Center, Korea Manuella Edler Zandoná Pontifical Catholic University of Rio Grande do Sul, Science Without Borders, Brazil/ Department of Neurology, Research Institute and Hospital of National Cancer Center, Korea Boram Park Jungnam Joo Biometric Research Branch, Research Institute and Hospital of National Cancer Center, Korea
http://msj.sagepub.com 1
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Multiple Sclerosis Journal Results In total, 131 patients were enrolled as follows: 116 females and 15 males. Of them, 82% (108 patients) experienced a third event. Their median age at disease onset was 31 (range, 6–54) years, and their median disease duration was 8 (range, 0–29) years. The median time between the first and second attack was 6 (range, 1–122) months. The first attacks were treated with intravenous methylprednisolone (1 g for 5 days) and one patient had subsequent plasmapheresis following steroid therapy. Complete remission from the first attack was observed in 76 (58%), partial remission in 36 (28%), and poor remission in 19 (14%) patients. 11 (19%) of the 58 patients with optic neuritis had severe visual impairment with visual acuity of 0.1 or worse (20/200 Snellen), and 8 (19%) of the 42 patients with myelitis had severe ambulatory disability that was higher than EDSS 6 from the first attack. In contrast, brain and brainstem attacks were completely recovered from in 76% and 100% of patients, respectively, and no patient with brain or brainstem attack had severe disability from the first attack. Second event location analysis (Table 1) The odds of a second event occurring in the same location as the first event compared with the odds of it occurring in another location were high in all groups. There was a more than 16-fold increase in the brain group (OR, 95% CI: 16.00, 4.55–56.30, p < 0.0001) and a more than 4-fold increase in the optic nerve and spinal cord groups (OR, 95% CI: 4.08, 1.96–8.50, p = 0.0002 and 4.59, 2.10–10.06, p = 0.0001, respectively). This association remained significant even when adjusted for all covariates or adjusted for significant covariates. In the brainstem group, the odds of predicting the second attack at the same location were also high, but not statistically significantly so (OR, 95% CI: 4.42, 0.38–52.19, p = 0.2376). Interestingly, if the first attack was optic neuritis, the odds of spinal cord involvement as a second attack, which is necessary to satisfy the diagnostic criteria for NMO, compared with the odds of it occurring in another location, were low (OR, 95% CI: 0.44, 0.21– 0.90, p = 0.0248). If the first attack was myelitis, the odds of optic neuritis as a second attack were also low (OR, 95% CI: 0.26, 0.11–0.58, p = 0.0012). Third event location analysis (Table 1) The odds of a third event occurring in the same location as the first event, compared with the odds of it
occurring in another location, were high in the brain, brainstem, and optic nerve groups (brain OR, 95% CI: 8.80, 2.17–35.74, p = 0.0024; brainstem OR, 95% CI: 17.09, 1.43–204.15, p = 0.0249; and optic nerve OR, 95% CI: 2.30, 1.02–5.19, p = 0.0441), but not in the spinal cord group (OR, 95% CI: 1.57, 0.70–3.55, p = 0.2764). When adjusted for potential confounders, there was no significant change in these associations. Linear trend analysis (Table 1) A positive linear trend was seen when evaluating the number of previous events in the same location as the third event location (brain OR, 95% CI: 62.52, 8.73–447.88, p < 0.0001; brainstem OR, 95% CI: 44.55, 1.14–999.99, p = 0.0426; optic nerve OR, 95% CI: 6.48, 2.21–19.04, p = 0.0007; and spinal cord OR, 95% CI: 2.98, 1.08–8.22, p = 0.0354). Again, none of the potential covariates markedly changed any association. Discussion This study revealed a pattern of localized clinical events among patients experiencing a relapsing course of NMO. An increase greater than double was seen in the odds of having a subsequent event in the same location as the first event, as was a positive linear trend of having neither, one, or both of the first two events in the same location as the third. This association reached statistical significance among three of the four groups studied: brain, optic nerve, and spinal cord. Furthermore, this association remained significant after adjustment for all covariates of interest. The low number of individuals