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Show Journal of Neuro- Ophthalmology 14( 1): 55- 57, 1994. © 1994 Raven Press, Ltd., New York Optic Neuritis Treatment Trial An Editorial Peter J. Savino, M. D. The Optic Neuritis Treatment Trial ( ONTT) was designed to evaluate the effect of corticosteroid treatment of acute optic neuritis on visual recovery. A secondary objective involved assessment of the development of multiple sclerosis ( MS) after optic neuritis ( 1- 3). The study, funded by the National Eye Institute, was a multicenter, clinical trial including 15 recruiting centers, a Visual Field Reading Center, a Data Coordinating Center, and a Study Headquarters separate from the clinical centers. Patients between the ages of 18 and 45, with acute ( visual symptoms lasting 8 days or less) optic neuritis were randomized to three clinical treatment arms: 1. Oral prednisone ( 1 mg/ kg/ day) for 14 days 2. Intravenous methylprednisolone sodium succinate ( 1,000 mg/ day) for 3 days followed by an oral prednisone ( 1 mg/ kg/ day) for 11 days 3. Oral placebo for 14 days The visual parameters monitored were Snellen acuity ( retroilluminated Bailey- Lovie chart at 4 m), color vision ( Farnsworth- Munsell 100- Hue), contrast sensitivity ( Pelli- Robson chart), and perimetry ( Humphrey Field Analyzer and Goldmann perimeter). Outcomes were assessed at seven visits during the first 6 months, after 1 year, and then yearly. A total of 457 patients were admitted to the study; 77% were women, and the mean age was 32.0 years. Pain associated with visual loss and usually aggravated by eye movement was present in 92% of patients. The optic disc was swollen in 35% of patients and normal in 65%. Retinal hemorrhages, exudates, and vitreous cells rarely were encountered. From the Wills Eye Hospital, Philadelphia, Pennsylvania, U. S. A. Address correspondence and reprint requests to Dr. Peter J. Savino, Wills Eye Hospital, 900 Walnut Street, Philadelphia, PA 19107, U. S. A. Central scotomas were plotted frequently, as expected; however, altitudinal defects were found in 29% of the 229 patients who had localized field loss that could be classified ( 4,5). Thus altitudinal and other nerve fiber bundle type visual field defects are compatible with the clinical diagnosis of optic neuritis. The ONTT found that, compared with the placebo group, the intravenous regimen provided a more rapid recovery of vision but no long- term benefit ( 3,6). Most of the difference in rate of recovery between groups was seen in the first 2 weeks. Thereafter, differences in visual function between groups were small. After 1 year of follow-up, there were no significant differences between the groups in visual acuity, contrast sensitivity, color vision, or visual field. The regimen of oral prednisone alone not only provided no benefit to vision but also was associated with an increased rate of new attacks of optic neuritis in both the initially affected and fellow eyes ( 3,6). Within the first 2 years of follow- up, new attacks of optic neuritis in either eye occurred in 30% of the patients in the oral prednisone group, compared with 16% in the placebo group and 14% in the intravenous group. Even without this finding, which is unexplained, the ONTT results indicate that oral prednisone alone, in the dosage used in the study, should not be prescribed for acute demyelinative optic neuritis, since it showed no benefit compared with placebo. Unexpectedly, the study found that the group receiving the intravenous regimen had a lower rate of development of MS within the first 2 years than did the placebo or prednisone groups ( 7). Among the patients in the intravenous group definitive MS developed within 2 years in only 7.5% compared with 16.7% of the placebo group and 14.7% of the prednisone group. The 2- year adjusted rate of definite MS in the intravenous group was 0.34 ( 95% confidence interval: 0.16- 0.74) compared 55 56 P. J. SAVINO with the placebo group and 0.38 ( 95% confidence interval: 0.17- 0.83) compared with the prednisone group. When the outcome was redefined to be either ( i) development of definite or probable MS or ( ii) development of definitive MS or a new attack of optic neuritis in the fellow eye, the results were similar. The ONTT found that brain magnetic resonance imaging ( MRI) was a powerful predictor of the 2- year risk of MS ( 7,8). Patients with abnormal brain MRI ( two or more lesions) had a 2- year risk of MS ( untreated) of about 36%, whereas patients with a normal scan had a risk of about 3%. A recent study from England supports this finding and indicates that with long- term follow- up the risk in the abnormal MRI group may approach 100%, whereas the risk in the normal MRI group is likely to remain low ( 9). In that study, with mean follow-up of 5.5 years, 82% of patients with abnormal MRI at the time of development of clinically isolated optic neuritis developed definitive MS, whereas in only 6% of those with a normal scan did MS develop. Most of the beneficial treatment effect seen in the ONTT in reducing the rate of development of MS was seen in patients with an abnormal MRI scan at study entry. Independent of treatment, the rate of development of definitive MS in patients with a normal MRI scan was so low that therapeutic efficacy for these patients could not be judged. Other factors that were identified in the ONTT as increasing the risk of MS included ( i) a history of nonspecific neurologic symptoms ( too ill- defined to consider consistent with MS) ( ii) prior optic neuritis in the fellow eye, ( iii) family history of MS, and ( iv) Caucasian race. Although younger age and female gender have been reported to be risk factors for MS in a long- term study ( 10), they did not increase the risk within the first 2 years of follow- up in the ONTT [ gender also was not found to be a risk factor in the recent British study ( 9)]. Other findings that have emerged from the ONTT include the following: 1. Side effects of the corticosteroid treatments generally were mild and no patients had lasting adverse effects ( 11). Therefore, outpatient administration of high- dose intravenous corticosteroids should be safe. 2. Deficits in visual function in the fellow eyes of the patients on entry into the study were common: 14% in visual acuity, 15% in contrast sensitivity, 22% in color vision, and 48% in visual field ( 12). 