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Assess the risk of developing MS after optic neuritis and factors predictive of high and low risk
Optic Neuritis Treatment Trial (ONTT) subjects enrolled between 1988 and 1991 were followed prospectively for 15 years with final examination in 2006.
Neurologic and ophthalmologic exams at 13 clinical sites
Three hundred eighty-nine subjects with acute optic neuritis
Development of MS and neurologic disability assessment
The cumulative probability of developing MS by 15 years was 50% (95% confidence interval 44% to 56%) and strongly related to presence of lesions on a non-contrast enhanced baseline brain MRI. Twenty-five percent of patients with no baseline brain MRI lesions developed MS during follow-up compared with 72% of patients with one or more lesions. After 10 years, the risk of developing MS was very low for patients without baseline lesions but remained substantial for those with lesions. Among patients without MRI lesions, baseline factors associated with a substantially lower risk of MS included male gender, optic disc swelling, and certain atypical features for optic neuritis.
The presence of brain MRI abnormalities at the time of an optic neuritis attack is a strong predictor of the 15-year risk of MS. In the absence of MRI lesions, male gender, optic disc swelling and atypical clinical features of optic neuritis are associated with a low likelihood of developing MS. This natural history information is important when considering prophylactic treatment for MS at the time of a first acute optic neuritis attack.
Optic neuritis, an acute inflammatory disorder of the optic nerve, typically presents with sudden monocular visual loss and eye pain in young adults, more commonly in women. It is a common initial manifestation of multiple sclerosis (MS).1 When optic neuritis occurs, brain magnetic resonance imaging (MRI) often demonstrates white-matter T2 signal abnormalities consistent with demyelination (referred to subsequently as “lesions”).2 The Optic Neuritis Treatment Trial (ONTT) was a randomized trial that evaluated the value of corticosteroids in the treatment of acute optic neuritis. The trial showed that a 3-day course of methylprednisolone given intravenously in a dose of 250 mg every 6 hours followed by 2 weeks of daily oral prednisone in a dose of 1 mg/kg/day accelerated visual recovery but did not improve the eventual visual outcome.3, 4 Treatment with oral prednisone alone in a dose of 1 mg/kg/day for 2 weeks also did not improve visual outcome and was associated with an increased rate of optic neuritis recurrences. An unexpected finding was that those who received intravenous corticosteroids followed by oral corticosteroids had a temporarily reduced risk of development of a second demyelinating event consistent with MS over the first two years compared with subjects who received oral corticosteroids alone or placebo.5
The ONTT cohort has been followed for 15 years. This report describes the results of the final examination, including the risk of developing MS after optic neuritis and factors predictive of high and low risk.
Written informed consent for study participation was obtained from all patients upon ONTT entry and again prior to each follow-up phase. Institutional review board oversight remained in effect for each participating clinical center. Methods and earlier results have been previously described.3, 5-9 Pertinent details are summarized here.
Patients with acute unilateral optic neuritis were enrolled between 1988 and 1991 and randomly assigned to one of two corticosteroid regimens or placebo. Standardized unenhanced brain MRI scans (5 mm thick slices with 2.5 mm gap using primarily 1.5 Tesla scanners) were performed at enrollment and the number of white-matter lesions at least 3 mm in diameter were determined with standardized grading by a central reading center.2 After the first year of follow up, examinations were performed annually through 1997 and then again in 2001-2002 (referred to as ‘10-year examination’). Phone contact was maintained with consenting patients until 2006 at which time patients returned for re-examination. The 2006 examinations (referred to as ‘15-year examination’) were performed at one of the 13 remaining ONTT centers when possible (two original centers were no longer participating). Similar to previous examinations, this examination included a neurologic and ophthalmologic assessment.
Diagnostic criteria for MS were based on the Poser clinical criteria for clinically definite MS10 and consistent with the clinical criteria for MS that are part of the McDonald criteria diagnostic scheme.11 Optic neuritis at study entry was considered one documented attack. To meet MS diagnostic criteria, a patient had to have a clinical examination documenting a second new neurologic deficit attributable to central nervous system demyelination, consistent with neurological symptoms lasting at least 24 hours and separated by at least 4 weeks from the initial optic neuritis event. Recurrent optic neuritis episodes in either eye were not considered in the diagnostic criteria for MS. Neurologic disability was assessed by a neurologist using the Kurtzke Functional Systems Scale and Expanded Disability Status Scale (EDSS).12 The EDSS score was estimated from telephone interview for two patients with MS who did not have a 15-year examination. Four patients who died from causes related to MS were assigned an EDSS score of 10.0.
