Share

May 10, 2016; 86 (19) Article

Evaluation of the 2015 diagnostic criteria for neuromyelitis optica spectrum disorder

Jae-Won Hyun, In Hye Jeong, AeRan Joung, Su-Hyun Kim, Ho Jin Kim
First published April 13, 2016, DOI: https://doi.org/10.1212/WNL.0000000000002655
Full PDF
Citation
Permissions

Make Comment

See Comments

Downloads
535

Share

Abstract

Objective: To evaluate the application of the 2015 International Panel for NMO Diagnosis (IPND) criteria to consecutive cases of neuromyelitis optica spectrum disorder (NMOSD) in a large cohort of individuals with CNS inflammatory diseases.

Methods: In total, 594 patients with CNS inflammatory diseases were included. Rigorous confirmation of the patients' aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) status throughout the disease duration (mean 9.2 ± 5.7 years) using repeated assays, including ELISA and cell-based assay, was performed.

Results: A total of 252 patients fulfilled the IPND criteria (AQP4-IgG positive: 226 [90%], AQP4-IgG negative: 26 [10%]). Of these, 136 (54%) patients met the 2006 neuromyelitis optica criteria. When we assumed an unknown AQP4-IgG status in the confirmed NMOSD group with AQP4-IgG, 162 of 226 (72%) patients with AQP4-IgG were classified as having NMOSD by the IPND criteria. The majority of patients were diagnosed with NMOSD within 2 years of onset (73%) or after a second attack (72%). Acute myelitis (83%) and optic neuritis (65%) were the most common clinical features throughout the disease duration. Optic neuritis (42%) was the most common initial manifestation, followed by acute myelitis (38%) and area postrema syndrome (14%).

Conclusions: The IPND criteria well-reflected the broader clinical spectrum of NMOSD and markedly improved the diagnostic yield compared to the previous criteria, even in patients with an unknown AQP4-IgG status.

GLOSSARY

AQP4-IgG=
aquaporin-4 immunoglobulin G antibody;
CBA=
cell-based assay;
CI=
confidence interval;
EDSS=
Expanded Disability Status Scale;
IPND=
International Panel for NMO Diagnosis;
IQR=
interquartile range;
LETM=
longitudinally extensive transverse myelitis;
MOG=
myelin oligodendrocyte glycoprotein;
NCC=
National Cancer Center;
NMO=
neuromyelitis optica;
NMOSD=
neuromyelitis optica spectrum disorder

The aquaporin-4 immunoglobulin G antibody (AQP4-IgG) is a highly specific marker for neuromyelitis optica spectrum disorder (NMOSD), which is an inflammatory disease of the CNS.1,–,4 Our understanding of the diverse clinical spectrum of NMOSD has increased remarkably since the discovery of AQP4-IgG.5,–,8 Previously, involvement of both the optic nerve and spinal cord was mandatory for a diagnosis of neuromyelitis optica (NMO) according to the 2006 diagnostic criteria.9 A limited form of NMO, including AQP4-IgG-positive isolated single or recurrent longitudinally extensive transverse myelitis (LETM) or recurrent or bilateral simultaneous optic neuritis, was introduced into the NMOSD definition in 2007,5 which demonstrated similar clinical presentations as definite NMO.7,10,11 In addition, involvement of the brain was observed in patients with AQP4-IgG, and radiologic characteristics of the brain in patients with NMOSD have been reported.12,–,23

The 2015 criteria of the International Panel for NMO Diagnosis (IPND) were recently established.24 The 2015 IPND criteria emphasize the clinical implications of AQP4-IgG and reflect broader phenotypes of NMOSD, to facilitate earlier and accurate NMOSD diagnoses. However, a concern with regard to overdiagnosis or underdiagnosis of NMOSD using the 2015 IPND criteria can be evolved if clinicians overly rely on the AQP4-IgG assay, which is not always available in a timely manner in clinical practice. In our clinic, we performed repeated AQP4-IgG assays using validated methods throughout the disease duration, thus establishing a large and reliable NMOSD with AQP4-IgG cohort. To reflect real-world settings, we assumed that the AQP4-IgG status of these patients with AQP4-IgG was unknown and applied the 2015 IPND criteria to diagnose them. Additionally, we assessed whether the core clinical characteristics of NMOSD, as outlined in the 2015 IPND criteria, reflected the signature features at disease onset as well as throughout the duration of the disease.

