The differential diagnosis of optic neuritis (ON) continues to expand. The clinician must not only differentiate ON associated with multiple sclerosis, (1) infectious causes, and autoimmune conditions (2,3) but must also include neuromyelitis optica (NMO) (4) and cases of recurrent ON without clinical evidence of disease beyond the anterior visual pathways (5–10). The discovery of aquaporin-4 antibody (NMO-IgG) (11) has shown that many inflammatory diseases of the central nervous system, including recurrent longitudinally extensive transverse myelitis, recurrent ON, and recurrent brainstem and encephalic syndromes, may fall within the disease spectrum of aquaporin-4 autoimmunity called NMO spectrum disorders (NMO-SD) (12,13).
In their original report of chronic relapsing inflammatory optic neuritis (CRION), Kidd et al (5) described patients with bilateral inflammatory optic neuritis with recurrent relapses over time and that worsened upon steroid or immunosuppression withdrawal. This led to reports differentiating other forms of relapsing ON from CRION (6–8). It is unclear whether there is a chronic progressive or relapsing course in CRION patients, because these patients tend to relapse upon medication withdrawal in weeks to months. Possibly, some patients with CRION would fit into NMO-SD (14,15).
Optical coherence tomography (OCT) has been used to evaluate RNFL thickness in various diseases, including multiple sclerosis, neuromyelitis optica, and clinical isolated syndromes (16–19). We performed a single center cross-sectional study comparing the visual acuity and RNFL thickness with spectral domain optical coherence tomography (SD-OCT) in patients with relapsing remitting multiple sclerosis (RRMS), NMO, and CRION, to assess whether this technique could distinguish ON in these 3 disorders.
We recruited patients with RRMS, NMO, and CRION seen in 2010 and 2011 in the neuroimmunology clinic at the Federal University of São Paulo, São Paulo, Brazil. Patients had to satisfy diagnostic criteria for RRMS (20) and NMO (21), while those with CRION experienced at least 2 inflammatory ON episodes 30 days apart without clinical or radiological signs of disease activity elsewhere in the central nervous system. We classified the patients with CRION if they had suffered >1 relapse of ON in the same, fellow, or both eyes, regardless of whether they were previously immunosuppressed. All patients had at least 1 brain and spinal cord magnetic resonance imaging (MRI) study at the first evaluation and were screened for autoimmune and systemic causes. This included testing for human immunodeficiency virus, hepatitis B and C, human T-cell lymphotropic virus, syphilis, toxoplasmosis, and cytomegalovirus. A thorough review of systems was completed on CRION patients to exclude a potential toxic or genetic cause.
Patients had an expanded disability status scale (EDSS) score of 0–5.5. Peripapillary RNFL thickness was measured by SD-OCT, using the Spectralis software (version 4.0, Heidelberg Engineering, Dossenheim, Germany). Only well-focused, evenly illuminated, and centered images were included in the analysis.
We collected demographic, clinical, laboratory, and MRI data of all patients. NMO-IgG testing using indirect immunofluorescence was performed in all patients with NMO or CRION seen after 2007, as this test was not available in Brazil before that date. Thus, some samples came from patients already on immunosuppressive medication, which is known to reduce the sensitivity of the test (22,23). To avoid bias because of disease duration, we normalized the EDSS (24) on last follow-up visit and total number of relapses by the total time of disease (in years), thus using the progression index (PI) and annualized relapse rate (25). Because patients with CRION would have a maximum EDSS of 4 due to conversion of visual functional system scores on the final EDSS step, we categorized each patient's visual acuity (VA) in each eye according to the EDSS visual functional system score (0 = normal; 1 = VA 20/20 to 20/29; 2 = VA 20/30 to 20/59; 3 = VA 20/60 to 20/99; 4 = 20/100 to 20/199; and 5 = VA worse than 20/200) and calculated the PI exclusively for this system. Almost all patients received treatment with 1 or a combination of drugs including corticosteroids, azathioprine, methotrexate, cyclophosphamide, interferon beta, glatiramer acetate, natalizumab, and IV immunoglobulin.
Statistical analysis was performed using GraphPad Prism version 5.0f, with data presented as mean ± SD or median and interquartile range. Unpaired t test was used when comparing 2 groups, and analysis of variance was used when appropriate. A receiver–operator characteristic curve (ROC curve) was established to estimate sensitivity and sensitivity to differentiate these diseases through the use of OCT. The Internal Review Board of the Universidade Federal de São Paulo approved our study, and written informed consent was obtained from all subjects before the performance of the neurophtalmologic and SD-OCT examinations.
Sixty-two patients completed neuroophthalmologic and SD-OCT examinations: 48 with RRMS, 9 with NMO (8 relapsing and 1 monophasic), and 5 with CRION. Of the 124 eyes evaluated with SD-OCT, only 99 were of sufficient quality for interpretation (79 from RRMS, 12 from NMO, and 8 from CRION) (See Supplemental Digital Content, Table 1, http://links.lww.com/WNO/A80). The main reasons for inadequate quality were nystagmus and difficulty in maintaining steady fixation because of impaired VA. Thirty-four percent of eyes from patients with RRMS, 84% of the eyes from patients with NMO, and all eyes from patients with CRION experienced at least 1 episode of ON.