with brainstem involvement in our cohort may have contributed to the lack of a significant correlation in this group. To our knowledge, this is the first reported study to evaluate the location of NMO lesions focusing on their presenting symptoms and their pattern of recurrence. The underlying biological mechanisms that contribute to this tendency of repeated attacks in the same location of CNS remain, as yet, unknown. There is evidence that the AQP4 antibody initiates the formation of NMO lesions once it enters the CNS.8 However, the particularities in each CNS region have not been determined. Our study had some limitations, such as its retrospective design and the lack of a control group. Moreover, as our center is a referral center, our patients often present with more severe disease, causing an unintentional selection bias. Thus, further
2 http://msj.sagepub.com
Downloaded from msj.sagepub.com at University of Hong Kong Libraries on October 9, 2014
Zandoná et al. Table 1. Odds ratios (ORs) of each event occurring in the same location. Model (N = number with the first attack in the same location)
1: Brain N = 17 OR (95% CI)
Second Event Location Analysis (N = 131) Unadjusted 16.000 (4.547, 56.300) Adjusted for all covariates 17.311 (3.977, 75.351) Adjusted for significant 17.161 (4.699, covariates 62.668) Model (N = number with the first attack in the same location)
2: Brainstem N = 14
3: Optic Nerve N = 58
4: Spinal Cord N = 42
p-value
OR (95% CI)
p-value
OR (95% CI)
p-value
OR (95% CI)
p-value
999.999)
0.0514
8.353 (2.491, 28.016)
0.0006
4.020 (1.331, 12.144)
0.0136
0.0426
7.968 (2.558, 24.818)
0.0003
3.284 (1.160, 9.300)
0.0252
Adjusted for significant covariates
OR (95% CI)
>999.999 (43.57, >999.999) >999.999 (44.762, >999.999)
0.0032
studies are needed to confirm these results and to evaluate individual underlying features that contribute to this pattern. In conclusion, we demonstrated that early clinical events of NMOSD tended to recur in the same anatomical location within the CNS. This finding highlights the necessity to revise the diagnostic criteria to cover the full spectrum of AQP4 autoimmunity. Author contribution Kim HJ, Zandoná ME, and Joo J had full access to all of the data in this study and are responsible for the data integrity and the accuracy of the data analysis. The author contributions are as follows: study concept and design: Kim HJ and Zandoná ME; data
acquisition: Kim HJ, Kim SH, and Hyun JW; data analysis and interpretation: Kim HJ, Zandoná ME, Joo J, and Park B; manuscript drafting: Kim HJ and Zandoná ME; critical revision of the manuscript for important intellectual content: Kim HJ, Zandoná ME, Kim SH, Hyun JW, and Park B; statistical analysis: Joo J and Park B; and study supervision: Kim HJ. Conflict of interest Manuella Edler Zandoná, Su-Hyun Kim, Jae-Won Hyun, Boram Park, and Jungnam Joo have no conflicts of interest to disclose. Ho Jin Kim has received honoraria for speaking or consulting from Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, and Novartis and received research grants from Genzyme, Merck Serono, and Kael-GemVax.
http://msj.sagepub.com 3
Downloaded from msj.sagepub.com at University of Hong Kong Libraries on October 9, 2014
Multiple Sclerosis Journal Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
5. Mowry EM, Deen S, Malikova I, et al. The onset location of multiple sclerosis predicts the location of subsequent relapses. J Neurol Neurosurg Psychiatry 2009; 80: 400–403.
References
6. Kitley J, Leite MI, Nakashima I, et al. Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain 2012; 135: 1834– 1849.
1.
Kim W, Kim SH and Kim HJ. New insights into neuromyelitis optica. J Clin Neurol 2011; 7: 115–127.
2.
Jarius S and Wildemann B. AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 2010; 6: 383–392.
3.
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
4.
Kim SH, Kim W, Li XF, et al. Clinical spectrum of CNS aquaporin-4 autoimmunity. Neurology 2012; 78: 1179–1185. Papadopoulos M and Verkman AC. Aquaporin 4 and neuromyelitis optica. Lancet Neurol 2012; 11: 535–544.
7. Kim SH, Kim W, Li XF, et al. Does interferon beta exacerbate neuromyelitis optica spectrum disorders? Mult Scler 2012; 18: 1480– 1483. 8.
Ratelade J and Verkman AS. Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies. Int J Biochem Cell Biol 2012; 44: 1519–1530.