The MS diagnosis date was the onset date of a second demyelinating event. For patients who did not develop MS, the last contact date (most recent neurologic examination or, for those with no 15-year exam, a phone assessment during which the patient reported no history consistent with development of MS) was used as the censoring date for analyses. Life-table methods were used to compute the cumulative probability of developing MS within intervals defined by the study's exam schedule (annual exams during the first five years, the period between 5 and 10 year exams, and the period between the 10 and 15 year exams). Cox proportional hazards modeling was used to assess baseline factors as potential predictors of MS separately for patients with and without baseline MRI lesions. Hazard ratios greater than 2.0, with 95% confidence intervals not including 1.0, were considered suggestive of a meaningful association. The association of disability and number of baseline MRI lesions was evaluated with Spearman's rank correlation test. Reported p-values are 2-tailed. SAS version 9.1 was used for analyses.
The study enrolled 389 patients with acute unilateral optic neuritis who were not diagnosed with probable or definite multiple sclerosis. Mean age at study entry was 32 ± 7 years; 77% were female and 85% Caucasian.
The aggregate cumulative probability of developing MS by the 15-year examination was 50% (95% confidence interval 44% to 56%) and strongly related to presence of lesions on the baseline brain MRI. That probability was 25% (95% confidence interval 18% to 32%) for patients with no lesions and 72% (95% confidence interval 63% to 81%) for patients with one or more lesions (Table 1 and Figure). Four deaths attributable to MS occurred and three of these patients had a baseline MRI; one had no lesions, one had two lesions, and one had more than 10 lesions. There was no appreciable difference in the risk of developing MS between the three original ONTT treatment groups (15-year cumulative probability of MS and 95% confidence interval = 45 ± 11% in the intravenous corticosteroid group, 51 ± 11% in the oral corticosteroid group, and 53 ± 11% in the placebo group).
The risk of developing MS was highest in the first 5 years and then decreased though the risk remained substantial throughout the 15 years of follow up in patients who had baseline brain MRI lesions. Among patients without MS at the 10-year examination, the probability of developing MS by the 15-year examination was 32% when one or more baseline lesions was present versus 2% when there were no baseline lesions (Table 2).
For the analysis of MS development, data were considered to be complete for 300 (77%) of the 389 patients (157 with MS, 136 without MS who completed the 15-year exam, and 7 who did not complete the exam but in whom phone contact verified that no neurologic symptoms consistent with MS occurred since the last examination). Among the remaining 89 patients, median follow-up time was 5.2 years (interquartile range 2.1 to 7.0). Twelve patients died of causes unrelated to MS. Four patients reported receiving immunomodulatory drugs, even though they did not meet the study's diagnostic criteria for MS.
The predictive value of baseline factors for the development of MS varied depending on presence or absence of baseline brain MRI lesions. When one or more lesions were present at study entry, no demographic or clinical characteristics were predictive of MS development (Table 3). In contrast, among patients without lesions, the risk of MS was higher for women; when there was a history of a viral syndrome preceding the optic neuritis onset; and when the optic disc appeared normal at the time of visual loss (“retrobulbar neuritis”).
One of 24 men (4%) with no baseline brain MRI lesions and optic disc swelling at onset of visual loss developed MS compared with nine of 57 women (16%) with these characteristics. Among patients with monofocal optic neuritis at study entry (no baseline brain MRI lesions, no prior contralateral eye optic neuritis and no prior neurologic symptoms or signs), MS did not develop in any patient when baseline ophthalmoscopy showed severe optic disc swelling (N=21), disc or peripapillary hemorrhages (N=16), retinal macular exudates (N=8), when pain was absent (N=18), or when vision was reduced to no light perception (N=6).
