Journal of Neuro-Ophthalmology, September 1995, Volume 15, Issue 3

The Optic Neuritis Treatment Trial

Journal of Neuro- Ophthalmology 15( 3): 131- 135, 1995. © 1995 Lippincott- Ravcn Publishers, Philadelphia The Optic Neuritis Treatment Trial Putting the Results in Perspective Roy W. Beck, M. D., Ph. D. and Jonathan D. Trobe, M. D. for the Optic Neuritis Study Group The publications of the Optic Neuritis Treatment Trial ( 1- 3) have generated some misconceptions about the study design and the results. In this ar­ticle, we offer a digest of how the ONTT was con­ducted, what it showed, how its results may affect management of optic neuritis, and answers to some of the most frequently asked questions about the validity of the results, particularly with respect to the development of multiple sclerosis. STUDY DESIGN The ONTT entered 457 patients between July 1988 and June 1991. Entry criteria included a diag­nosis of acute unilateral optic neuritis with visual symptoms of eight days or less, age between 18 and 46 years, no previous history of optic neuritis or ophthalmoscopic signs of optic atrophy in the affected eye, no evidence of a systemic disease that might be associated with the optic neuritis, and no previous treatment with corticosteroids for optic neuritis in the fellow eye. Patients were randomly assigned to one of three treatment regimens: ( 1) intravenous methylpred-nisolone ( IVMP) 250 mg every 6 h for three days followed by oral prednisone 1 mg/ kg/ day for 11 days ( the intravenous group), ( 2) oral prednisone 1 mg/ kg/ day for 14 days ( the prednisone group), and ( 3) oral placebo for 14 days ( the placebo group). Manuscript received February 8, 1995. From the Jaeb Center for Health Research, ( R. W. B.) Tampa, Florida; and Kellogg Eye Center ( J. D. T.), University of Michi­gan, Ann Arbor, Michigan, U. S. A. Supported by cooperative agreements EY07212, EYO7460, EY07461, EY07659, EY07671, EY07673, EY07674, EY07675, EY07676, EY07678, EY07679, EYO7680, EY07683, EY07685, EY07687, EY07689, EY07694 and EY07695 with the National Eye Institute, National Institutes of Health Address correspondence and reprint requests to Dr. Roy W. Beck, Jaeb Center for Health Research, Inc., 3010 E. 138 Ave., Suite 9, Tampa, FL 33613, U. S. A. Regimens 1 and 2 were followed by a short oral prednisone taper consisting of 20 mg on day 15 and 10 mg on days 16 and 18. Whereas patients in the prednisone and placebo groups were masked to their treatment allocation, patients in the intra­venous group were not. Measures of visual acuity, visual field, contrast sensitivity, and color vision were made at seven visits during the first six months, after one year, and then yearly. Highly structured, detailed neu­rologic examinations were performed at baseline and in follow- up after six months, one year, and then yearly. Additional examinations were per­formed at times that patients developed symptoms of new neurologic disease or recurrences of optic neuritis. Clinically definite multiple sclerosis ( CDMS) was diagnosed when a patient developed a new neurologic event other than a new attack of optic neuritis at least four weeks after study entry with symptoms lasting at least 24 h and docu­mented with objective abnormalities on a neuro­logic evaluation. RESULTS Clinical Characteristics Mean age of the 457 patients was 32.0 ± 6.7 years; 77% were female and 85% Caucasian. Pa­tients entered the trial within a mean of 5.0 ± 1.6 days from the onset of visual symptoms. Ocular pain, usually worsened by eye movement, was re­ported by 92%. The optic disc in the affected eye was swollen in 35%. Treatment Effects Compared with the placebo group, the intrave­nous followed by oral corticosteroid regimen pro- 232 132 R. W. BECK ET AL. vided a more rapid recovery of vision but no long-term visual benefit ( 1,2). Most of the difference in rate of visual recovery between groups was seen in the first two weeks. Thereafter, differences in vi­sual function between groups were small. After one year of follow- up, there were no significant differences between the groups in visual acuity, contrast sensitivity, color vision, or visual field ( 2). 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. Within the first two 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. Unexpectedly, the study found that among the 389 patients with monosymptomatic MS ( i. e., not diagnosed as probable or definite MS based on clinical criteria at the time of entry into the ONTT), the intravenous group had a lower rate of devel­opment of CDMS within the first two years than did the placebo or prednisone groups ( 3). CDMS developed within two years in only 7.5% of pa­tients in the intravenous group compared with 16.7% in the placebo group and 14.7% in the pred­nisone group. The two- year adjusted rate ratio of CDMS in the intravenous group was 0.34 ( 95% confidence interval 0.16- 0.74; p = 0.0063) com­pared with the placebo group and 0.38 ( 95% con­fidence interval 0.17- 0.83; p = 0.015) compared with the prednisone group. When the outcome was redefined as either development of CDMS or probable MS or development of CDMS or a new attack of optic neuritis in the fellow eye, the results were similar. Most of the beneficial treatment effect on the neurologic course was manifested in the