4 http://msj.sagepub.com
The onset location of neuromyelitis optica spectrum disorder predicts the location of subsequent relapses Manuella Edler Zandoná, Su-Hyun Kim, Jae-Won Hyun, Boram Park, Jungnam Joo and Ho Jin Kim Mult Scler published online 31 March 2014 DOI: 10.1177/1352458514528763 The online version of this article can be found at: http://msj.sagepub.com/content/early/2014/03/31/1352458514528763 A more recent version of this article was published on - Apr 2, 2014
Published by: http://www.sagepublications.com
On behalf of: European Committee for Treatment and Research in Multiple Sclerosis
Americas Committee for Treatment and Research in Multiple Sclerosis
Pan-Asian Committee for Treatment and Research in Multiple Sclerosis
Latin American Committee on Treatment and Research of Multiple Sclerosis
Additional services and information for Multiple Sclerosis Journal can be found at: Email Alerts: http://msj.sagepub.com/cgi/alerts Subscriptions: http://msj.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Downloaded from msj.sagepub.com at University of Hong Kong Libraries on October 9, 2014
Permissions: http://www.sagepub.com/journalsPermissions.nav
OnlineFirst Version of Record - Apr 2, 2014 >> OnlineFirst Version of Record - Mar 31, 2014 What is This?
Downloaded from msj.sagepub.com at University of Hong Kong Libraries on October 9, 2014
528763
research-article2014
MSJ0010.1177/1352458514528763Multiple Sclerosis JournalZandoná
MULTIPLE SCLEROSIS MSJ JOURNAL
Short Report
The onset location of neuromyelitis optica spectrum disorder predicts the location of subsequent relapses
Multiple Sclerosis Journal 1–4 DOI: 10.1177/ 1352458514528763 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Manuella Edler Zandoná, Su-Hyun Kim, Jae-Won Hyun, Boram Park, Jungnam Joo and Ho Jin Kim
Abstract: We evaluated whether the location of the initial attack predicted the locations of subsequent events in neuromyelitis optica spectrum disorder (NMOSD). In the retrospective analysis from 164 patients with NMOSD, increased odds of a second attack occurring in the initial event location were seen in all locations (odds ratio [OR] brain: 16.00; brainstem: 4.42; optic nerve: 4.08; and spinal cord: 4.59), as was a positive linear trend when evaluating the number of previous events in the same location as the third event location (OR brain: 62.52; brainstem: 44.55; optic nerve: 6.48; and spinal cord: 2.98). This study suggests early clinical events of NMOSD tend to recur in the same anatomical location within the central nervous system (CNS).
Keywords: Neuromyelitis optica, neuromyelitis optica spectrum disorder, aquaporin-4, onset location Date received: 24 November 2013; revised: 21 February 2014; accepted: 26 February 2014 Background Neuromyelitis optica (NMO) was originally defined as a disease confined to the optic nerve and spinal cord. However, after the identification of a disease-specific autoantibody against aquaporin-4 (AQP4), NMO is now recognized as a spectrum disease that affects other regions of the central nervous system (CNS) and includes more diverse clinical presentations.1–4 It has often been observed that some patients with the AQP4 antibody experience clinical relapses in a specific location of the CNS and a limited form of NMO remains long after disease onset. Such a pattern of localized clinical relapses has been demonstrated in patients with relapsing–remitting multiple sclerosis.5 In this study, we evaluated whether the location of the initial attack predicted the location of future clinical events. Methods The Institutional Review Board at the National Cancer Center, Korea, approved the protocol and waived the need for informed consent. In total, 164 patients with NMO and NMO spectrum disorder (NMOSP) who had at least two previous clinical events were selected from the NMO database at the National Cancer Center.
All patients were positive for AQP4 antibody and seronegative NMO was excluded. Those presenting with polyregional attacks were also excluded to preserve the quality of the statistical evaluation. The 131 remaining patients were then enrolled and analyzed retrospectively. Attacks were defined as objective worsening of new neurological symptoms that lasted at least 24 h and were preceded by stability for at least 1 month. They were divided by their location into four groups: brain, brainstem, optic nerve, and spinal cord. We analyzed whether the location of the first clinical event predicted subsequent events and also whether having neither, one, or both of the first two events in the same location showed a positive linear trend for having a third event in that location. Age, gender, disease duration, recovery from each attack, presence of other autoimmune disease or autoantibodies, and interferon-beta or immunosuppressive treatments during clinical symptoms were considered as important variables in this analysis.6, 7 A patient was considered as being on a given therapy if he/she had at least three months of continuous treatment before the subsequent relapse. Statistical significance was determined by logistic regression, performed using the SAS software. A p-value < 0.05 was considered to indicate statistical significance.
