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Show Comparison of Visual Acuity and Automated Perimetry Findings in Patients With Neuromyelitis Optica or Multiple Sclerosis After Single or Multiple Attacks of Optic Neuritis Danilo B. Fernandes, MD, Renata de Iracema P. Ramos, MD, Carolina Falcochio, MD, Samira Apóstolos-Pereira, MD, Dagoberto Callegaro, MD, PhD, Mário Luiz Ribeiro Monteiro, MD, PhD Objective: To review the clinical characteristics of patients with neuromyelitis optica (NMO) and to compare their visual outcome with those of patients with optic neuritis (ON) and multiple sclerosis (MS). Methods: Thirty-three patients with NMO underwent neuro-ophthalmic evaluation, including automated perimetry along with 30 patients with MS. Visual function in both groups was compared overall and specifically for eyes after a single episode of ON. Results: Visual function and average visual field (VF) mean deviation were significantly worse in eyes of patients with NMO. After a single episode of ON, the VF was normal in only 2 of 36 eyes of patients with NMO compared to 17 of 35 eyes with MS (P , 0.001). The statistical analysis indicated that after a single episode of ON, the odds ratio for having NMO was 6.0 (confidence interval [CI]: 1.6-21.9) when VF mean deviation was worse than -20.0 dB while the odds ratio for having MS was 16.0 (CI: 3.6-68.7) when better than -3.0 dB. Conclusion: Visual outcome was significantly worse in NMO than in MS. After a single episode of ON, suspicion of NMO should be raised in the presence of severe residual VF deficit with automated perimetry and lowered in the case of complete VF recovery. Journal of Neuro-Ophthalmology 2012;32:102-106 doi: 10.1097/WNO.0b013e31823a9ebc © 2012 by North American Neuro-Ophthalmology Society Neuromyelitis optica (NMO), or Devic disease, is a severe idiopathic immune-mediated inflammatory dis-ease predominantly affecting the spinal cord and optic nerves (1,2). NMO was originally considered an unusual variant of multiple sclerosis (MS), characterized by monophasic bilat-eral optic neuritis (ON) and acute transverse myelitis. How-ever, recent studies have demonstrated that most NMO patients have a relapsing course and that NMO and MS differ with regard to histopathologic and immunopathologic features (3,4). The discovery of NMO antibodies has made it possible to differentiate NMO from MS and define the clinical spectrum of the disorder (4,5). ON may occur simultaneously with, precede, or follow the development of myelitis. NMO patients with early isolated ON are often misdiagnosed with idiopathic or MS-related ON, a rela-tively common disorder, which tends to run a benign clinical course with spontaneous visual recovery over a 1-year period (6). The frequent occurrence of normal cranial MRI in NMO patients can further mislead to the diagnosis of benign self-limited disease. However, NMO is a much more disa-bling condition requiring prompt recognition and immuno-suppressive treatment. While establishing the diagnosis has been facilitated by the detection of NMO antibodies, clinical signs and symptoms are crucial for suspecting the disease and pursuing appropriate investigations. Furthermore, the sensi-tivity of currently available antibody assays is variable, and false-negative results are common (7,8). Several authors have reviewed the neurological and visual findings of NMO patients in attempting to distinguish between NMO and MS (9-11). Merle et al (12) addressed the visual outcome in patients with NMO in evaluating 30 patients with NMO and 47 patients with MS. They found visual impairment to be more severe in NMO than in MS. Division of Ophthalmology and Laboratory of Investigation in Oph-thalmology (LIM 33) (DBF, RIPR, CF, MLRL); and Department of Neurology (SA-P, DC), University of São Paulo Medical School, São Paulo, Brazil. Supported by a grant from Fundação de Amparo a Pesquisa do Estado de São Paulo FAPESP (No 2009/50174-0), São Paulo, Brazil. The authors report no conflicts of interest. Address correspondence to