Neuromyelitis optica (NMO) is a chronic inflammatory and demyelinating autoimmune disorder of the central nervous system that predominantly affects the optic nerves and spinal cord. It was considered a clinical variant of multiple sclerosis (MS) in the past. However, NMO is now recognized as a distinct disease entity because of its unique immunologic features and pathogenic mechanisms. Furthermore, NMO has a treatment strategy and treatment response different from MS.1
Aquaporin-4-IgG antibody is a sensitive and highly specific serum marker of NMO,2 which further differentiates NMO from MS. In 2015, the International Panel for NMO Diagnosis set up the diagnostic criteria and defined the unifying term neuromyelitis optica spectrum disorder (NMOSD).3 The criteria stratified patient groups by serologic testing into NMOSD with or without aquaporin-4-IgG antibodies. The core clinical characteristics required for patients with NMOSD with aquaporin-4-IgG antibodies include clinical syndromes or magnetic resonance imaging (MRI) findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without aquaporin-4-IgG antibodies or when serologic testing is unavailable. Previous reports about the prevalence rate and clinical course of NMOSD showed large variability and the follow-up period was relatively short.4-8
The aim of the present study was to report the clinical course and long-term treatment response in a large cohort of NMOSD patients from a single tertiary referral center in Taiwan.
This was a retrospective case series. Patients diagnosed with NMOSD who received treatment and follow-up at National Taiwan University Hospital between January 1, 2008 and December 31, 2016 were included. All patients met the criteria of International Panel for NMO Diagnosis published in 2015.3 For the majority of our patients, the diagnosis of NMOSD was established within months from symptom onset. However, in some patients, the diagnosis of NMOSD was confirmed when the attack of optic neuritis, transverse myelitis, or area postrema syndrome occurred during the follow-up period. All patients underwent complete neurologic and neuro-ophthalmologic evaluations. They were examined at least every 6 months and during each episode of relapse. Clinical information, including demographics, the presence of other autoimmune diseases, initial presentation, disease onset, treatment course, status of aquaporin-4-IgG antibodies, MRI findings, and follow-up time, were recorded. The presence of aquaporin-4-IgG antibodies was determined using an enzyme-linked immunosorbent assay (ELISA) at disease onset if feasible and during the episodes of recurrence if needed. If the serologic testing was positive, the subject was defined as seropositive NMOSD. For patients with optic neuritis, we also collected visual acuity, visual field, optical coherence tomographic findings, and visual evoked potential. We excluded patients with insufficient follow-up (less than 2 years) or incomplete data. The study conformed to the tenets of the Declaration of Helsinki and was approved by the institutional review board of National Taiwan University Hospital; informed consent was also obtained from all patients.
All patients were admitted for pulse therapy involving intravenous administration of 1 g methylprednisolone for 3 to 5 days with an oral steroid tapering period during acute episodes of optic neuritis or transverse myelitis. Five cycles of plasmapheresis at alternate-day intervals were administered, if feasible, to cases without recovery 2 weeks to 1 month after pulse therapy. Patients with optic neuritis were basically treated according to the Optic Neuritis Treatment Trial protocol. After an acute episode, continued care with maintenance therapy such as azathioprine, rituximab, or mycophenolate mofetil was administered as soon as the diagnosis of NMO was confirmed. Treatment protocol for subjects with optic neuritis, transverse myelitis, or both of them was the same. Immunosuppressant was continued for at least 5 years if there were no contraindications.
Values are shown as mean ± SD. Quantitative data were compared using the t test. Categorical variables were compared using the χ2 test. To assess the prognostic factors associated with the visual outcome, a simple regression model with only 1 explanatory variable was used. Variables with a P value of less than 0.1 were retained for subsequent multiple regression analysis. Age and sex were also adjusted in multiple regression analysis. A P value of less than 0.05 was considered statistically significant. Statistical analyses were conducted using SPSS V.17.0 (Chicago, Illinois, US).
