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Show Neuromyelitis Optica Antibodies in Patients With Severe Optic Neuritis in China Chuntao Lai, MD, Guohong Tian, MD, PhD, Toshiyuki Takahashi, MD, PhD, Wu Liu, MD, PhD, Ling Yang, PhD, Xiaojun Zhang, MD, PhD Background: Severe visual loss is seen in both multiple sclerosis-associated optic neuritis (ON) and neuro-myelitis optica (NMO)-associated ON. NMO (aquaporin 4) antibodies have been reported to have diagnostic and prognostic value for visual and neurological outcomes of recurrent ON. We performed this study to investigate the frequency of NMO antibodies and its prognostic value for visual and neurological outcomes in Chinese patients with severe ON. Methods: Single-center prospective cohort study. Detection of NMO antibodies was by indirect immunoflu-orescence method using human aquaporin 4-transfected cells. Severe ON was defined as visual acuity of 20/200 or worse in at least 1 eye at the nadir of the patients' course. Clinical features at baseline, visual outcome, and sequential neurological events were compared between seropositive and seronegative groups. Results: NMO antibodies were detected in 11 of 34 patients (32.4%) with severe ON. Five seropositive patients with recurrent ON had significantly higher titers (range: 1:512 to 1:65,536; median: 1:512) than those of 6 seropositive patients with only 1 episode (range: 1:16 to 1:512; median: 1:32) (P = 0.021). Female to male ratio (10:1) and antinuclear autoantibody positivity in seropositive patients (3 of 9, 33.3%) were statistically higher than those of the seronegative group (12:11; 0 of 19; P = 0.026). The seropositive patients had signifi-cantly poorer visual outcomes than seronegative patients (P = 0.025). During the averaged 32-month follow-up, 2 of 11 seropositive patients (18.2%) developed clinically incomplete transverse myelitis, while no similar symp-toms were reported in the seronegative group. Conclusion: NMO antibody positivity is relatively high in Chinese patients with severe ON and suggests a poorer visual outcome, probably higher risk of developing spinal cord lesions and a closer association with systemic autoimmune disorders. Journal of Neuro-Ophthalmology 2011;31:16-19 doi: 10.1097/WNO.0b013e3181f8a693 2011 by North American Neuro-Ophthalmology Society Severe visual loss may occur in both demyelinating optic neuritis (ON), which is strongly associated with mul-tiple sclerosis (MS) and neuromyelitis optica (NMO) (1,2). In 2004, Lennon et al (3) reported a highly sensitive and specific antibody (NMO-immunoglobulin G) in patients with NMO and subsequently found that this antibody was bound selectively to aquaporin 4 (AQP4) water channel of astrocytic foot processes (4). More recently, patients with recurrent ON who are seropositive for this antibody were found to have a poorer visual outcome and increased chances of developing NMO compared to seronegative patients (5). The purpose of this study was to determine the fre-quency of NMO antibody seropositivity in Chinese patients with severe ON, characterize the clinical features of these individuals, and determine their visual and neurological outcome. METHODS The study cohort consisted of patients with unilateral or bilateral isolated or recurrent ON seen from May 2007 to May 2008 and admitted to the Department of Neurology of Beijing Tongren Hospital, Capital Medical University. Only patients with ON with visual acuity of 20/200 or worse in at least 1 eye at the nadir were included for this study. All Department of Neurology, Beijing Tongren Hospital (CL, GT, XZ), Capital Medical University, Beijing, China; Department of Neurol-ogy (TT), Tohoku University Graduate School of Medicine, Sendai, Japan; and Beijing Tongren Eye Center (WL), Central Laboratory (LY), Beijing Tongren Hospital, Capital Medical University, Beijing, China. Funding received: Beijing ‘‘Ten-hundred-thousand'' Talented Doc-tor Project, 2009. Conflict of interest: No. Address correspondence to Dr Xiaojun Zhang, MD, PhD, De-partment of Neurology, Beijing Tongren Hospital, Capital Medical University, No 1 Dong Jiao Min Xiang, Dongcheng District, Beijing 100730, China; E-mail: zxjsusan1@yahoo.com 16 Lai et al: J Neuro-Ophthalmol 2011; 31: 16-19 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. patients had complete medical history, ophthalmological and neurological examinations, brain and orbital MRI with short T1 inversion recovery sequences, laboratory testing for fluorescent treponemal antibody absorption, and