Neurologic Impairment 10 Years After Optic Neuritis

Background  Participants enrolled in the Optic Neuritis Treatment Trial have been observed for more than a decade to assess the relationship between optic neuritis and the development of clinically definite multiple sclerosis.

Objective  To assess neurologic disability 10 to 12 years after an initial episode of optic neuritis.

Design  Longitudinal follow-up of a clinical trial.

Setting  Fourteen Optic Neuritis Treatment Trial clinical centers performed standardized neurologic examinations, including an assessment of neurologic disability.

Participants  One hundred twenty-seven patients who had developed clinically definite multiple sclerosis.

Main Outcome Measures  Functional Systems Scale and Expanded Disability Status Scale.

Results  The disability of most patients was mild, with 65% of patients having an Expanded Disability Status Scale score lower than 3.0. The degree of disability appeared to be unrelated to whether the baseline magnetic resonance imaging scan was lesion-free or showed lesions (P = .51). Among patients with baseline lesions, the degree of disability was unrelated to the number of lesions that were present on the scan (P = .14). Two patients died owing to severe multiple sclerosis, one of whom had no lesions revealed on the baseline scan.

Conclusion  Most patients who develop clinically definite multiple sclerosis following an initial episode of optic neuritis will have a relatively benign course for at least 10 years.

The cohort of participants enrolled in the Optic Neuritis Treatment Trial (ONTT) between 1988 and 1991 has been observed in follow-up to assess the relationship between optic neuritis and the development of clinically definite multiple sclerosis (CDMS). In a separate publication, we reported that the 10-year risk of developing CDMS was 38%.¹ Consistent with other reports,^2,3 the risk was strongly associated with the presence of one or more lesions shown on the baseline brain magnetic resonance (MR) imaging. However, among those with lesions shown on MR imaging, the risk with multiple lesions was not significantly higher than it was with a single lesion. These findings are consistent with the recent recommendations of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology with regard to the role of MR imaging in the diagnosis of multiple sclerosis (MS).⁴ This committee concluded that 3 or more T2-weighted lesions shown on MR imaging are a sensitive predictor of the subsequent development of CDMS and that 1 or 2 lesions may be equally predictive of future MS, but more data are needed before a definitive conclusion can be made. The ONTT results provide the needed data with regard to the risk of CDMS with 1 or 2 lesions. We provide further details about the patients who have developed CDMS with regard to disability and the course of MS.

The study protocol has been reported in detail in prior publications.^5-9 The protocol was approved by the institutional review board at each clinical center, and patients provided written informed consent for participation in the original treatment trial as well as the additional follow-up phases. The key elements of the protocol are summarized below.

The study enrolled 388 patients between the ages of 18 and 46 years with acute optic neuritis who did not already have CDMS.¹⁰ Patients were randomized to receive a single course of either intravenous methylprednisolone followed by oral prednisone, oral prednisone alone, or oral placebo.

Baseline unenhanced brain MR imaging scans were graded at a central reading center by a standardized protocol that included a count of the number of T2 white matter lesions at least 3 mm in diameter.¹¹ Most scans were performed on a 1.5 Tesla MR imaging machine (General Electric Co, Milwaukee, Wis) with 5-mm thick T2 axial slices with a 2.5-mm gap.

Standardized neurologic examinations were performed at the time of study enrollment, after 6 and 12 months, and then annually until 1997. Thereafter, semiannual telephone contact was made with the patients until 2001 to 2002, when willing patients underwent another standardized neurologic examination, which included an assessment of neurologic disability using the Functional Systems Scale and Expanded Disability Status Scale (EDSS).¹² For living patients who were unwilling or unable to complete a neurologic examination, an attempt was made to obtain information from a telephone interview and from medical records.

Patients were classified as having CDMS based solely on clinical criteria without regard to brain MR imaging findings. For patients with CDMS, the disease course was defined as relapsing-stable if there were no relapses or progression in the previous 12 months and no previous evidence of progressive disease, relapsing-active if there were relapses in the previous 12 months regardless of evidence of progression in the past 12 months, progressive-active if there was progressive deterioration in neurologic function during the previous 12 months without evidence of a relapse, or progressive-stable if the patient had progressive active disease but experienced no documented relapses or progression in the previous 12 months.

The association between the presence or absence of lesions shown on baseline brain MR imaging and the degree of disability was assessed with a Wilcoxon rank sum test. The association between the number of lesions shown on baseline brain MR imaging and the degree of disability was assessed by a Spearman rank correlation coefficient.