Mário L. R. Monteiro, MD, PhD, Av. Angélica 1757 conj 61, 01227-200, São Paulo, Brazil; E-mail: mlrmonteiro@terra. com.br 102 Fernandes et al: J Neuro-Ophthalmol 2012; 32: 102-106 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. However, visual field (VF) data were not reported, and no distinction was made between eyes affected by one or multiple attacks of ON. The purpose of the present study was to compare a cohort of NMO patients to a group of MS patients with regard to visual outcome, including automated perimetry findings. In addition, the study compared visual outcome in the 2 groups after a single episode of ON. PATIENTS AND METHODS This was a comparative study of 33 patients with NMO and 30 patients with MS who were evaluated on the neuro-ophthalmology service of the Division of Ophthalmology and the Department of Neurology of the University of São Paulo Medical School, São Paulo, Brazil, between October 2009 and February 2011. The study was approved by the Research Ethics Committee of the University of São Paulo Medical School. Subjects Group 1 included 33 patients with previously diagnosed NMO who underwent comprehensive ophthalmic exami-nation, including measurement of best-corrected visual acuity (VA) using the full-contrast Early Treatment Diabetic Retinopathy Study chart and VF measured with a Hum-phrey perimeter model HFA II 750 (Humphrey systems, San Diego, CA). All patients had been in remission for at least 6 months. The diagnosis of NMO was based on the revised diagnostic criteria of Wingerchuck et al (13), which consist of 2 index events, ON and acute transverse myelitis, and at least 2 of 3 supportive findings: contiguous spinal cord lesion on MRI involving more than 3 vertebral segments, brain MRI not meeting diagnostic criteria for MS and NMO-seropositive status. Group 2 included 30 consecutive patients who had previously diagnosed MS, had been in remission for at least 6 months, and received the same ophthalmic evaluation during follow-up visits in the same period. All patients had clinically definitive MS according to the McDonald criteria (14). In both groups, exclusion criteria were diagnosis of optic neuropathies other than ON, history of intraocular pressure elevation, clinical signs of glaucomatous optic neuropathy, and optic disc anomaly. The diagnosis of ON was based on the history of acute progressing vision loss usually associated with pain on eye movement and documentation of decreased VA, VF defect, relative afferent pupillary defect and a com-patible fundus examination (normal or optic disc edema). VF was initially classified as normal or abnormal. A normal VF was defined as a pattern standard deviation within the 95% confidence limits, a mean deviation (MD) above −3.0 dB and a glaucoma hemifield test result within normal limits. Abnormal VF was either diffuse or isolated, according to the classification used in the Optic Neuritis Treatment Trial (ONTT) (15). Loss of sensitivity was graded as normal (MD above −3.0 dB), minimal (MD from −3.0 to −6.0 dB), moderate (MD from −6.1 to −20.0 dB), or severe (MD worse than −20.0 dB). To qualify as diffuse sensitivity loss, most of the VF loss appearing on the overall deviation probability plot had to be absent on the pattern deviation probability plot. Localized loss on VF was defined as a defect on the overall deviation probability plot persisting on the pattern deviation plot. For localized deficits, the most prominent pattern (i.e., central, superotemporal, superonasal, inferotemporal, and inferonasal) (15,16) was used in the classification procedure. Statistical Analysis We used the unpaired "t" test for comparisons of normally distributed parameters and the Mann-Whitney test for parameters that did not satisfy the normality assumption. In addition, the x2 or Fisher exact test was used for com-parison of proportions. The odds ratio was calculated in the usual manner. A P value of less than .05 was considered statistically significant. RESULTS Group 1 comprised 33 patients with NMO (female, n = 30; white, n = 7; black, n = 8; Asian, n = 2; mixed race, n = 16). The average age at onset of disease was 31.8 ± 10.0 years (range, 17-50 years; distribution: ,20 years, n = 1; 20-40 years, n = 24; .40 years, n = 8). Eighteen patients pre-sented with transverse myelitis, 9 with ON (7 unilateral and 2 bilateral), and 6 with simultaneous transverse myelitis and ON. The clinical course was relapsing in 20 and nonrelapsing in 13. NMO antibody was obtained in 23 patients and tested positive in 11. Thirty-two patients were treated with high-dose corticosteroids at the disease onset. One eye only (n = 14) or both eyes (n = 19) were affected. Group 2 comprised 30 MS patients (female, n = 26; white, n = 20; black, n = 4; mixed race, n = 6). The average age at onset was 28.1 ± 7.4 years (range, 13-42 years; dis-tribution: ,20 years, n = 4; 20-40 years, n = 25; .40 years, n = 1). Sixteen patients presented with ON (10 unilateral and 6 bilateral). One eye only (n = 17) or both eyes (n = 13) were affected. In Group 1, 11 patients had severe VA loss (worse than 20/200) (bilateral, n = 9; unilateral, n = 2). In Group 2, only 1 patient had severe VA loss (unilateral) (P , 0.001) (Table 1). In the group of MS patients, 2 had the last ON attack 9 months prior to examination; all others had ON more than 1 year previously (median = 36 months; range, 9-144 months). In the group of NMO patients, ON occurred 8 months (n = 1) or 9 months (n = 2) or more than 1 year previously (n = 27) (median = 21.5 months, range, 8-120 months). No significant difference was found between the groups with regard to the time from the ON attack to the examination (P = 0.119; Mann-Whitney test) Fernandes et al: J Neuro-Ophthalmol 2012; 32: 102-106 103 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. In the 33 NMO patients, ON occurred in 52 eyes. The average VF MD was −10.8 ± 8.6 dB in the 43 affected eyes (excluding 9 eyes that were unable to perform automated VF due to poor vision). In Group 2, the average VF MD of 43 eyes affected with ON secondary to MS was −4.6 ± 5.2 dB (excluding 1 due to poor vision) (P , 0.001, Student t test). Analysis of the VF results of the 36 eyes from 33 NMO patients and the 35 eyes from 30 MS patients affected by a single attack of ON is shown in Table 2. A significant difference was observed between the groups with regard to the number of eyes with normal VF (MD better than −3.0 dB) (P , 0.001; x2 test). The 2 groups also differed significantly with regard to average VF MD after a single episode of ON (P , 0.001, x2 test). Based on the findings presented on Table 2, the odds ratio for having NMO or MS after a single episode of severe ON was calculated. Thus, the odds ratio for having NMO was 6.0 (confidence interval [CI], 1.6-21.9) when MD was worse than −20.0 dB, while the odds ratio for having MS was 16.06 (CI, 3.6-68.7) when better than −3.0 dB. In assessing the pattern of VF defect after a single episode of ON, 9 abnormal eyes in group 1 and 1 in group 2 had to be excluded because of poor VA leaving 27 abnormal eyes in group 1 and 17 in group 2. VF defects were diffuse in 9 of 27 eyes with NMO-related ON and in 5 of 17 eyes with MS-related ON. Specific patterns of localized VF loss are shown in Table 2. No significant difference was observed between the 2 groups. DISCUSSION In the present study, the final visual outcome was initially evaluated for both the groups regardless of the number of ON attacks. NMO patients fared significantly worse than MS patients, matching results published elsewhere (12,17). Average final VA was poorer, and severe visual loss was more prevalent in group 1 than in group 2. Likewise, the mean VF loss was significantly greater in group 1 than in group 2 (Table 1). Merle et al (12) evaluated the VA out-come of 30 NMO and 47 MS patients of Afro-Caribbean TABLE 1. Comparison of visual outcome between patients with NMO (n = 33) and MS (n = 30) Clinical Manifestation NMO MS P ON attack Eyes, n = 66 (%) Eyes, n = 60 (%) 0.130* None 14 (21) 16 (27) One 35 (53) 37 (62) Two or more 17 (26) 07 (1) Final VA Affected eyes, n = 52 (%) Affected eyes, n = 44 (%) 0.001* 20/20 to 20/60 30 (58) 39 (89) 20/70 to 20/200 09 (17) 04 (9) Worse than 20/200 13 (25) 01 (2) Severe visual loss (VA worse than 20/200) NMO patients, n = 33 MS patients, n = 30 ,0.001* Present 11 1 Absent 22 29 VF MD in affected eyes (in dB) n = 43 eyes, mean ± SD n = 43 eyes, mean ± SD ,0.001† −10.8 ± 8.6 −4.6 ± 5.2 Significant values in italics. *x2 test. †Student t test. TABLE 2. After a single episode of ON, VF characteristics of 36 eyes in patients with NMO and 35 eyes in patients with MS Parameter Number of Eyes P NMO, n = 36 MS, n = 35 VF analysis Normal 2 17 ,0.001* Abnormal 34 18 MD (dB) Better than −3.0 2 17 ,0.001* −3.0 to −6.0 9 8 −6.1 to −20.0 12 7 Worse than −20.0 13 3 Types of VF defect in abnormal eyes n† n‡ Diffuse 9 5 0.786* Localized 18 12 VF profile of eyes with localized field defect Three quadrants 4 1 0.562* Quadrant 0 1 Centrocecal 1 0 Hemianopic 3 2 Central 0 1 Arcuate superior 4 2 Peripheral rim 4 1 Enlarged blind spot 0 1 Double arcuate 1 3 Vertical step 1 0 *x2 test. †Excluding 9 eyes with poor vision. ‡Excluding 1 eye with poor vision. 104 Fernandes et al: J Neuro-Ophthalmol 2012; 32: 102-106 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. origin and found that the number of ON attacks and the incidence of severe VA loss were much more prevalent in NMO compared to MS eyes (12). VF findings were not reported, and no analysis of visual outcome following a single episode of ON was performed. Rather than simply comparing the final visual outcome of eyes with NMO and MS, we also specifically evaluated visual function after a single attack of ON. ON secondary to NMO may precede spinal cord involvement. Because testing for NMO antibody has a sensitivity of 73% and specificity of 94% (4,13), clinical criteria are important in establishing the diagnosis of NMO. We found that a large number of eyes from patients with NMO presented severe VF defects, despite the fact that most patients were treated with cortico-steroids in the acute stage of visual loss. On the other hand, most patients with MS experienced full VF recovery after the same event. Our statistical analysis shows that after a single episode of ON, a MD worse than −20.0 dB was associated with an odds ratio of 6.0 of having NMO, while a MD worse than −3.0 dB was associated with an odds ratio of 16.0 for having MS. Although the 95% CI is wide for such odds ratios (probably because the sample size is small), the striking difference between them indicate that VF recovery may be important in differentiating the 2 conditions. It is interesting to compare the visual outcome of our NMO patients after a single episode of ON to that of the participants of the ONTT after 1 year of follow-up (6). In that study, 401 eyes were evaluated 1 year after the diagnosis of isolated ON; VF was normal in 55.9% and abnormal in 44.1% eyes (16). These percentages are signif-icantly different from what we observed in eyes with NMO (P , 0.001) and similar to our group of patients with MS after a single episode of ON. Whereas the severity of VF defect differed between the eyes with ON secondary to NMO and MS, respectively, the pattern of VF loss was similar in the 2 groups. Diffuse VF defects were observed in 33.3% and 29.4% of group 1 and group 2, respectively (Table 2). Nakajima et al (17) retrospec-tively reviewed the manual perimetry findings of 15 NMO and 20 MS patients and found that in 90% of MS patients, but only in 54% of NMO patients, ON attacks were associ-ated with central scotoma. They found that altitudinal VF loss was the most frequent noncentral scotoma pattern in NMO following an episode of ON, and the prevalence of noncentral scotoma was greater in NMO than in MS, sug-gesting that an altitudinal defect is characteristic of ON in NMO patients (17). Our study did not confirm this finding since none of the 27 eyes of patients with NMO displayed altitudinal VF defect patterns (Table 2). 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