|Year : 2013 | Volume
| Issue : 3 | Page : 376-379
Neuromyelitis optica-IgG testing in an Indian cohort with neuromyelitis optica and related demyelinating disorders: Our experience
Narayanan Unni1, Kavita Barhate2, Nisha Ahmad3, Malti Ganeshan2, Bhim Singhal2
1 Department of Neurology, Daya General Hospital, Trichur, India
2 Department of Neurology, Bombay Hospital Institute of Medical Sciences, Mumbai, India
3 Department of Clinical Chemistry and Haematology, Metropolis Health Services, Mumbai, India
|Date of Submission||05-Oct-2012|
|Date of Decision||24-Oct-2012|
|Date of Acceptance||16-Jan-2013|
|Date of Web Publication||26-Aug-2013|
131, MRC Building, Bombay Hospital Institute of Medical Sciences, 12 New Marine Lines, Mumbai - 400 020, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Neuromyelitis optica (NMO) is an immune-mediated inflammatory demyelinating disorder of the central nervous system with a predilection for the optic nerves and the spinal cord. Immunopathological evidence suggests that the target antigen of the disease is aquaporin-4. An IgG antibody against this protein has been explored as a molecular marker for the disease and as a diagnostic tool due to its high sensitivity and specificity in various populations. Objective: To assess the value of NMO-IgG testing in Indian patients with clinical and magnetic resonance imaging features consistent with NMO and longitudinally extensive transverse myelitis (LETM). Materials and Methods: Forty-five patients with clinical and magnetic resonance imaging features consistent with NMO, LETM, and MS were tested for serum NMO-IgG. Of these patients, 22 patients satisfied revised (2006) Wingerchuk criteria for NMO (excluding NMO-IgG status) and 11 patients had LETM. Twelve patients satisfied the revised (2010) McDonald criteria for multiple sclerosis (MS). Results: Of the 21 patients, satisfying the criteria for NMO and for whom the test results were available, 17 were positive for NMO-IgG (80.9%), and of the 11 patients having LETM, 6 (54.5%) were positive for NMO-IgG. In one patient with NMO, the test result was not available. None of the 12 patients satisfying McDonald criteria for MS showed NMO-IgG seropositivity. Conclusion: Our study suggests that it is worthwhile to pursue NMO-IgG testing as a diagnostic tool for patients with clinical and Magnetic Resonance Imaging (MRI) features consistent with NMO and LETM in the Indian population.
Keywords: Anti-aquaporin-4 seropositivity, neuromyelitis optica, neuromyelitis optica-Immunoglobulin G seropositivity, transverse myelitis
|How to cite this article:|
Unni N, Barhate K, Ahmad N, Ganeshan M, Singhal B. Neuromyelitis optica-IgG testing in an Indian cohort with neuromyelitis optica and related demyelinating disorders: Our experience. Ann Indian Acad Neurol 2013;16:376-9
|How to cite this URL:|
Unni N, Barhate K, Ahmad N, Ganeshan M, Singhal B. Neuromyelitis optica-IgG testing in an Indian cohort with neuromyelitis optica and related demyelinating disorders: Our experience. Ann Indian Acad Neurol [serial online] 2013 [cited 2019 Sep 15];16:376-9. Available from: http://www.annalsofian.org/text.asp?2013/16/3/376/116945
| Introduction|| |
Neuromyelitis optica (NMO) has several unique features which distinguish it from multiple sclerosis (MS), with respect to lesional topography, severity of exacerbations, MR imaging findings, cerebrospinal fluid (CSF) CSF abnormalities, immunopathology, therapy, and therapeutic response. 
The diagnosis is made by the revised Wingerchuk diagnostic criteria, which requires the presence of optic neuritis and myelitis, plus any two of the following: (a) brain MRI not satisfying the McDonald criteria; (b) MRI T2 lesions spanning three or more vertebral segments; and (c) positive serology for NMO-IgG (anti-Aquaporin-4 antibody).  NMO antibody is said to be 91% sensitive and 100% specific. 
Although NMO is known to occur in India,  there is a paucity of data concerning NMO-IgG status. The objective of the study was to assess the value of NMO-IgG testing in Indian patients with clinical and magnetic resonance imaging features consistent with NMO and longitudinally extensive transverse myelitis (LETM).
| Materials and Methods|| |
During the study period from January 2010 to April 2012, 347 patients with demyelinating diseases were seen by us at the outpatient and inpatient department of a tertiary care hospital. These included 230 new cases and 117 follow-up cases. For this retrospective study, inclusion criteria were as follows:
- NMO: Patients with clinical and MRI features satisfying revised Wingerchuk criteria (2006).
- LETM: Patients having myelitis involving ≥ 3 spinal segments on MRI and brain MRI not satisfying revised McDonald criteria (2010).
- MS: Patients satisfying revised McDonald criteria (2010) for whom NMO-IgG test results were available from the records.