An EDSS score was available for 113 patients with MS who completed the 15-year examination, four patients who died from effects of MS, and two patients for whom EDSS was estimated from telephone interview. Among these patients, 66% had an EDSS score <3 and 13% had an EDSS score ≥6. Degree of disability was not related to the number of baseline brain MRI lesions (Spearman correlation coefficient ± 95% CI: r=0.07±0.19, Table 4). Among the 38 patients with MS for whom a current EDSS score was unavailable, median follow-up was 6 years (interquartile range, 5 to 8). At the last neurologic examination after MS diagnosis, the EDSS score for these patients was <3 in 25, 3 to <6 in four, and ≥6 in three (six had not had an EDSS assessment after being diagnosed with MS). Among the 113 patients completing the examination, 67 (59%) reported current use of disease-modifying therapy, 26 (23%) use in the past but not current, and 20 (18%) no current or past use. The use of disease-modifying therapy among subjects with and without baseline brain MRI lesions was similar.
A relationship between optic neuritis and MS has been well recognized for many years. In this longitudinal study, the 15-year risk of developing MS was 50% based on clinical criteria alone. The risk was strongly related to MRI evidence of prior demyelination in the white matter of the brain at the time of optic neuritis onset (25% when no MRI lesions were present and 72% when MRI lesions were present). When at least one lesion was present, the risk was fairly consistent throughout the 15 years and did not substantially increase when additional lesions were present. For patients without brain lesions at onset, the risk of MS was greatest in the first 5 years, and if MS did not develop in the first 10 years, the risk between 10 and 15 years approached zero; only one patient without lesions at study entry developed MS between the 10 and 15-year examinations.
Regardless of whether brain MRI lesions were present at the time of optic neuritis, neurologic disability was mild in most patients who developed MS. However, because treatment of MS was not controlled in the study and most patients who developed MS were treated with disease-modifying therapies, we could not determine the degree of disability that occurs without treatment.
There was a clear distinction in the risk profile between patients with and without evidence of prior demyelination on brain MRI (one or more lesions). Patients with abnormal brain MRI already have morphologic evidence of disseminated disease and could be considered to have MS at the time of optic neuritis. Thus, it is not surprising that we did not identify any factors modifying the risk of MS in this group. In contrast, among patients with normal brain MRI, two subsets may exist, one destined to have MS and the other with a non-MS related process of unknown cause. Among these patients, the risk of MS was three times higher in women, consistent with the well-described gender predilection of MS. Additionally, MS was more than twice as likely to develop when optic neuritis affected the retrobulbar part of the optic nerve rather than the anterior optic nerve, consistent with the common belief that retrobulbar neuritis is the typical form of optic neuritis in MS. Men with anterior optic neuritis had a lower risk of MS, while both genders had a low risk when atypical features of the optic neuritis were present, namely no light perception vision in the affected eye, absence of periocular pain, and ophthalmoscopic findings of severe optic disc swelling, peripapillary hemorrhages, or retinal exudates.
Our finding of a 50% 15-year risk of multiple sclerosis after optic neuritis is similar to several prior reports13-15 and lower than others;16-18 however, all previous series had smaller sample sizes. Differences in risk estimates across studies also may be attributable to differences in patient inclusion criteria, retention rates, and diagnostic criteria for MS. The most similar study included 71 patients who presented with an acute demyelinating syndrome, 36 (51%) of whom had optic neuritis.16 During mean follow-up of 14.1 years, clinically definite MS developed in 4 (19%) of 21 patients with normal brain MRI at study entry and in 44 (88%) of 50 patients with an abnormal MRI. That study found, as we did, that once there was at least one brain MRI lesion, more lesions did not appreciably affect long-term risk of MS.
Our finding of a low frequency of substantial disability among patients developing MS is similar to some prior studies13, 19 but not others16, 20. Unlike Brex et al,16 we found that the number of baseline brain MRI lesions was not associated with the degree of disability. In our study, moderate or severe disability was present in 39% of patients with no baseline lesions and in 31% of patients with one or more lesions. As the reported use of disease-modifying therapy among subjects with and without brain MRI lesions was similar, it is unlikely that the difference in severe disability between these two groups can be attributed to a higher rate of treatment among those with lesions. Previous studies have reported that the MS course is more benign when the initial event is optic neuritis rather than a brainstem or spinal cord syndrome.21, 22 Thus, differences in results between our study and that of Brex et al may be related to the fact that optic neuritis patients comprised only 50% of their study cohort.