A total of 130 patients with NMOSD were recruited. Thirty-four patients were excluded because of insufficient follow-up (less than 2 years) or incomplete data. We finally analyzed the data from 96 patients (10 men, 86 women) with a mean follow-up period of 107.4 ± 84.1 months (range, 24-384 months). The mean age of disease onset among all patients was 36.8 ± 16 years (range, 9-81 years). Thirteen subjects had NMOSD diagnosed when the attack of optic neuritis, transverse myelitis, or area postrema syndrome occurred during the follow-up period. Aquaporin-4-IgG antibodies were present in 74.0% of patients. Of the 25 seronegative patients, 19 had core clinical characteristics of optic neuritis and acute myelitis, 4 had acute myelitis and area postrema syndrome, and the other 2 had optic neuritis, acute myelitis, and area postrema syndrome. Additional MRI requirements were met in all seronegative patients. We found that 22.9% of patients had associated autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, thyroid disorders, or myasthenia gravis. Relapse within 1 year from disease onset was observed in 51.0% of patients. Among all patients, 68 (70.8%) had optic neuritis.
Optic neuritis was the initial presentation of NMOSD in 44 patients. Among them, 11 patients had only recurrent optic neuritis, 8 patients had only recurrent transverse myelitis, and others had both recurrent optic neuritis and transverse myelitis. Initial bilateral ocular involvement occurred in 8 patients (8/44, 18.2%). Of all the patients, optic neuritis was the first relapse sign in 39 patients. In this group, bilateral optic neuritis developed in 5 patients (5/39, 12.8%). Among the patients with optic neuritis, 22 (22/68, 32.4%) had recurrent optic neuritis within 1 year from the first episode. The final visual outcome was poor: 51.5% of patients had a final visual acuity of worse than 20/200 in the diseased eye, and 11 patients had no light perception at least in 1 eye.
Compared with the group without optic neuritis, the group with optic neuritis had a younger age of presentation (34.4 ± 15.9 vs 42.4 ± 14.8 years, P = 0.02) and a higher 1-year relapse rate (64.7% vs 17.9%, P < 0.001; Table 1). However, there was no difference in the sex distribution, aquaporin-4-IgG antibody detection rate, time to first relapse, or correlation with other autoimmune diseases between the 2 groups.
Regarding the association between aquaporin-4-IgG antibodies and the clinical features, we found that the group without aquaporin-4-IgG antibodies had a higher percentage of initial presentation with simultaneous optic neuritis and transverse myelitis (24.0% vs 2.8%, P = 0.001; Table 2).
Among the patients with NMOSD and optic neuritis, the group without aquaporin-4-IgG antibodies had better visual outcome than the group with positive aquaporin-4-IgG antibodies (final visual acuity better than 20/200, 66.7% vs 40.4%, P = 0.05; Table 3). However, there was no difference in the percentage of initial bilateral simultaneous attack, percentage of lengthy optic nerve lesions on MRI during acute episode, correlation with autoimmune diseases, frequency of optic neuritis relapse, and relapse of optic neuritis within 1 year from the first episode between the 2 groups.
We assessed the prognostic factors associated with visual outcome (Table 4) and found that the presence of aquaporin-4-IgG antibodies and poorer initial visual acuity were the risk factors for worse visual outcome (worse than 20/200). Frequency of optic neuritis relapses was associated with visual outcome in simple regression model, but it did not reach significance in multiple regression analysis. Compared with patients without recurrent optic neuritis, those with recurrent optic neuritis within 1 year from the first episode tended to have poorer visual acuity, but the difference between the 2 groups did not reach significance. Other prognostic factors, including age of onset, sex, initial presentation in both eyes, and the presence of other autoimmune diseases, did not have significant effects on the final visual outcome.
This observational study with a long follow-up period reported the clinical course and treatment response in a cohort of patients with NMOSD. We found that NMOSD patients with optic neuritis had a younger age of disease onset and a higher relapse rate within 1 year. The presence of aquaporin-4-IgG antibodies and poorer initial visual acuity were risk factors for worse visual outcome in these patients.
The mean age of onset in our study was comparable to that of a previous report9 and was higher than that in those with MS. Similar to other autoimmune diseases, NMOSD is predominant in females. In our case series, 89.6% of patients were female. Furthermore, the female-to-male ratio was similar to that in previous reports and was higher than that in those with MS.10,11
Primarily, NMOSD is mediated by the humoral immune system.1 Therefore, aquaporin-4 autoantibodies play an important role in the pathogenesis of NMOSD.2 The process of inflammation and demyelination mainly involves the optic nerves and multiple segments of the spinal cord and causes axonal loss, vascular proliferation, and perivascular lymphocytic infiltration.
Aquaporin-4-IgG antibodies were detected in 74% of patients in our case series. This proportion was comparable to that reported in a comprehensive review (60%-90%).12 However, it was higher than that reported by Wang et al (41%).13 Cell-based assays (CBA) have a higher sensitivity and specificity than ELISA.14-16 As our study was a retrospective case series, the majority of aquaporin-4-IgG antibodies were detected with ELISA.
