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.