METHODS

A total of 744 consecutive patients who visited the National Cancer Center (NCC) for possible CNS inflammatory diseases between 2005 and 2015 were enrolled. Of these, 116 patients with known causes, including neoplastic, vascular, compressive, infectious, and metabolic etiologies, and 34 patients with inappropriate medical records were excluded. Finally, 594 patients were enrolled from the NCC registry of CNS inflammatory diseases. The AQP4-IgG serostatus was confirmed rigorously in all enrolled patients throughout the disease duration using at least 2 of the following 3 methods: a commercial cell-based assay (CBA) (Euroimmun, Lübeck, Germany),25 an in-house CBA at Tohoku University,8 and an in-house ELISA at the NCC.26 We performed repeated tests during follow-up using at least 3 different time points, particularly at the time of any acute exacerbation in patients who were AQP4-IgG-negative in the initial test.

We first retrospectively applied the 2015 IPND criteria (table 1), according to AQP4-IgG status, to determine NMOSD diagnoses in our cohort.24 We also applied the 2006 NMO diagnostic criteria to determine the diagnostic improvement of the 2015 IPND criteria.9 Second, we assumed an unknown AQP4-IgG status in patients with NMOSD with AQP4-IgG and subsequently applied the 2015 IPND criteria to diagnose them based on the following: (1) at least one core clinical characteristic must be optic neuritis, LETM, or area postrema syndrome; (2) dissemination in space; and (3) fulfillment of additional MRI requirements, as applicable, to reflect real-world clinical practice in which the AQP4-IgG is not always available in a timely manner.24 We also applied the 2006 NMO diagnostic criteria to determine the diagnostic improvement of the 2015 IPND criteria within patients who were assumed to have an unknown AQP4-IgG status. The time to diagnosis by each criteria and the Expanded Disability Status Scale (EDSS) score at the time of diagnosis were also evaluated. Additionally, we stratified the first-, second-, and third-year data of the onset- or attack–diagnosis rate to investigate the usefulness of the 2015 IPND criteria for early-stage NMOSD. Third, we investigated the presence of the following core clinical characteristics over the entire disease duration and at the disease onset: (1) optic neuritis, (2) acute myelitis, (3) area postrema syndrome, (4) acute brainstem syndrome, (5) symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical MRI lesions, and (6) symptomatic cerebral syndrome with NMOSD-typical brain lesions.24 The manifestations of the patients with NMOSD were investigated to evaluate the adequacy of the signature features outlined in the 2015 IPND criteria.

View this table:
Table 1

The 2015 International Panel for NMO Diagnosis criteria for neuromyelitis optica spectrum disorder (NMOSD)24

Standard protocol approvals, registrations, and patient consents.

The Institutional Review Board of the NCC approved the study protocol. Written informed consent was obtained from all patients or guardians of the patients participating in the study.

Statistics.

All data were compared between patients with NMOSD with and without AQP4-IgG using the χ2 test or Fisher exact test. A Mann-Whitney test or Student t test was also used to analyze differences, and p values less than 0.05 were considered to indicate statistical significance. The Kaplan-Meier technique was used to estimate the median time to diagnosis of the patients with AQP4-IgG who were assumed to have an unknown AQP4-IgG status.