Serum aquaporin-4-IgG antibody titers have been reported to be correlated with the length of longitudinally extensive spinal cord lesions and clinical disease activity.17 The titer may drop after immunosuppressive treatment and remain low during remission. In contrast to previous reports,18 we found that the status of aquaporin-4-IgG antibodies was not associated with the possibility of ocular involvement and 1-year relapse rate. However, in agreement with previous studies,19,20 seropositive NMOSD patients with optic neuritis had poorer final visual acuity. In addition, the group with seronegative NMOSD had a significantly higher percentage of simultaneous optic neuritis and transverse myelitis at first presentation. Similar results have been reported before.21,22 The diagnostic criteria are more stringent in seronegative NMOSD patients, and this might partially explain the higher percentage of initially simultaneous optic neuritis and transverse myelitis. According to the literature, approximately 25% of aquaporin-4-IgG seronegative patients have antibodies against myelin oligodendrocyte glycoprotein (MOG).23 Patients with MOG antibodies have a lower risk for visual and motor disability.22-24 To predict the clinical outcome accurately, future studies should consider detection of MOG antibodies.
Typically, NMOSD follows a relapsing course. Approximately 60% of patients have episodes of relapse within the first year.25,26 In our case series, the relapse rate within 1 year of disease onset was 51%. However, the mean time to first episode of relapse was 27.6 months, which was longer than that reported in a previous study.26 In addition, the percentage of recurrent optic neuritis occurring within 1 year from the first episode was only 32.4%. Ethnic background could be the possible explanation for this observation.
Bilateral simultaneous optic neuritis could be highly suggestive of NMOSD. In our study, 18.2% of patients had bilateral simultaneous optic neuritis as the first presentation of ocular involvement. Approximately 12.8% of patients had involvement of both eyes in the first relapse episode of optic neuritis. The visual impairment due to NMOSD was severe in our case series: 51.5% of patients had a final visual acuity of worse than 20/200 in the diseased eye. The visual outcome in our study was largely comparable to that of the majority of previous reports.8,10,27,28 Early initiation of long-term immunosuppressive therapy including azathioprine, rituximab, or mycophenolate mofetil can delay a second relapse and reduce the relapse rate.29-31 Our cohorts included 8 patients who had been initially diagnosed with MS but were mistreated until NMOSD was recognized. Limited observational evidence suggests that treatment of NMO with interferon beta, natalizumab, or fingolimod is not effective and may be harmful.21,32-34
Regarding the prognostic factors for visual outcome, we found that the presence of aquaporin-4-IgG antibodies and poor initial visual acuity during an acute attack were associated with visual morbidity. Patients with more episodes of optic neuritis relapse and recurrent optic neuritis within 1 year from the first episode tended to have poor vision. Older age at disease onset and an association with other autoimmune disorders have been reported to be the predictors of a worse prognosis.6 However, this was not observed in our study.
This study has some limitations. We retrospectively collected data from patients who met the 2015 diagnostic criteria for NMOSD3 and recorded their follow-up data between 2008 and 2016. However, some patients had their initial attack more than 20 years ago. The diagnosis of NMO was more difficult at that time because aquaporin-4-IgG antibodies were not discovered. As stated above, 8 patients had been initially diagnosed with MS and treated for MS. In these patients, we modified the treatment regimen once NMOSD was confirmed. This might have influenced the clinical course of disease and visual outcome in these patients. Further, in this study, the detection of aquaporin-4-IgG antibodies was based on ELISA. The sensitivity and specificity of ELISA are relatively lower than CBA. As the present study was a retrospective case series, we could not retest all our patients with the newly developed CBA. However, our case series had a long follow-up period and relatively large number of cases in a single tertiary referral center. We believe that the clinical data of this study will provide some useful information for future practice.
In conclusion, our case series showed that NMOSD patients with optic neuritis were younger and had a higher 1-year recurrence rate. Seronegative NMOSD patients had a higher possibility of developing simultaneous optic neuritis and transverse myelitis at first presentation than seropositive NMOSD patients. Despite using pulse steroid therapy in the acute phase and immunosuppressive agents as the long-term treatment, the visual prognosis was poor. The presence of aquaporin-4-IgG antibodies and poor initial visual acuity were the risk factors for worse visual outcome.
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