Forty-five patients (22 NMO, 11 LETM, and 12 MS) satisfied these criteria. Of the 22 patients with clinical and MRI features consistent with NMO, test results were available for 21 and unavailable for 1 patient. MS patients were included as internal controls. Patients came to the department mostly as referrals and therefore were seen by us at variable intervals from the onset of the disease and from the time of treatment for acute episodes.
NMO (anti-aquaporin-4) antibody testing was done by indirect immunofluorescence using the Euroimmun kit (Luebeck, Germany), a visual fluorescence-observation cell-based assay that incorporated fixed HEK293 cells transfected singly with either human AQP4-M1 or M23 isoform.  Testing was carried out at Metropolis Healthcare Limited, Mumbai. The study was approved by the institutional ethics committee.
| Results|| |
Seventeen of 21 (80.9%) patients with clinical and MRI features consistent with NMO and 6 of 11 (54.5%) patients with LETM were positive for NMO-IgG [Graph 1] [Additional file 1]. None of the MS patients was positive for NMO-IgG. One female NMO patient was lost to follow-up and NMO-IgG result was not available. She had presented at the age of 24 with unilateral optic neuritis and had one subsequent relapse of optic neuritis and one of myelitis.
Clinical details of NMO and LETM patients are summarized in [Table 1] and [Table 2], respectively.
|Table 2: Clinical details of longitudinally extensive transverse myelitis group|
Click here to view
| Discussion|| |
Historically, NMO was characterized by near-simultaneous development of bilateral optic neuritis and acute transverse myelitis with no other CNS involvement.  It was postulated to have a monophasic course resulting in significant neurodeficit.  Furthermore, whether NMO is a subtype of MS or a separate entity remained controversial till recently.  There were many reports about the higher incidence of NMO in Asia, especially in Japan, than in Western populations.  A similarly high rate of incidence of NMO was reported in India, 7.1% of total number of MS patients, comparable to 7.6% in a series in Japan.  Subsequently, NMO was reported to have a relapsing course  and has been recognized as a separate entity from MS with distinct clinical, radiological, and pathological features. 
Studies to isolate a molecular marker for NMO identified an NMO-specific human IgG  that binds selectively to aquaporin-4, a water channel.  Distribution of aquaporin-4-rich sites in the CNS is highly compatible with that of NMO lesions.  The identification of the anti-aquaporin-4 antibody led to revision of the diagnostic criteria for NMO to include NMO-IgG (anti-aquaporin-4) seropositivity status.  This increased the sensitivity and specificity of the criteria. 
The advent of the NMO antibody refined the diagnosis of NMO and NMO spectrum disorders to include various limited syndromes with NMO-IgG seropositivity.  NMO-IgG testing aids the diagnosis of limited syndromes such as severe optic neuritis or isolated LETM, or when the MRI shows a long lesion less than three vertebral segments in length. This has significant therapeutic implications.  Relying solely on MRI appearances for diagnosis can be misleading for two reasons: The first is that MRI should preferably be performed in the acute myelitis stage, as long lesions may resolve entirely or atrophy may ensue in later stages.  The second is that coalescence of multiple plaques can occur in MS, which may be mistaken for a long cord lesion. 
NMO antibody seropositivity needs to be tested within diverse populations to assess its usefulness as a diagnostic tool. Jarius et al.  found a seropositivity of 61.11% (22 of 36) among NMO patients as defined by the 1999 Wingerchuk criteria; 35 of these 36 patients had long cord lesions. A Brazilian study  found NMO-IgG seropositivity in 18 of 28 (64.3%) of NMO patients as defined by 1999 Wingerchuk criteria. In a study by Takahashi et al.,  20 of 22 (90.9%) NMO patients, defined by the 2006 Wingerchuk criteria, were positive for NMO-IgG. Our study found that 80.9% of patients with NMO and 54.5% patients with LETM were positive for NMO-IgG. Our result contrasts with the findings in a study by Pandit  where only 1 out of 8 patients of NMO (12.5%) was positive. Our study suggests that it is worthwhile to consider the diagnostic usefulness of NMO-IgG testing even in Indian patients, given that NMO-IgG testing has been shown to be highly sensitive and specific in several studies ,, [Graph 2] [Additional file 2].
Takahashi et al.  found a positive correlation between antibody titers and lesion length at the nadir of exacerbation. They also found a decrease in antibody titer during relapse-free periods under immunosuppressive therapy, as well as after high-dose intravenous methylprednisolone. This has not been systematically examined in this study. However, one patient was seronegative when tested post-treatment with methylprednisolone and plasmapheresis, but tested positive 14 months later. Therefore, there is evidence of fluctuation in antibody titer depending on the state of the disease. Hence, the timing of sample collection for NMO testing would be crucial if it is to be accepted as a diagnostic marker.