RESULTS

Of the 594 patients, 252 were diagnosed with NMOSD by the 2015 IPND criteria. A total of 226 (90%) patients tested positive and 26 (10%) patients tested negative for AQP4-IgG. Of the 226 patients with AQP4-IgG, 94% and 97% were positive by ELISA and CBA, respectively, and 91% were positive by both assays. Positive seroconversion was found in 8% of patients. All 26 seronegative patients were tested with 3 different assays, and the results were consistently negative for AQP4-IgG.

The demographics of the patients with NMOSD are shown in table 2. The female-to-male ratio and mean age at onset were 6.2:1 and 33.4 ± 12.3 years, respectively. The mean disease duration was 9.2 ± 5.7 years, and the median current EDSS was 3.0 (interquartile range [IQR] 2.0–4.5).

View this table:
Table 2

Demographics of the patients with neuromyelitis optica spectrum disorder (NMOSD)

Figure 1A demonstrates the comparison of the 2006 criteria and the 2015 IPND criteria. Of the 252 patients with NMOSD meeting the 2015 IPND criteria, only 136 (54%) patients satisfied the 2006 criteria: 119 patients with AQP4-IgG and 17 patients without AQP4-IgG. As a result, 116 (46%) patients with and without AQP4-IgG were newly defined as having NMOSD by the 2015 IPND criteria compared with the 2006 criteria.

Figure 1
Figure 1 Comparison of the 2006 criteria and the 2015 International Panel for NMO Diagnosis criteria

(A) Under a known aquaporin-4 immunoglobulin G antibody (AQP4-IgG) status and (B) under an unknown AQP4-IgG status. NMOSD = neuromyelitis optica spectrum disorder.

When the 2015 IPND criteria were applied to the patients with AQP4-IgG, all were diagnosed with NMOSD. Indeed, all patients with AQP4-IgG demonstrated at least one of the core clinical characteristics of NMOSD, while none of the patients with clinical or imaging features of otherwise typical for other diagnoses showed AQP4-IgG seropositivity. Figure 1B demonstrates the comparison of the 2006 criteria and the 2015 IPND criteria under the assumption of an unknown AQP4-IgG status. After assuming that the group with AQP4-IgG had an unknown AQP4-IgG status, 162 (72%) of 226 patients with AQP4-IgG met the 2015 IPND criteria. The diagnosis rate of the 2015 IPND criteria remained high even with an unknown AQP4-IgG status. When we estimated the diagnosis rate after the exclusion of the 12 patients who were treated with an immunosuppressant after their first attack, 161 (75%) of 214 patients with AQP4-IgG satisfied the 2015 IPND criteria. In contrast, only 93 patients met the 2006 criteria under the assumption of an unknown AQP4-IgG status. Of 119 patients who were diagnosed by the 2006 criteria with AQP4-IgG, 26 patients (2 with non-LETM and 24 with brain MRIs that met the diagnostic criteria for multiple sclerosis) became disqualified due to an unknown AQP4-IgG status.

Figure 2 reveals the application of the 2015 IPND criteria to the 226 patients with AQP4-IgG under the assumption of an unknown AQP4-IgG status. A total of 219 (97%) of 226 patients with AQP4-IgG had at least 1 of the 3 major core clinical characteristics and thus fulfilled the first criterion. Seven patients who did not fulfill the first criterion presented with brain symptoms (including acute brainstem, diencephalic, and symptomatic cerebral syndromes) alone with NMOSD-typical brain lesions during the disease duration. A total of 167 (74%) of 226 patients with AQP4-IgG satisfied the second criterion: dissemination in space. A total of 59 patients demonstrated the following clinical phenotypes restricted to one anatomical lesion in the CNS: isolated optic neuritis (n = 19, 32%), acute myelitis (n = 36, 61%), or brain syndrome (n = 4, 7%). A total of 43 (73%) of these patients had a relapsing clinical course during their disease duration (median 5 years [IQR 4–9]). Only 4 patients, who had isolated brain syndrome, did not meet both the first and second criteria. A total of 224 (99%) of the 226 patients with AQP4-IgG met the third criterion, associated with the fulfillment of additional MRI requirements, and 2 patients did not have acute myelitis extending over 3 contiguous vertebral segments throughout the entire disease duration. Brain MRIs were not performed in 14 patients with area postrema syndrome when symptoms existed, but their symptoms occurred most of each day for at least 7 days and were not attributable to other causes.