patients with an abnormal MRI scan at study entry. Among those patients with two or more MRI signal abnor­malities, CDMS developed within two years in 35.9% of 39 patients in the placebo group, 32.4% of 37 patients in the prednisone group, and only 16.2% of 37 patients in the intravenous group. In­dependent of treatment, the rate of development of CDMS in patients with a normal or nonspecifi-cally abnormal scan was so low that therapeutic efficacy for these patients could not be judged. As expected, the apparent beneficial effect of treat­ment was not permanent. By the end of the third year of follow- up, the cumulative incidence of def­inite MS in each group was similar: 17.3% in the intravenous group, 21.3% in the placebo group and 24.7% in the prednisone group ( 4). INTERPRETATION OF NEUROLOGIC RESULTS Although the study was designed primarily to assess visual recovery, the assessment of MS was a preplanned secondary objective. Recognizing the potential importance of the trial's findings, the ONTT Study Group took exhaustive efforts to evaluate all potential sources of bias, confounding, and errors in data recording or analysis as possible explanations for the surprising treatment effect. These efforts included: ( 1) review of all neurologic data by a masked observer to classify each patient in regard to whether CDMS had developed, ( 2) phone contact of patients who had missed the two-year follow- up visit to determine whether any symptoms of MS had developed, ( 3) survey of ex­amining neurologists to determine whether they had any suspicion of a beneficial treatment effect, ( 4) assessment of all potential confounding vari­ables, and ( 5) complete evaluation of the integrity of the dataset and replication of all data analyses at a second biostatistical center. Several questions have been asked repeatedly in regard to the credibility of the neurologic outcomes in the ONTT. We answer them in the section be­low. Did the incidence of MS in placebo- treated patients conform to that of other studies? Yes. The two- year rate of development of CDMS in the placebo group approximated that of other reported series; therefore, the ONTT findings are that the intravenous group fared better than expected, not that the placebo group fared worse ( 5- 9). Is there any rationale for the beneficial effect of intravenous corticosteroids on the development of MS? Yes. There is abundant evidence that MS is an autoimmune disease directed against myelin com­ponents. Experimental studies show that lympho-kine release up- regulates antigen presentation that may prime lymphocytes recruited to the site of tis­sue injury ( 10,11). Such priming may set in motion a continuing or recurring illness. By interfering with lymphokine release, early corticosteroid treat­ment may prevent this process. Furthermore, by limiting the amplification of antigenic sites ( i. e., epitope spreading) that occurs early in the initial attack, immediate immunomodulatory treatment may set the stage for effective intervention later ( 12- 14). Notably, clinical trials with copolymer I and interferon- p have shown greater effectiveness / Neiiw- Ophthalmol, Vol. 15, No. 3, 1995 ONTT RESULTS 133 in patients in early stages of MS than in patients with chronic progressive MS ( 15- 19). Why did intravenous corticosteroid treatment exert a beneficial effect while oral prednisone treatment exerted no benefit and actually predisposed to more frequent optic neuritis recurrences? Although a definitive answer is not available, it is well recognized that high- dose corticosteroid treatment produces immunomodulatory effects that are not seen with low- dose corticosteroid treatment ( 20). The intravenous regimen may, for example, have achieved higher trough levels that had a greater effect on reducing helper/ inducer CD8+ T- cell subsets known to be active in demy-elination associated with optic neuritis and MS. The adverse effect of prednisone may have re­sulted from a preferential reduction in suppressor/ inducer CD4+ T- cell subsets ( 21- 24). In experi­mental allergic encephalomyelitis, Reder et al. ( 25) demonstrated that varying the corticosteroid treat­ment regimen can produce markedly different ef­fects on relapse rate. Wasn't the ONTT designed to assess the effect of treatment on vision rather than on MS? No. Although the study was designed primarily to measure visual outcome, assessment of the de­velopment of MS was a preplanned secondary ob­jective. Board- certified neurologists performed all neurologic examinations at designed intervals and recorded their findings on highly detailed and standardized forms designed with the assistance of an experienced MS investigator ( Donald W. Paty, M. D.). Could the patients in the intravenous group have under reported new symptoms of MS relative to the placebo group? Unlikely. There is no reason to believe that any patient had a preconceived notion that treatment would benefit the neurologic course. Since visual recovery began quickly in all three groups, there should not have been a greater belief on the part of any patient group that treatment was affecting neurologic status. Because the neurologists were not completely masked, could they have underinterpreted new symptoms and signs of MS in the intravenous group relative to the other