Eligibility criteria were sufficiently broad that our results should be applicable to most patients presenting with optic neuritis as a first demyelinating event. Having incomplete data for 23% of the cohort is unlikely to be a source of appreciable bias as most of these patients completed at least 5 years of follow up. Since few patients without MS in our study were treated prophylactically with immunomodulatory drugs, our risk estimate is not biased by use of therapies that have become available since the study began. One important factor to consider in interpreting our results is the technologic MRI advances that have occurred since the initiation of our study in 1988. Current imaging techniques are more sensitive in the detection of demyelination and might distinguish risk of MS according to the presence or absence of MRI abnormalities to an even greater extent than we found. Current diagnostic criteria for MS permit dissemination of demyelinative lesions in time to be documented with MRI in lieu of a second clinical event.11
Our results are important to clinicians in several respects. They reaffirm the prognostic value of a brain MRI at the time of a first episode of optic neuritis because presence of even a single lesion more than doubles the future risk of MS. Patients with abnormal brain MRI at the time of optic neuritis continue to be at substantial risk for the development of MS even if they have not developed MS within 10 years after optic neuritis. The very low risk of MS when atypical features of optic neuritis are present highlights the importance of an ophthalmologic examination to identify these features, particularly for patients with normal brain MRI. With normal brain MRI, MS is extremely unlikely to develop more than 10 years after the initial attack of optic neuritis. Although our follow up is only 15 years, it seems reasonable to conclude that the future risk for these patients will remain exceedingly low. Among patients who develop MS, most will follow a relatively benign neurologic course for many years.
Initiation of prophylactic treatment for MS at the time of optic neuritis or other first demyelinating events is controversial.23, 24 Although our study cannot define which patients may benefit from prophylactic treatment, the results certainly justify withholding treatment in patients with a typical first episode of acute monosymptomatic optic neuritis who have a normal brain MRI, as many may never develop MS. For patients with an abnormal brain MRI at the time of a first attack of optic neuritis, one must balance their risk of developing MS with the potential side effects and cost of disease-modifying agents. Treatment may be appropriate, but that decision must be made on an individual basis for each patient, with consideration given to the results of additional ancillary testing.
Roy W. Beck, MD, PhD had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Listed below are the Optic Neuritis Study Group investigators active in the 15-year phase of the study. Optic Neuritis Study Group authors are denoted by italicized font.
University of Arkansas, Little Rock, AR: Michael Brodsky, MD, Sarkis Nazarian, MD, Baylor College of Medicine, Houston, TX: Silvia Orengo-Nania, MD, George J. Hutton, MD Duke University, Durham, NC: Edward G. Buckley, MD, E. Wayne Massey, MD University of Florida, Gainesville, FL: M. Tariq Bhatti, MD (Dr. Bhatti is currently affiliated with Duke University), Melvin Greer, MD, University of Illinois, Chicago, IL: James Goodwin, MD, University of Iowa, Iowa City, IA: Michael Wall, MD, Neuro-Ophthalmologic Associates, Philadelphia, PA: Peter J. Savino, MD, Thomas Leist, MD, Johns Hopkins University, Baltimore, MD: Neil R. Miller, MD, David Irani, MD, University of Michigan, Ann Arbor, MI: Jonathan D. Trobe, MD, Wayne Cornblath, MD, Michigan State University, East Lansing, MI: David I. Kaufman, DO, Eric Eggenberger, DO, Roosevelt Hospital, New York, NY: Mark J. Kupersmith, MD, Devers Eye Institute, Portland, OR: William T. Shults, MD, Leslie McAllister, MD, Neuro-ophthalmic Consultants Northwest, Seattle, WA: Steve Hamilton, MD
COORDINATING CENTER: Jaeb Center for Health Research, Inc., Tampa, FL: Roy W. Beck, MD, PhD, Mariya Dontchev, MPH, Robin L. Gal, MSPH, Craig Kollman, PhD., John L. Keltner, MD (Visual Field Reading Center Director, University of California, Davis), Craig H. Smith, MD (Executive Committee member and former clinical center principal investigator, (Dr. Smith is currently affiliated with Genentech, Inc.)
Funding/Support: Supported by a cooperative agreement from the National Eye Institute, National Institutes of Health, EY09435
Disclosure: Craig Smith, MD is an employee of Genentech, Inc. There are no other potential conflicts of interest to report for authors.
Publisher's Disclaimer: This is an author-created, electronic version of an article accepted for publication in Archives of Neurology (http://archneur.ama-assn.org/), which predates the post-acceptance editing process. The Archives Journals assume no responsibility for any errors or omissions in this version of the manuscript. The definitive publisher-authenticated version is available online at http://archneur.ama-assn.org/cgi/content/short/65/6/727