Figure 2
Figure 2 Application of the 2015 International Panel for NMO Diagnosis criteria under the assumption of unknown aquaporin-4 immunoglobulin G antibody (AQP4-IgG) status

Out of 226 patients with AQP4-IgG, 219 (97%), 167 (74%), and 224 (99%) fulfilled the first, second, and third criterion under the assumption of unknown AQP4-IgG status. LETM = longitudinally extensive transverse myelitis.

The median time to diagnosis was 11 months (95% confidence interval [CI] 7–15 months) by the 2015 criteria and 53 months (95% CI 28–78 months) by the 2006 criteria (log rank test: p < 0.001, figure e-1 on the Neurology® Web site at Neurology.org). In the 93 patients fulfilling both 2006 and 2015 criteria, median time to diagnosis was 11 months (95% CI 6–16 months) by the 2015 criteria and 13 months (95% CI 8–18 months) by the 2006 criteria.

In addition, we stratified the first, second, and third year of the onset- or attack–diagnosis rate of patients with AQP4-IgG under the assumption of an unknown AQP4-IgG status. Of the 162 patients who were diagnosed with NMOSD by the 2015 IPND criteria, 89 (55%), 118 (73%), and 132 (81%) patients were diagnosed 1, 2, and 3 years after onset, respectively. The median EDSS at diagnostic confirmation was 2 (IQR 1–4) by the 2015 IPND criteria. We also estimated the attack–diagnosis rate in 162 patients, of whom 7 (4.3%) met the 2015 IPND criteria at onset, 116 (72%) were diagnosed with NMOSD at the second attack, and only 15 (9%) remained to be diagnosed with NMOSD at the third attack. Of the 26 seronegative patients, 6 (23%) patients who had multiregional involvement diagnosed at the onset and 24 (92%) and 26 (100%) patients were diagnosed at the second and third attacks, respectively.

Figure 3 and table e-1 show the presence of the core clinical characteristics in all patients with NMOSD confirmed by the 2015 IPND criteria. Among the 252 patients with NMOSD, the most common clinical feature throughout the disease duration was acute myelitis (n = 210, 83%), followed by optic neuritis (n = 165, 65%) (figure 3A). Symptomatic brain syndromes were observed in 100 (40%) of 252 patients with NMOSD. Area postrema (n = 40, 16%), brainstem (n = 41, 16%), and cerebral (n = 38, 15%) syndromes were commonly observed, while diencephalic clinical syndrome (n = 6, 2%) had a low prevalence in our cohort. Initial presentations most frequently included optic neuritis (n = 107, 42%), followed by acute myelitis (n = 96, 38%) (figure 3B). The brain was involved in the first disease manifestation in 55 (22%) patients; area postrema syndrome (n = 36, 14%) was the most common initial brain manifestation, followed by symptomatic cerebral (n = 19, 8%), acute brainstem (n = 14, 6%), and acute diencephalic (n = 2, 1%) syndromes. Among the 226 patients with NMOSD with AQP4-IgG, acute myelitis (n = 190, 84%) was the most common clinical feature throughout the disease course and optic neuritis (n = 93, 41%) was most frequently observed as an initial presentation. Among the 26 patients with NMOSD without AQP4-IgG, optic neuritis was the most common manifestation throughout the disease course (n = 23, 88%), as well as the most common initial feature (n = 14, 54%). The proportions of the presence of optic neuritis (88 vs 63%, p = 0.01) and symptomatic cerebral syndrome (31% vs 13%, p = 0.04) were higher in patients with NMOSD without AQP4-IgG than in those with AQP4-IgG.