groups? Unlikely. First, the neurologists were not gener­ally aware of the patient treatment group at follow-up visits. Second, a formal survey of the neurolo­gists provided no indication that they expected treatment to benefit the neurologic course. Third, all of the neurologic examinations were conducted by a detailed, standardized protocol, and com­pleted forms were reviewed in a masked fashion by an authority in MS ( Donald W. Paty, M. D.) to ascertain that the appropriate criteria for classifica­tion of MS status had been applied. Could a placebo effect have produced the results? Unlikely. Previous studies have found that im­munologic changes can occur in MS patients treated with a placebo ( 26,27), but it is improbable that the brief intravenous regimen or patient awareness of treatment assignment could have produced physiologic effects powerful enough to account for such a large difference in the rate of MS between groups. Moreover, virtually all patients in all three groups were starting to show improve­ment in vision after the first few days. Thus, they should all have been expected to believe that they were receiving an active drug. Could the apparent treatment effect have been due to an imbalance in risk factors among the three groups? Unlikely. This was extensively evaluated in the data analysis. Controlling for potential confound­ing variables, including age, gender, race, family history of multiple sclerosis, previous history of optic neuritis in the fellow eye, prior nonspecific neurologic symptoms, and number of signal ab­normalities on brain MRI, did not alter the results. In fact, the intravenous group had a slightly higher baseline risk for MS than the other groups; con­trolling for this increased the magnitude of the treatment effect estimate slightly. Had the treatment effect not abated in time, there would have been concern that the intrave­nous group was, in some unmeasurable way, in­herently at lower risk for MS than were the other two groups, despite randomization and control for potential confounders in the analyses. Could the apparent treatment effect have been due to chance? Unlikely. The two- year time period for analysis was preplanned. The p values for the treatment group comparisons were very small. The treat­ment effect was remarkably consistent across clin­ical centers and levels of baseline covariates. An effect of similar magnitude to that found at two years was found after six months and one year of follow- up ( Table 1). / Neuro- Ophthalmol, Vol. 15, No. 3, 1995 134 R. W. BECK ET AL. TABLE 1. Cumulative percentage of ONTT patients with clinically definite multiple sclerosis3 Time period 6 months 1 year 2 years Treatment group Intravenous 3.1 6.4 8.1 Placebo 7.4 13.4 17.7 (%) Prednisone 7.2 10.5 15.6 0 Cumulative percentages are from life- table analysis. What were the conclusions of the independent panel convened by the NIH to review the study results? The National Institutes of Health review panel ( three biostatisticians- Marian Fisher, Ph. D., Daniel Seigel, Ph. D., Roy Milton, Ph. D.- and five MS experts- Stephen Reingold, Ph. D., Henry Mc- Farland, M. D., Kenneth Johnson, M. D., George Ebers, M. D., and John Whitaker, M. D.), shared the study investigators' reservations with regard to the fact that the study had not been primarily de­signed to assess the development of MS and that the finding was unexpected without a firm physi­ologic basis. They nevertheless concluded that the results were likely valid and the treatment effect likely real ( 20), and they recommended that the results should be published. IMPLICATIONS FOR CLINICAL PRACTICE The two principal treatment recommendations for cases of acute optic neuritis that fit the ONTT clinical patient profile are: ( 1) oral prednisone treatment should be abandoned; and ( 2) patients should undergo MRI scans and be treated with intravenous corticosteroid if their scans show two or more signal abnormalities. Your acceptance of these practices depends on whether you trust the ONTT results ( see Interpre­tation of Neurologic Results, above), and whether you believe that these practices would be practical, cost- effective, and desired by your patients. With regard to oral prednisone treatment, there should be no issue. At doses used in the ONTT, prednisone is ineffective and possibly harmful, and its use should be avoided. With regard to in­travenous corticosteroid treatment, the issues are more complex. You may conclude that the treat­ment is not worthwhile because the benefit is tem­porary and does not affect the patient's long- term disability status. Three years after an attack of op­tic neuritis, ONTT placebo- treated and intrave­nous- treated patients had similar incidences of CDMS and similar levels of neurologic and visual disability. There is no evidence at present that re-treatment with intravenous corticosteroids or treatment with other agents would prolong the beneficial effect. On the other hand, if you believe a low- risk treatment that confers even a temporary benefit is worthwhile, you must decide whether to treat all patients or only those who have abnormal MRI scans. Only one third of the ONTT patients had abnormal scans associated with significant treat­ment benefit. 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