Age of onset and age at SD-OCT measurements did not differ between the groups (ANOVA with Bonferroni multiple comparison test) and disease duration was also similar (ANOVA with Dunn multiples comparison test) (Table 1). Last measured VA was worse in NMO and CRION eyes than RRMS (P < 0.0001 for NMO or CRION vs RRMS and P = 0.4703 for NMO vs CRION), but there was no difference between NMO and CRION (P = 0.4703). The PI for visual functional system of patients with NMO was worse than patients with RRMS (P < 0.0001), and patients with CRION had higher rates than patients with NMO (P < 0.0075). Clinical comparison of other aspects of the expanded EDSS was not possible, as patients with NMO and CRION presented with fewer neurologic symptoms, and the analysis would be biased towards worse results in RRMS patients. Since only patients with mild-to-moderate EDSS were recruited, patients with RRMS presented low scores on other functional systems as well. NMO-IgG testing was performed in all patients categorized as NMO or CRION, with 45% and 20% positivity, respectively. Patients who fulfilled criteria for multiple sclerosis were not routinely tested for NMO-lgG, because this test has limited value in the typical multiple sclerosis patient (26). However, 7 patients with RRMS were tested for NMO-IgG, all with negative results.
In evaluating eyes with ON, patients with RRMS had RNFL substantially thicker than patients with NMO or CRION (Table 2). There was no statistical difference in the RNFL between NMO and CRION eyes. We analyzed eyes by the number of ON episodes (0, 1, 2, and ≥3) to identify whether the differences observed in RNFL were an effect of the number of relapses or severity (Tables 3 and 4). This appeared to have no effect, that is, NMO and CRION eyes were more severely affected than RRMS, but without a significant difference between them (Table 4). Although the number of eyes was small, there was no difference in RNFL thickness and VA between the 63 eyes from RRMS patients and the 3 eyes from NMO patients who lacked a history of ON.
An ROC curve was created comparing eyes that had ON from patients with RRMS, NMO, and CRION to establish sensitivity and specificity values that could differentiate these conditions. The eyes from RRMS patients were used as controls and the eyes from NMO and NMO + CRION were pooled together (Fig. 1). The comparison of RRMS eyes to NMO with an ROC curve presented an area under the curve (AUC) of 0.7991 with P = 0.0083, and when using NMO and CRION eyes pooled together as patients and RRMS as controls, an AUC of 0.8507 with P = 0.0001. In both cases, a RNFL thickness of 41 µm or less was 100% specific for ON associated with NMO or CRION when compared to RRMS. None of the eyes from RRMS patients had values below 41 µm, as opposed to 2 with NMO (1 patient) and 4 with CRION (3 patients).
The recognition of distinct clinical and pathophysiological features of NMO-SD has placed these conditions into a separate category of CNS inflammatory disorders (12,27,28). In this context, we demonstrated that changes in RNFL thickness of optic neuritis patients with CRION are similar to NMO, and both are distinct from RRMS.
Previous reports of relapsing ON not related to RRMS have included patients with severe visual loss and a mean age of onset between 20 and 50 years. Nearly 50% of relapses occur within 1 year, but in some up to 10 years (5–8, 29, 30). The rate of NMO-IgG positivity in relapsing ON has been reported between 20% and 50% (7, 8, 10, 29, 30), and with nearly 50% of patients with relapsing ON converting to NMO (29,31).
We recognize the limitations of our study. All patients with RRMS received immunomodulatory treatment, and all patients with NMO and all but 1 with CRION were given immunosuppressive medication. This likely biased our analysis due to treatment duration and intensity. Patients exclusively with ON relapses were less likely to receive treatment or receive it later in the clinical course than those with additional neurologic findings (data not shown). This delay could have contributed to differences in RNFL thickness between NMO and CRION. Also, the selection of RRMS and NMO patients with low-to-moderate EDSS scores created a cohort bias. Yet, this allowed us to include patients within the first 10 years of disease onset, producing a more homogenous sample of patients with similar disease duration. Although statistical comparison of RNFL thickness from patients with RRMS and NMO with 1 or 2 ON episodes was not significant (Table 4), differing from the analysis of all eyes together (Table 2), we believe that this trend was due to splitting the groups into smaller samples and reducing statistical power. The inclusion of patients after their first clinical event, as performed by Collongues et al (32), requires a longitudinal study, which is currently underway in our center.
Our study has shown that in patients with ON, measurement of RNFL thickness is similar in NMO and CRION patients compared to those with RRMS. Although the value of 41 μm for RNFL thickness is 100% specific for NMO and CRION, and may assist in differentiation from RRMS, establishing the diagnosis of these 3 disorders still rests on clinical, neuroimaging, and serologic findings.
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