Figure 3
Figure 3 Evaluation of the core clinical characteristics in the 2015 International Panel for NMO Diagnosis criteria

(A) Throughout the whole disease duration and (B) at disease onset. AQP4 = aquaporin-4; SD = syndrome.

DISCUSSION

Using a large cohort of patients with inflammatory diseases of the CNS, the present study demonstrated that the 2015 IPND criteria reflect the broader clinical spectrum and implications of the AQP4-IgG status for the diagnosis of NMOSD.24 The 2015 IPND criteria significantly improved the diagnostic yield compared to the 2006 diagnostic criteria. Compared with the 2006 diagnostic criteria for NMO, 116 of 252 (46%) patients were newly diagnosed with NMOSD by the 2015 IPND criteria.9,24 It was possible to diagnose NMOSD in patients with NMOSD-typical brain lesions or a negative AQP4-IgG status using the 2015 IPND criteria.

When we applied the 2015 IPND criteria to the patients with NMOSD with AQP4-IgG who were assumed to have an unknown AQP4-IgG status, 72% (162/226) of the patients with NMOSD with AQP4-IgG were diagnosed by the 2015 IPND criteria. If 12 patients who were treated with immunosuppressants after their first attack were excluded to avoid the treatment effect, the diagnosis rate increased to 75% (161/214). Under the assumption of an unknown AQP4-IgG status, the difference in the diagnosis rate between the previous criteria (93/226, 41%) and the 2015 IPND criteria was remarkable. Considering the real-world circumstance in which the AQP4-IgG assay is not always available in a timely manner, such an improved diagnosis rate without AQP4-IgG is meaningful. In addition, under the assumption of an unknown AQP4-IgG status, the median time to diagnosis after onset was within 1 year (11 months), and over 70% of patients fulfilled the 2015 IPND criteria within 2 years of onset (73%) or after a second attack (72%). These findings elucidated that the 2015 IPND criteria properly detected NMOSD at the early stage of the disease, even without knowing the AQP4-IgG status.

On the other hand, confirmation of the AQP4-IgG status was particularly important in a subset of the patients with NMOSD who presented with isolated CNS syndromes. Seven (3%) patients who presented with isolated brain syndromes (including acute brainstem, diencephalic syndromes, and symptomatic cerebral syndrome) with NMOSD-typical brain lesions did not fall into the first criterion associated with the core clinical characteristics. The second criterion, associated with dissemination in space, had the lowest positivity (74%) in patients with NMOSD with AQP4-IgG. Several previous studies have suggested that isolated CNS syndromes evolve from a diverse etiologic spectrum.27,28 However, isolated CNS syndromes (26%) were not uncommon in patients with NMOSD with AQP4-IgG, and 73% (43/59) of them experienced relapses, restricted to one of the optic nerves or the spinal cord or the brain, during the median disease duration of 5 years. In our cohort, patients with isolated CNS syndromes were diagnosed with NMOSD because of AQP4-IgG positivity; however, if the AQP4-IgG status was not defined, the diagnosis would be delayed. Furthermore, we previously observed that the early clinical events of NMOSD tended to recur in the same anatomical location of the CNS.29 Therefore, for the diagnosis of NMOSD in suspected patients with an unknown AQP4-IgG status who present with isolated CNS syndromes, repetition of the AQP4-IgG assays using validated methods is required.24,30,–,32

Not surprisingly, we found that acute myelitis and optic neuritis were the core clinical characteristics of NMOSD.5,–,7,9,10 Acute myelitis was the most common clinical presentation in patients with NMOSD with AQP4-IgG throughout the duration of the disease. Optic neuritis was the most common initial clinical manifestation in patients with or without AQP4-IgG. Symptomatic brain syndromes (40%) were not uncommon, and area postrema syndrome (16%), acute brainstem syndrome with periependymal lesions (16%), and other cerebral syndromes with NMOSD-typical lesions (15%) were observed at similar frequencies throughout the disease duration.