3. The ancillary workup performed on the patients at baseline, which included ANA and FTA blood tests, chest radiograph, and brain MRI had such a low yield that they are not necessary for diagnostic purposes in a patient with typical features of optic neuritis ( 2). However, as discussed above, brain MRI should be performed to assess the patient's risk for MS. 4. A positive ANA did not appear to have any effect on the patient's course or response to treatment ( 13). Therefore, a positive ANA alone in patients without other signs of collagen vascular disease who have typical features of optic neuritis and follow a typical course should not alter management decisions. 5. At least some visual improvement is expected in all patients with optic neuritis ( 13). Recovery of vision generally begins quickly. Although visual improvement began sooner in patients treated with intravenous corticosteroids than in the other two groups, it started within 2 weeks of study entry ( about 19 days from the onset of visual symptoms) in the vast majority of patients, regardless of treatment. In very few patients did vision improve then worsen after corticosteroids were discontinued. Thus patients who do not begin to show visual improvement within 3 weeks, or who worsen after corticosteroids are stopped, are atypical, and further workup for etiology should be considered. 6. Severity of initial visual loss was the only strong predictor of the visual outcome ( 13). However, even when vision was severely reduced, even to no light perception, the visual recovery was generally good. 7. Patients with altitudinal- type visual field defects at baseline had as good a recovery as patients with more " typical" defects, indicating that such patients almost certainly had optic neuritis rather than anterior ischemic optic neuropathy ( 13). Thus, we have learned an enormous amount about optic neuritis from the ONTT. The study's findings should change our approach to the patient with monosymptomatic optic neuritis. I now perform brain MRI on all patients in order to determine their risk for MS. When the MRI shows signal abnormalities suggestive of MS, I encourage treatment with intravenous methylprednisolone, explaining the decreased incidence of MS over 2 years. I presently administer corticosteroids once daily in the patient's home as an alternative to in-hospital treatment. REFERENCES 1. Cleary PA, Beck RW, Anderson MM, Kenny DJ, Backlund J, Gilbert PR, Optic Neuritis Study Group. Design, methods and conduct of the Optic Neuritis Treatment Trial. Controlled Clinical Trials 1993; 14: 123- 42. / Neuro- Ophthatmol, Vol. 14, No. 1, 1994 EDITORIAL: OPTIC NEURITIS TREATMENT TRIAL 57 2. Optic Neuritis Study Group. The clinical profile of acute optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 1991; 109: 1673- 78. 3. Beck RW, Cleary PA, Anderson MA, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl j Med 1992; 326: 581- 88. 4. Keltner JL, Johnson CA, Beck RW, Cleary PA, Spurr JO, Optic Neuritis Study Group. Quality control functions of the visual field reading center ( VFRC) for the Optic Neuritis Treatment Trial ( ONTT). Controlled Clinical Trials 1993; 14: 143- 59. 5. Keltner JL, Johnson CA, Spurr JO, Beck RW, Optic Neuritis Study Group. Baseline visual field profile of optic neuritis: the experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 1993; 111: 231- 4. 6. Beck RW, Cleary PA, and the Optic Neuritis Study Group. Optic Neuritis Treatment Trial: one- year follow- up results. Arch Ophthalmol 1993; 111: 773- 5. 7. Beck RW, Cleary PA, Trobe JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med 1993; 329: 1764- 69. 8. Beck RW, Arrington J, Murtagh FR, Cleary PA, Kaufman DI, Optic Neuritis Study Group. Brain MRI in acute optic neuritis experience of the Optic Neuritis Study Group. Arch Neurol 1993; 8: 841- 6. 9. Morrissey SP, Miller DH, Kendall BE, et al. The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis: a 5- year follow- up study. Brain 1993; 116: 135- 46. 10. Rizzo JF, Lessell S. Risk of developing multiple sclerosis after uncomplicated optic neuritis: a long- term prospective study. Neurology 1988; 38: 185- 90. 11. Chrousos GA, Kattah JC, Beck RW, Cleary PA, Optic Neuritis Study Group. Side effects of glucocorticoid treatment: experience of the Optic Neuritis Treatment Trial. JAMA 1993; 269: 2110- 12. 12. Beck RW, Kupersmith MJ, Cleary PA, Katz B, Optic Neuritis Study Group. Fellow eye abnormalities in acute unilateral optic neuritis experience of the Optic Neuritis Treatment Trial. Ophthalmology 1993; 100: 691- 98. 13. Beck RW, Cleary PA, Backlund JC, Optic Neuritis Study Group. The course of visual recovery after optic neuritis: experience of the Optic Neuritis Treatment Trial ( to be submitted shortly for publication). / Neuw- Ophthalmol, Vol. 14, No. I, 2994 [CLontt] |