Clinically definite multiple sclerosis has been diagnosed in 145 patients; 83% are women, and 90% are white. The average age of the patients was 31.7 years at the time of optic neuritis and 35.5 years at the time of diagnosis of CDMS. The median time to diagnosis of CDMS was 3 years (25th percentile, 1.1 years; 75th percentile, 5.3 years). A standardized neurologic examination was completed 10 to 12 years after entry into the ONTT for 111 (77%) of the 145 patients diagnosed as having CDMS. Two patients, severely disabled by MS, died prior to this examination. For an additional 14 patients, an EDSS score was estimated from a phone interview with the patient. Thus, a current estimate of the EDSS score could be made for 127 (88%) of the patients. The median time from the diagnosis of CDMS to the EDSS assessment was 8.3 years (25th percentile, 6 years; 75th percentile, 9.9 years). For the remaining 18 patients with CDMS, 1 discontinued follow-up in the first year, 4 discontinued between 1 and 3 years, and 13 discontinued after 3 years.

Among the 111 patients with CDMS who completed the examination, the disease course was characterized as relapsing-stable in 50%, relapsing-active in 33%, progressive-active in 9%, and progressive-stable in 7%. Forty-eight patients (43%) were receiving no disease-modifying therapy. Disease-modifying treatment among the remaining 63 patients (57%), which was initiated on average 7.9 years after the episode of optic neuritis, included interferon beta-1a (27 patients), glatiramer acetate (22), interferon beta-1b (13), and methotrexate (1).

Among the 111 patients with CDMS who completed the current phase examination, neurologic impairment was mild in the majority of patients (Table). Only 22 (20%) of the patients had moderate disability (EDSS score, 3.0 to 5.5), and 16 (14%) had severe disability (EDSS≥6.0). Based on available information from medical records and telephone contacts with 16 of the other patients (including the 2 who died from severe MS), 7 were estimated to have moderate or severe disability. The addition of these patients increased the number of patients with moderate or severe disability to 45 patients, representing 35% of the 127 patients with available EDSS data. Expanded Disability Status Scale scores were similar when comparing patients with an examination with patients for whom the EDSS score was estimated from medical records and phone interview (P = .38). Among the 18 patients with incomplete follow-up (who were not included in the analysis), 14 had an EDSS assessment prior to leaving the study: 11 had a score lower than 3.0, 2 had a score of 3.0 to <6.0, and 1 had a score of 6.0 or higher.

The degree of disability appeared to be unrelated to whether the baseline MR imaging scan was lesion-free or showed lesions (P = .51) and, when lesions were present, unrelated to the number of lesions that were present on the scan (r = 0.17; P = .14) (Table). For the 2 patients with severe MS who died, one had no lesions revealed on baseline brain MR imaging, and the other had 2 lesions.

Visual loss contributed little to the EDSS score of most patients. A formal ophthalmologic examination with standardized visual acuity testing was performed on 108 of the 111 patients with CDMS who completed the most recent neurologic examination. Visual acuity in the worse eye was 20/20 or better in 61%, 20/25 to 20/40 in 25%, 20/50 to better than 20/200 in 7%, and 20/200 or worse in 6% of patients. Visual acuity in the better eye was 20/20 or better in 88%, 20/25 to 20/40 in 7%, 20/50 to better than 20/200 in 3%, and 20/200 or better in 2% of patients.

Among the 38 patients completing the current phase examination whose EDSS score was 3.0 or higher, nearly all patients had some motor weakness, ataxia, hypesthesia, and urinary urgency/frequency. Sixteen of the 38 were fully ambulatory, 6 had limited but unassisted ambulation, 4 had limited and intermittently assisted ambulation, 8 had limited and constantly assisted ambulation, and 4 were nonambulatory.

Among patients developing CDMS within 10 to 12 years after an episode of optic neuritis, neurologic disability is generally mild irrespective of whether lesions are present on brain MR imaging at the time of optic neuritis. In our study, approximately two thirds of the patients with CDMS had an EDSS score lower than 3.0, whereas severe disability (EDSS score, ≥6.0) was present in less than 20% of patients. The disease course at this time point was considered stable in about half of the patients and active or progressive in half.

We were able to estimate an EDSS score for almost 90% of the patients with CDMS. Thus, incomplete follow-up is unlikely to be an appreciable source of bias. Furthermore, because most patients with incomplete follow-up had mild or no disability, it is unlikely that our results overestimate the degree of disability. Because slightly more than half of the patients were being treated with disease-modifying therapies, the degree of disability that occurs without treatment may be underestimated. However, none of the patients initiated disease-modifying therapy (in addition to the initial course of corticosteroids) at the time of optic neuritis (there were no approved treatments at the time the last patient was enrolled in 1991), and most of the patients did not begin disease-modifying therapy until the last few years. Consequently, it is unlikely that we are substantially underestimating the degree of disability.