mito-chondrial DNA sequencing to rule out other possible causes of optic neuropathy. The majority of patients had a lumbar puncture and testing for autoimmune diseases including erythrocyte sedimentation rate, C-reactive protein, anti-nuclear antibody (ANA), extractable nuclear antigen, and antineutrophil cytoplasmic antibody (ANCA). After the protocol was approved by the Institutional Review Board of Beijing Tongren Hospital, Capital Medical University, patients gave informed consent and blood was obtained for NMO antibody within 1 month of onset of visual loss. The serum samples were sent to the Department of Neurology, Tohoku University Graduate School of Medicine, and the antibody was detected by the indirect immunofluorescence method using human AQP4- transfected cells. The cutoff value for positivity (minimal dilution of serum) was 1:4. Demographic and clinical data were recorded together with the NMO antibody results. Visual acuity of each eye was scaled as follows: 0 = 20/20; 1 = better than 20/30; 2 = 20/30 to 20/59; 3 = 20/60 to 20/199; 4 = 20/200 to 20/800; 5 = count fingers only; 6 = light perception; and 7 = no light perception. Patients were followed up clinically or by phone if the patient could not come to the clinic. We compared the demographic and clinical features at baseline, the visual and neurological outcomes of the NMO antibody seropositive and seronegative groups, using Fisher exact test for frequency data, t test for continuous data, and Mann- Whitney U test for non-normally distributed data. RESULTS NMO Antibody Test NMO antibody testing was performed in 34 patients with severe ON. Patients ranged in age from 16 to 54 years (average: 31.1 years). There were 22 women and 12 men. NMO antibody was positive in 11 of 34 patients (32.4%) with severe ON. While 6 of 23 patients (26.1%) with 1 episode of ON were seropositive, the rate was higher (5 of 11, 45.5%) in patients with recurrent ON but did not reach statistical significance (Fisher exact test, P = 0.434). The overall range of antibody titers was from 1:16 to 1:65,536. The 5 seropositive patients with recurrent ON had signif-icantly higher titers (range: 1:512 to 1:65,536; median: 1:512) than those of the 6 seropositive patients with isolated ON (1:16 to 1:512; median, 1:32) (P = 0.021). Comparison of Seropositive and Seronegative Patients Clinical features, MRI findings, blood and cerebro-spinal fluid results at baseline, and follow-up data were compared between the seropositive and seronegative groups. Baseline Data No statistically significant differences were found between the 2 groups regarding the age of onset, number of attacks, visual acuity at nadir, and bilateral or subsequent in-volvement of both optic nerves (Table 1). Mild and sparse white matter lesions on brain MRI were reported in 7 of 23 seronegative patients (30.4%) and 3 of 11 seropositive patients (27.3%). No difference was found with respect to the number or location of white matter lesions between the 2 groups. The female gender ratio was much higher in the seropositive group (female:male = 10:1) than in the sero-negative group (female:male = 12:11), but the difference did not reach statistical significance (P = 0.053). ANA was tested in 9 seropositive patients, 3 of which (33.3%) were positive at over 1:320 level, while none of the 19 sero-negative patients were ANA positive (P = 0.026). At the time of testing, no patient with ANA positivity met the diagnostic criteria for Sjo¨gren syndrome, systemic lupus erythematosus, or any other autoimmune disease. Follow-up Data Follow-up information was available in 10 of 11 seropos-itive patients (91.0%) and 19 of 23 seronegative patients (82.6%). Follow-up time was similar between the 2 groups (Table 1). Two of 10 seropositive ON cases and 1 of 19 seronegative ON cases had at least 1 additional episode of ON (P = 0.239). Final visual scores of the seropositive group were worse than those of the seronegative group (P = 0.025) (Table 1). At the last follow-up examination, 8 of 10 seropositive patients (80%) had visual acuity worse than 20/ 200 in at least 1 eye, while this poor visual outcome was present in only 3 of 20 seronegative patients (15%). During follow-up, while none of the seronegative patients reported symptoms due to lesions other than the optic nerve, 2 seropositive patients developed incomplete transverse myelitis. DISCUSSION Lennon et al (4) initially reported that 25% of patients with recurrent ON (simultaneous or sequential) were seroposi-tive