In our cohort, reliable assays for AQP4-IgG, including ELISA and CBA, were performed repeatedly over the course of the disease duration (9.2 ± 5.7 years). Although the mean sensitivity of CBA, which is strongly recommended in the 2015 IPND criteria, has been reported to be up to 76.7%,8,24,31,32 the sensitivity in routine clinical practice, especially during the early phases of disease and in non-NMOSD-specialized hospitals, was unknown. Thus, repetition of such assays is highly recommended, particularly in suspected patients who have not yet satisfied the dissemination in space criteria. Using these repeated validated assays, only a minority (10%) of patients with NMOSD fell into the group without AQP4-IgG. The overall demographics and clinical presentation were not significantly different between the patients with NMOSD with and without AQP4-IgG. However, the proportions of optic neuritis and symptomatic cerebral syndrome were significantly higher in patients with NMOSD without AQP4-IgG than those with AQP4-IgG throughout the disease duration. Previous studies have suggested that seronegative NMO may reflect suboptimal assay sensitivity, the effects of immunotherapy, or uniform clinical phenotypes with heterogeneous pathogenesis.5,33,34 Recent studies have reported a subset of anti–myelin oligodendrocyte glycoprotein (MOG) antibody–positive patients who were negative for AQP4-IgG.35,36 Further studies, including the assessment of the MOG antibody, are required to fully elucidate the etiologic spectrum and pathogenesis of patients with NMOSD without AQP4-IgG.

The retrospective nature of this study and enrollment of patients from a single referral center with only Asian population were methodologic shortcomings and resulted in an unintentional selection bias, such as the preferred enrollment of patients with high disease activity, which might have affected the results. Further studies that are preferably prospective and include other ethnic groups are required. In addition, because of the difficulties with selection of the standard reference, diagnostic specificity remained unknown, particularly in the seronegative group.

Nevertheless, we verified the usefulness of the 2015 IPND criteria for the diagnosis of NMOSD, even with an unknown AQP4-IgG status in a large cohort. However, no clinical or radiologic characteristics were pathognomonic for NMOSD, and AQP4-IgG false-positive and false-negative results were observed in previous studies.30,–,32,37 Therefore, integral clinical judgment with a comprehensive understanding of the clinical and radiologic characteristics of NMOSD and the repetition of validated assays for AQP4-IgG are warranted to maximize the usefulness of the 2015 IPND criteria.

AUTHOR CONTRIBUTIONS

Dr. Hyun and Dr. H.J. Kim had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Dr. Hyun, Dr. H.J. Kim, and Dr. S.-H. Kim. Drafting of the manuscript: Dr. Hyun, Dr. H.J. Kim, and Dr. S.-H. Kim. Acquisition, analysis, and interpretation of data: Dr. Hyun, Dr. H.J. Kim, Dr. S.-H. Kim, Dr. Jeong, and A. Joung. Statistical analysis: Dr. Hyun, Dr. H.J. Kim, and Dr. S.-H. Kim. Critical revision of the manuscript for important intellectual content: Dr. Hyun, Dr. H.J. Kim, Dr. S.-H. Kim, Dr. Jeong, and A. Joung.

STUDY FUNDING

No targeted funding reported.

DISCLOSURE

J. Hyun, I. Jeong, A. Joung, and S. Kim report no disclosures relevant to the manuscript. H. Kim has received honoraria for speaking or consulting for Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, Novartis, MedImmune, and Teva-Handok and has received research grants from Genzyme, Merck Serono, and Kael-GemVax. He serves on a steering committee for MedImmune and serves as an editor for the Multiple Sclerosis Journal: Experimental, Translational and Clinical. Go to Neurology.org for full disclosures.

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Received September 23, 2015.
  • Accepted in final form January 28, 2016.