Another factor in the use of NMO-IgG status as a diagnostic tool is the sensitivity and specificity of the assay method used. A multicenter study conducted by Waters et al.  compared commercially available transfected cell-based assays (CBA), a commercially available ELISA-based assay, a fluorescence immunoprecipitation assay, a tissue-based immunofluorescence assay, an in-house quantitative flow cytometry assay, and a combination of commercially available cell-based and ELISA assays. The most sensitive assays were those detecting IgG binding to cells expressing recombinant AQP4 with quantitative flow cytometry (77%; 46 of 60) or visual observation (CBA, 73%; 44 of 60).  The present study employed the commercially available CBA.
This retrospective study has the limitation that most patients came to us in the form of referrals. Therefore, NMO-IgG status at the time of the first relapse could not be determined. In addition, our study included only NMO patients with clinical and MRI features satisfying revised Wingerchuk criteria (2006). This brings in a selection bias which influences NMO-IgG seropositivity in our study group. Previous studies have indicated the influence of selection bias in reported NMO-IgG seropositivity.  The higher proportion of patients with relapsing forms of the disease  and the female preponderance  in our data set may also have contributed to the high seropositivity. Further investigation with a larger sample size should help to clarify the Indian scenario with regard to NMO-IgG seropostivity.
| Conclusion|| |
Our study suggests that it is worthwhile to pursue NMO-IgG testing as a diagnostic tool for patients presenting with clinical and MRI features consistent with NMO and LETM in the Indian population.
| References|| |
|1.||Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet 2004;364:2106-12. |
|2.||Wingerchuk DM, Lennon VA, Pittock SJ, Luchinetti CF, Weinshenker BG. Revised diagnostic criteria for Neuromyelitis optica. Neurology 2006;66:1485-9. |
|3.||Takahashi T, Fujihara K, Nakashima I, Misu T, Miyazawa I, Nakamura M, et al. Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: A study on antibody titre. Brain 2007;130:1235-43. |
|4.||Jain S, Maheshwari MC. Multiple sclerosis: Indian experience in the last thirty years. Neuroepidemiology 1985;4:96-107. |
|5.||Waters PJ, McKeon A, Leite MI, Rajasekharan S, Lennon VA, Villalobos A, et al. Serologic diagnosis of NMO: A multicenter comparison of aquaporin-4-IgG assays. Neurology 2012;78:665-71. |
|6.||Kuroiwa Y. Neuromyelitis optica. Demyelinating diseases. In: Vinken PJ, Bruyn GW, Klawans HL, editors. Handbook of Clinical Neurology. Vol. 3. Amsterdam: Elsevier Science Publishers; 1985. p. 397-408. |
|7.||Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic's syndrome). Neurology 1999;53:1107-14. |
|8.||Singhal BS. Clinical profile and HLA-studies in Indian multiple sclerosis patients from the Bombay region. In: Kuroiwa Y, Kurland LT, editors. Multiple Sclerosis East and West. Japan: Kyushu University Press; 1982. p. 123-34. |
|9.||Weinshenker BG. Neuromyelitis optica in western countries: Establishing diagnostic criteria and characterization of the spectrum. Neurol Asia 2008;13:161-6. |
|10.||Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005;202:473-7. |
|11.||Lana-Peixoto MA. Devic's neuromyelitis optica: A critical review. Arq Neuropsiquiatr 2008;66:120-38. |
|12.||Jacob A. Neuromyelitis optica-an update: 2007-2009. Ann Indian Acad Neurol 2009;12:231-7. |
|13.||Jacob A, Matiello M, Wingerchuk DM, Lucchinetti CF, Pittock SJ, Weinshenker BG. Neuromyelitis optica: Changing concepts. J Neuroimmunol 2007;187:126-38. |
|14.||Jarius S, Franciotta D, Bergamaschi R, Wright H, Littleton E, Palace J, et al. NMO-IgG in the diagnosis of neuromyelitis optica. Neurology 2007;68:1076-7. |
|15.||Adoni T, Lino AM, Marchiori PE, Kok F, Callegaro D. Seroprevalence of NMO-IgG antibody in Brazilian patients with neuromyelitis optica. Arq Neuropsiquiatr 2008;66:295-7. |
|16.||Pandit L. Neuromyelitis optica antibody (NMO-IgG) status in Indian patients with multiple sclerosis and allied demyelinating disorders. Neurol Asia 2008;13:175-8. |
|17.||Jarius S, Paul F, Franciotta D, Aktas O, Hohlfeld R, Zipp F, et al. Revised diagnostic criteria for neuromyelitis optica: Incorporation of NMO-IgG status. Nat Clin Pract Neurol 2007;3:e1. |
|18.||Kira J. Neuromyelitis optica and asian phenotype of multiple sclerosis. Ann N Y Acad Sci 2008;1142:58-71. |
|19.||Jarius S, Ruprecht K, Wildemann B, Kuempfel T, Ringelstein M, Geis C, et al. Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients. J Neuroinflammation 2012;9:14-31. |
[Table 1], [Table 2]
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