for NMO antibodies and noted a similar result (5 of 25, 20%) in a more recent study (5). Chan et al (6), in the first report dealing with NMO antibody in Chinese patients, found that 2 of 9 patients (22%) with recurrent ON were seropositive and 1 of 11 patients (9.1%) with isolated ON. Our study showed that 11 of 34 Chinese patients (32.4%) with severe ON were seropositive, and there was an even higher rate (45.5%) of positivity in the group with recurrent ON. Compared to the previous reports in both white (3,5,7) and Asian (6) patients, our rate of seropositivity is Lai et al: J Neuro-Ophthalmol 2011; 31: 16-19 17 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. higher. Because these studies identified patients with both mild and severe ON, our results suggests that NMO antibodies are more likely to be found in cases of severe ON. Our results are similar to those of Matiello et al (5) in finding no significant difference between seropositive and seronegative groups regarding age, bilaterally simultaneous or subsequent onset of visual loss, and the number of recurrent attacks. No difference was found in the brain MRI findings between the 2 groups. The only statistically significant dif-ference we found was the frequency of a positive ANA test. One third of the seropositive patients were ANApositive, while none of the seronegative patients were ANA positive. It has been reported that NMO is often associated with clinical or serological markers of systemic autoimmune disorders such as ANA and Sjo¨gren syndrome A antibodies (1,8), although the basis of coexisting NMO and systemic autoimmune disorders is unknown. The comparison of follow-up data in our study docu-mented that seropositive patients had much worse visual scores at the last follow-up than seronegative patients. This confirms that Chinese patients with severe ON have poorer visual outcome if they have NMO antibodies. Matiello et al (5) showed that during an average 8-year follow-up period, only 1 seronegative patient (6.6%) but 6 of 12 seropositive patients (50%) developed transverse myelitis (P = 0.03). Similarly, 2 of our seropositive patients with ON developed myelitis during the average 8-year months follow-up, while none of the seronegative patients reported myelitis episode. Yet, the number of patients is small and the length of follow-up is limited in both our report and that of Matiello et al (5), and further study is warranted to better define these seropositive patients with ON and subsequent development of spinal cord lesions. The findings of such investigation might also clarify the controversy regarding classification of NMO and optical-spinal MS (9-11). There were limitations to our study. Not all patients with ON were studied, only those admitted to hospital. Follow-up time was relatively short (Table 1). Due to financial reasons, we could not perform brain or spinal MRI on all patients during follow-up. In conclusion, we have shown that Chinese patients with severe ON have a higher frequency of NMO antibodies, which increase with recurrence of the optic neuropathy. Seropositive patients are more likely women with a greater likelihood of having autoimmune serological markers. Fi-nally, seropositive patients have a poor visual prognosis, and TABLE 1. Demographic, clinical, and outcome data stratified by NMO-immunoglobulin G (IgG) antibody status Baseline Characteristics Seronegative (n = 23) Seropositive (n = 11) P Age at onset, years, median (IQR) 35 (17-54) 28 (16-48) 0.164* Sex, F:M 12:11 10:1 0.053† No. patients with bilateral episodes (simultaneously and subsequently) of ON 4 2 1.000† No. patients with recurrent ON 6 5 0.240† Visual score at nadir, median (IQR) 5 (4-7) 5 (4-7) 0.976‡ Abnormal brain MRI (n, %) 7/23 (30.4) 3/11 (27.3) 1.000† Blood test Accelerated ESR (n, %) 1/20 (5) 1/10 (10) 1.000† Increased CRP (n,%) 1/22 (4.5) 0/11 1.000† ANCA positive (n, %) 0/19 0/8 - ANA ($1:320, %) 0/19 3/9 (33.3) 0.026† CSF analysis WBC ($10/mm3, n, %) 0/23 0/11 - OB of CSF (n, %) 2/11 (18.2) 2/11 (18.2) 1.000† IgG synthesis rate of CSF (n, %) 4/16 (25) 3/11 (27.3) 1.000† Follow-up data No. cases 19 10 - Time (mean 6 SD, months) 31.6 6 19.1 33.7 6 8.2 0.741* Visual score at the last follow-up of visual loss, median (IQR) 1 (0-6) 4 (0-7) 0.01‡ No. cases with final VA , 20/200 3 8 0.001† No. cases with recurrent ON 1 2 0.239† Cases with myelitis episodes (n, %) 0 (0) 2 (18.2) 0.111† *t test. †Fisher exact test. ‡Mann-Whitney U test. 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