REFERENCES

  1. 1.↵
    1. Lennon VA,
    2. Wingerchuk DM,
    3. Kryzer TJ,
    4. et al
    . A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004;364:2106–2112.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Lennon VA,
    2. Kryzer TJ,
    3. Pittock SJ,
    4. Verkman AS,
    5. Hinson SR
    . IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005;202:473–477.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Bennett JL,
    2. Lam C,
    3. Kalluri SR,
    4. et al
    . Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol 2009;66:617–629.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Papadopoulos MC,
    2. Verkman AS
    . Aquaporin 4 and neuromyelitis optica. Lancet Neurol 2012;11:535–544.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Wingerchuk DM,
    2. Lennon VA,
    3. Lucchinetti CF,
    4. Pittock SJ,
    5. Weinshenker BG
    . The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805–815.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Nagaishi A,
    2. Takagi M,
    3. Umemura A,
    4. et al
    . Clinical features of neuromyelitis optica in a large Japanese cohort: comparison between phenotypes. J Neurol Neurosurg Psychiatry 2011;82:1360–1364.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Kim SH,
    2. Kim W,
    3. Li XF,
    4. Jung IJ,
    5. Kim HJ
    . Clinical spectrum of CNS aquaporin–4 autoimmunity. Neurology 2012;78:1179–1185.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Sato DK,
    2. Nakashima I,
    3. Takahashi T,
    4. et al
    . Aquaporin-4 antibody-positive cases beyond current diagnostic criteria for NMO spectrum disorders. Neurology 2013;80:2210–2216.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Wingerchuk DM,
    2. Lennon VA,
    3. Pittock SJ,
    4. Lucchinetti CF,
    5. Weinshenker BG
    . Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485–1489.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Collongues N,
    2. Marignier R,
    3. Zephir H,
    4. et al
    . High-risk syndrome for neuromyelitis optica: a descriptive and comparative study. Mult Scler 2011;17:720–724.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Yanagawa K,
    2. Kawachi I,
    3. Toyoshima Y,
    4. et al
    . Pathologic and immunologic profiles of a limited form of neuromyelitis optica with myelitis. Neurology 2009;73:1628–1637.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Misu T,
    2. Fujihara K,
    3. Nakashima I,
    4. Sato S,
    5. Itoyama Y
    . Intractable hiccup and nausea with periaqueductal lesions in neuromyelitis optica. Neurology 2005;65:1479–1482.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Poppe AY,
    2. Lapierre Y,
    3. Melancon D,
    4. et al
    . Neuromyelitis optica with hypothalamic involvement. Mult Scler 2005;11:617–621.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Pittock SJ,
    2. Lennon VA,
    3. Krecke K,
    4. Wingerchuk DM,
    5. Lucchinetti CF,
    6. Weinshenker BG
    . Brain abnormalities in neuromyelitis optica. Arch Neurol 2006;63:390–396.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Pittock SJ,
    2. Weinshenker BG,
    3. Lucchinetti CF,
    4. Wingerchuk DM,
    5. Corboy JR,
    6. Lennon VA
    . Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol 2006;63:964–968.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Nakamura M,
    2. Misu T,
    3. Fujihara K,
    4. et al
    . Occurrence of acute large and edematous callosal lesions in neuromyelitis optica. Mult Scler 2009;15:695–700.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Magana SM,
    2. Matiello M,
    3. Pittock SJ,
    4. et al
    . Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders. Neurology 2009;72:712–717.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Kim W,
    2. Park MS,
    3. Lee SH,
    4. et al
    . Characteristic brain magnetic resonance imaging abnormalities in central nervous system aquaporin-4 autoimmunity. Mult Scler 2010;16:1229–1236.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Kremer L,
    2. Mealy M,
    3. Jacob A,
    4. et al
    . Brainstem manifestations in neuromyelitis optica: a multicenter study of 258 patients. Mult Scler 2014;20:843–847.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Kim W,
    2. Kim SH,
    3. Lee SH,
    4. Li XF,