Correspondence to: Ho Jin Kim Department of Neurology, Research Institute and Hospital of the National Cancer Center, 323 Ilsan Street, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, Korea. [email protected] Su-Hyun Kim Jae-Won Hyun Department of Neurology, Research Institute and Hospital of National Cancer Center, Korea Manuella Edler Zandoná Pontifical Catholic University of Rio Grande do Sul, Science Without Borders, Brazil/ Department of Neurology, Research Institute and Hospital of National Cancer Center, Korea Boram Park Jungnam Joo Biometric Research Branch, Research Institute and Hospital of National Cancer Center, Korea
http://msj.sagepub.com 1
Downloaded from msj.sagepub.com at University of Hong Kong Libraries on October 9, 2014
Multiple Sclerosis Journal Results In total, 131 patients were enrolled as follows: 116 females and 15 males. Of them, 82% (108 patients) experienced a third event. Their median age at disease onset was 31 (range, 6–54) years, and their median disease duration was 8 (range, 0–29) years. The median time between the first and second attack was 6 (range, 1–122) months. The first attacks were treated with intravenous methylprednisolone (1 g for 5 days) and one patient had subsequent plasmapheresis following steroid therapy. Complete remission from the first attack was observed in 76 (58%), partial remission in 36 (28%), and poor remission in 19 (14%) patients. 11 (19%) of the 58 patients with optic neuritis had severe visual impairment with visual acuity of 0.1 or worse (20/200 Snellen), and 8 (19%) of the 42 patients with myelitis had severe ambulatory disability that was higher than EDSS 6 from the first attack. In contrast, brain and brainstem attacks were completely recovered from in 76% and 100% of patients, respectively, and no patient with brain or brainstem attack had severe disability from the first attack. Second event location analysis (Table 1) The odds of a second event occurring in the same location as the first event compared with the odds of it occurring in another location were high in all groups. There was a more than 16-fold increase in the brain group (OR, 95% CI: 16.00, 4.55–56.30, p < 0.0001) and a more than 4-fold increase in the optic nerve and spinal cord groups (OR, 95% CI: 4.08, 1.96–8.50, p = 0.0002 and 4.59, 2.10–10.06, p = 0.0001, respectively). This association remained significant even when adjusted for all covariates or adjusted for significant covariates. In the brainstem group, the odds of predicting the second attack at the same location were also high, but not statistically significantly so (OR, 95% CI: 4.42, 0.38–52.19, p = 0.2376). Interestingly, if the first attack was optic neuritis, the odds of spinal cord involvement as a second attack, which is necessary to satisfy the diagnostic criteria for NMO, compared with the odds of it occurring in another location, were low (OR, 95% CI: 0.44, 0.21– 0.90, p = 0.0248). If the first attack was myelitis, the odds of optic neuritis as a second attack were also low (OR, 95% CI: 0.26, 0.11–0.58, p = 0.0012). Third event location analysis (Table 1) The odds of a third event occurring in the same location as the first event, compared with the odds of it
occurring in another location, were high in the brain, brainstem, and optic nerve groups (brain OR, 95% CI: 8.80, 2.17–35.74, p = 0.0024; brainstem OR, 95% CI: 17.09, 1.43–204.15, p = 0.0249; and optic nerve OR, 95% CI: 2.30, 1.02–5.19, p = 0.0441), but not in the spinal cord group (OR, 95% CI: 1.57, 0.70–3.55, p = 0.2764). When adjusted for potential confounders, there was no significant change in these associations. Linear trend analysis (Table 1) A positive linear trend was seen when evaluating the number of previous events in the same location as the third event location (brain OR, 95% CI: 62.52, 8.73–447.88, p < 0.0001; brainstem OR, 95% CI: 44.55, 1.14–999.99, p = 0.0426; optic nerve OR, 95% CI: 6.48, 2.21–19.04, p = 0.0007; and spinal cord OR, 95% CI: 2.98, 1.08–8.22, p = 0.0354). Again, none of the potential covariates markedly changed any association. Discussion This study revealed a pattern of localized clinical events among patients experiencing a relapsing course of NMO. An increase greater than double was seen in the odds of having a subsequent event in the same location as the first event, as was a positive linear trend of having neither, one, or both of the first two events in the same location as the third. This association reached statistical significance among three of the four groups studied: brain, optic nerve, and spinal cord. Furthermore, this association remained significant after adjustment for all covariates of interest. The low number of individuals with brainstem involvement in our cohort may have contributed to the lack of a significant correlation in this group. To our knowledge, this is the first reported study to evaluate the location of NMO lesions focusing on their presenting symptoms and their pattern of recurrence. The underlying biological mechanisms that contribute to this tendency of repeated attacks in the same location of CNS remain, as yet, unknown. There is evidence that the AQP4 antibody initiates the formation of NMO lesions once it enters the CNS.8 However, the particularities in each CNS region have not been determined. Our study had some limitations, such as its retrospective design and the lack of a control group. Moreover, as our center is a referral center, our patients often present with more severe disease, causing an unintentional selection bias. Thus, further
2 http://msj.sagepub.com
Downloaded from msj.sagepub.com at University of Hong Kong Libraries on October 9, 2014
Zandoná et al. Table 1. Odds ratios (ORs) of each event occurring in the same location. Model (N = number with the first attack in the same location)
1: Brain N = 17 OR (95% CI)
Second Event Location Analysis (N = 131) Unadjusted 16.000 (4.547, 56.300) Adjusted for all covariates 17.311 (3.977, 75.351) Adjusted for significant 17.161 (4.699, covariates 62.668) Model (N = number with the first attack in the same location)
2: Brainstem N = 14
3: Optic Nerve N = 58
4: Spinal Cord N = 42
p-value
OR (95% CI)
p-value
OR (95% CI)
p-value
OR (95% CI)
p-value
999.999)
0.0514
8.353 (2.491, 28.016)
0.0006
4.020 (1.331, 12.144)
0.0136
0.0426
7.968 (2.558, 24.818)
0.0003
3.284 (1.160, 9.300)
0.0252
Adjusted for significant covariates
OR (95% CI)
>999.999 (43.57, >999.999) >999.999 (44.762, >999.999)
0.0032
studies are needed to confirm these results and to evaluate individual underlying features that contribute to this pattern. In conclusion, we demonstrated that early clinical events of NMOSD tended to recur in the same anatomical location within the CNS. This finding highlights the necessity to revise the diagnostic criteria to cover the full spectrum of AQP4 autoimmunity. Author contribution Kim HJ, Zandoná ME, and Joo J had full access to all of the data in this study and are responsible for the data integrity and the accuracy of the data analysis. The author contributions are as follows: study concept and design: Kim HJ and Zandoná ME; data
acquisition: Kim HJ, Kim SH, and Hyun JW; data analysis and interpretation: Kim HJ, Zandoná ME, Joo J, and Park B; manuscript drafting: Kim HJ and Zandoná ME; critical revision of the manuscript for important intellectual content: Kim HJ, Zandoná ME, Kim SH, Hyun JW, and Park B; statistical analysis: Joo J and Park B; and study supervision: Kim HJ. Conflict of interest Manuella Edler Zandoná, Su-Hyun Kim, Jae-Won Hyun, Boram Park, and Jungnam Joo have no conflicts of interest to disclose. Ho Jin Kim has received honoraria for speaking or consulting from Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, and Novartis and received research grants from Genzyme, Merck Serono, and Kael-GemVax.
http://msj.sagepub.com 3
Downloaded from msj.sagepub.com at University of Hong Kong Libraries on October 9, 2014
Multiple Sclerosis Journal Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
5. Mowry EM, Deen S, Malikova I, et al. The onset location of multiple sclerosis predicts the location of subsequent relapses. J Neurol Neurosurg Psychiatry 2009; 80: 400–403.
References
6. Kitley J, Leite MI, Nakashima I, et al. Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain 2012; 135: 1834– 1849.
1.
Kim W, Kim SH and Kim HJ. New insights into neuromyelitis optica. J Clin Neurol 2011; 7: 115–127.
2.
Jarius S and Wildemann B. AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 2010; 6: 383–392.
3.
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
4.
Kim SH, Kim W, Li XF, et al. Clinical spectrum of CNS aquaporin-4 autoimmunity. Neurology 2012; 78: 1179–1185. Papadopoulos M and Verkman AC. Aquaporin 4 and neuromyelitis optica. Lancet Neurol 2012; 11: 535–544.
7. Kim SH, Kim W, Li XF, et al. Does interferon beta exacerbate neuromyelitis optica spectrum disorders? Mult Scler 2012; 18: 1480– 1483. 8.
Ratelade J and Verkman AS. Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies. Int J Biochem Cell Biol 2012; 44: 1519–1530.
4 http://msj.sagepub.com