Ghezzi et al¹³ reported similar results: among 21 patients with CDMS who had optic neuritis, 6 (29%) had an EDSS score of 3.0 or higher when examined 6 to 11 years after the episode of optic neuritis. However, only 1 patient had an EDSS score higher than 6.0. Rizzo and Lessell¹⁴ reported that 6 (17%) of 35 patients developing CDMS after optic neuritis had an EDSS score of 3.0 or higher when examined at a mean of 15 years after the optic neuritis episode.

The degree of disability in our cohort is somewhat lower than that reported by Brex et al,³ who found that after a mean of 14.1 years following an initial demyelinating event, the median EDSS score for 48 patients with CDMS was 3.25. Likewise, greater disability was also reported by Weinshenker et al¹⁵ in 1099 patients developing MS after an initial demyelinating event (median time to reach EDSS≥3.0, 7.7 years). The differences between the results of our study and those of Brex and colleagues and Weinshenker and colleagues could be due to the fact that those studies included patients with brainstem and spinal cord syndromes as well as optic neuritis. Previous studies have reported that the course of MS is more benign when the initial event is optic neuritis compared with other presenting events.^16,17

Surprisingly, unlike Brex et al,³ we did not find that the number of lesions shown on baseline MR imaging was significantly correlated with the degree of disability after 10 years. Moderate or severe disability was present in 29% of patients with no lesions on baseline brain MR imaging and in 38% of patients with 1 or more lesions. One patient who had no lesions on baseline brain MR imaging died owing to severe MS.

In summary, based on follow-up of the ONTT cohort, most patients who develop CDMS following an initial episode of optic neuritis will have a relatively benign course for at least 10 years. Although brain MR imaging is extremely valuable for assessing the risk of CDMS following optic neuritis,^1,3,4 we did not find the results of the baseline brain MR imaging to be useful in predicting which patients are likely to develop moderate or severe disability after 10 years.

Correspondence: Robin L. Gal, MSPH, Jaeb Center for Health Research, 15310 Amberly Dr, Suite 350, Tampa, FL 33647 (rgal@jaeb.org).

Lead Authors

Roy W. Beck MD, PhD; Craig H. Smith MD; Robin L. Gal MSPH; Dongyuan Xing MPH

Additional Authors

M. Tariq Bhatti MD; Michael C. Brodsky MD; Edward G. Buckley MD; Georgia A. Chrousos MD; James Corbett MD; Eric Eggenberger DO; James A. Goodwin MD; Barrett Katz MD; David I. Kaufman DO; John L. Keltner MD; Mark J. Kupersmith MD; Neil R. Miller MD; Pamela S. Moke MSPH; Sarkis Nazarian MD; Silvia Orengo-Nania MD; Peter J. Savino MD; William T. Shults MD; Jonathan D. Trobe MD; Michael Wall MD

A listing has been published of the clinical centers and their investigators and clinical center staff who participated in the current phase of the study.¹

Accepted for Publication: March 9, 2004.

Author Contributions:Study concept and design: Beck, Gal, Buckley, Corbett, Kupersmith, Miller, Savino, and Trobe. Acquisition of data: Beck, Smith, Gal, Bhatti, Brodsky, Buckley, Chrousos, Corbett, Goodwin, Katz, Kaufman, Keltner, Miller, Moke, Nazarian, Orengo-Nania, Savino, Shults, Trobe, and Wall. Analysis and interpretation of data: Beck, Xing, Eggenberger, Katz, Kupersmith, Miller, Trobe, and Wall. Drafting of the manuscript: Beck, Smith, Gal, Kupersmith, Trobe, and Wall. Critical revision of the manuscript for important intellectual content: Beck, Smith, Gal, Xing, Bhatti, Brodsky, Buckley, Chrousos, Eggenberger, Corbett, Goodwin, Katz, Kaufman, Keltner, Kupersmith, Miller, Moke, Na- zarian, Orengo-Nania, Savino, Shults, Trobe, and Wall. Statistical expertise: Beck and Xing. Obtained funding: Beck. Administrative, technical, and material support: Beck, Gal, Bhatti, Brodsky, Katz, Kaufman, Keltner, Kupersmith, Moke, and Wall. Study supervision: Beck, Smith, Gal, Chrousos, Eggenberger, Moke, Orengo-Nania, and Trobe.

Funding/Support: This study was supported by a cooperative agreement (U10 EY09435) from the National Eye Institute, National Institutes of Health, Bethesda, Md.