    5. Kim HJ
    . Brain abnormalities as an initial manifestation of neuromyelitis optica spectrum disorder. Mult Scler 2011;17:1107–1112.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Matthews L,
    2. Marasco R,
    3. Jenkinson M,
    4. et al
    . Distinction of seropositive NMO spectrum disorder and MS brain lesion distribution. Neurology 2013;80:1330–1337.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Kim HJ,
    2. Paul F,
    3. Lana-Peixoto MA,
    4. et al
    . MRI characteristics of neuromyelitis optica spectrum disorder: an international update. Neurology 2015;84:1165–1173.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Kim SH,
    2. Huh SY,
    3. Hyun JW,
    4. et al
    . A longitudinal brain magnetic resonance imaging study of neuromyelitis optica spectrum disorder. PLoS One 2014;9:e108320.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Wingerchuk DM,
    2. Banwell B,
    3. Bennett JL,
    4. et al
    . International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85:177–189.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Jarius S,
    2. Probst C,
    3. Borowski K,
    4. et al
    . Standardized method for the detection of antibodies to aquaporin-4 based on a highly sensitive immunofluorescence assay employing recombinant target antigen. J Neurol Sci 2010;291:52–56.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Kim W,
    2. Lee JE,
    3. Li XF,
    4. et al
    . Quantitative measurement of anti-aquaporin-4 antibodies by enzyme-linked immunosorbent assay using purified recombinant human aquaporin-4. Multi Scler 2012;18:578–586.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    1. Jarius S,
    2. Frederikson J,
    3. Waters P,
    4. et al
    . Frequency and prognostic impact of antibodies to aquaporin-4 in patients with optic neuritis. J Neurol Sci 2010;298:158–162.
    OpenUrlCrossRefPubMed
  28. 28.↵
    1. Hyun JW,
    2. Kim SH,
    3. Huh SY,
    4. et al
    . Idiopathic aquaporin-4 antibody negative longitudinally extensive transverse myelitis. Mult Scler 2015;21:710–717.
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    1. Zandoná ME,
    2. Kim SH,
    3. Hyun JW,
    4. et al
    . The onset location of neuromyelitis optica spectrum disorder predicts the location of subsequent relapses. Mult Scler 2014;20:1908–1911.
    OpenUrlAbstract/FREE Full Text
  30. 30.↵
    1. Jarius S,
    2. Wildemann B
    . AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 2010;6:383–392.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Waters PJ,
    2. McKeon A,
    3. Leite MI,
    4. et al
    . Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays. Neurology 2012;78:665–671.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    1. Jiao Y,
    2. Fryer JP,
    3. Lennon VA,
    4. et al
    . Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica. Neurology 2013;81:1197–1204.
    OpenUrlAbstract/FREE Full Text
  33. 33.↵
    1. Marignier R,
    2. Bernard-Valnet R,
    3. Giraudon P,
    4. et al
    . Aquaporin-4 antibody-negative neuromyelitis optica: distinct assay sensitivity-dependent entity. Neurology 2013;80:2194–2200.
    OpenUrlAbstract/FREE Full Text
  34. 34.↵
    1. Jarius S,
    2. Ruprecht K,
    3. Wildemann B,
    4. et al
    . Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicenter study of 175 patients. J Neuroinflammation 2012;9:14.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Kitley J,
    2. Woodhall M,
    3. Waters P,
    4. et al
    . Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 2012;79:1273–1277.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Sato DK,
    2. Callegaro D,
    3. Lana-Peixoto MA,
    4. et al
    . Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 2014;82:474–481.
    OpenUrlAbstract/FREE Full Text
  37. 37.↵
    1. Pittock SJ,
    2. Lennon VA,
    3. Bakshi N,
    4. et al
    . Seroprevalence of aquaporin-4-IgG in a northern California population representative cohort of multiple sclerosis. JAMA Neurol 2014;71:1433–1436.
    OpenUrlPubMed

Letters: Rapid online correspondence

Comment

REQUIREMENTS

You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. [email protected]
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
Advertisement

Topics Discussed

Alert Me

Recommended articles