The Effect of Corticosteroids for Acute Optic Neuritis on the Subsequent Development of Multiple Sclerosis
Roy W. Beck, Patricia A. Cleary, Jonathan D. Trobe, David I. Kaufman, Mark J. Kupersmith, Donald W. Paty, C. Hendricks Brown, for The Optic Neuritis Study Group
Background Optic neuritis is often the first clinical manifestationof multiple sclerosis, but little is known about the effectof corticosteroid treatment for optic neuritis on the subsequentrisk of multiple sclerosis.
Methods We conducted a multicenter study in which 389 patientswith acute optic neuritis (and without known multiple sclerosis)were randomly assigned to receive intravenous methylprednisolone(250 mg every six hours) for 3 days followed by oral prednisone(1 mg per kilogram of body weight) for 11 days, oral prednisone(1 mg per kilogram) alone for 14 days, or placebo for 14 days.Neurologic status was assessed over a period of two to fouryears. The patients in the first group were hospitalized forthree days; the others were treated as outpatients.
Results Definite multiple sclerosis developed within the firsttwo years in 7.5 percent of the intravenous-methylprednisolonegroup (134 patients), 14.7 percent of the oral-prednisone group(129 patients), and 16.7 percent of the placebo group (126 patients).The adjusted rate ratio for the development of definite multiplesclerosis within two years in the intravenous-methylprednisolonegroup was 0.34 (95 percent confidence interval, 0.16 to 0.74)as compared with the placebo group and 0.38 (95 percent confidenceinterval, 0.17 to 0.83) as compared with the oral-prednisonegroup. The beneficial effect of the intravenous-steroid regimenappeared to lessen after the first two years of follow-up.
Signal abnormalities on magnetic resonance imaging (MRI) ofthe brain were a strong indication of risk for the developmentof definite multiple sclerosis (adjusted rate ratio in patientswith three or more lesions, 5.53; 95 percent confidence interval,2.41 to 12.66). The beneficial effect of treatment was mostapparent in patients with abnormal MRI scans at entry.
Conclusions In patients with acute optic neuritis, treatmentwith a three-day course of high-dose intravenous methylprednisolone(followed by a short course of prednisone) reduces the rateof development of multiple sclerosis over a two-year period.
Optic neuritis is frequently the first manifestation of multiplesclerosis1. Even when optic neuritis occurs without other clinicalsigns of multiple sclerosis ("isolated optic neuritis"), magneticresonance imaging (MRI) of the brain often demonstrates signalabnormalities of white matter,2,3,4,5 and analysis of cerebrospinalfluid often shows oligoclonal bands6,7,8. Within 2 years ofan attack of optic neuritis, the risk of multiple sclerosisis approximately 20 percent,8,9,10,11,12 and within 15 yearsit is in the range of 45 to 80 percent8,9,10,11.
The Optic Neuritis Treatment Trial, a multicenter, randomizedclinical trial of corticosteroid treatment of optic neuritisthat is supported by the National Eye Institute, found thatpulsed intravenous treatment with methylprednisolone (Solu-Medrol)followed by oral prednisone (Deltasone) accelerated visual recoverybut did not improve visual outcome after one year13,14. A regimenof oral prednisone alone did not improve visual outcome andwas associated with an increased rate of new attacks of opticneuritis14. Therefore, oral prednisone was considered contraindicatedand intravenous methylprednisolone to be of marginal therapeuticvalue.
Little has been known about the effect of corticosteroid treatmenton the long-term neurologic course of patients with optic neuritisor multiple sclerosis15. We report the results of a two-yearevaluation of the Optic Neuritis Treatment Trial cohort as partof an ongoing study of the risk of new demyelinating eventsconsistent with multiple sclerosis among patients treated withintravenous methylprednisolone followed by oral prednisone,oral prednisone alone, or placebo.
Methods
Fifteen clinical centers in the United States enrolled 457 patientsfrom July 1, 1988, through June 30, 1991, according to a protocolreported elsewhere and approved by the investigational reviewboards14,16,17. Because the primary objective of this studywas to evaluate risk factors for the development of definitemultiple sclerosis in patients with isolated optic neuritis,we excluded 65 patients (14.2 percent) from the original cohortbecause they had been given diagnoses of either definite (35patients) or probable (30 patients) multiple sclerosis at entryinto the trial. Also excluded were two patients found afterentry not to have optic neuritis and one patient who droppedout before the base-line neurologic examination. Hence, thestudy cohort comprised 389 patients.
The criteria for entry into the original study included a diagnosisof acute unilateral optic neuritis with visual symptoms of eightdays or less, age between 18 and 46 years, no history of opticneuritis or ophthalmoscopic signs of optic atrophy in the affectedeye, no evidence of a systemic disease associated with the opticneuritis, and no previous treatment with corticosteroids foroptic neuritis in the other eye.
Treatment Assignments
The randomization scheme used a permuted-block design with aseparate sequence for each clinical center. Patients were randomlyassigned to one of three treatment regimens: 250 mg of intravenousmethylprednisolone every six hours for 3 days followed by 1mg of oral prednisone per kilogram of body weight per day for11 days (the intravenous-methylprednisolone group), 1 mg oforal prednisone per kilogram per day for 14 days (the oral-prednisonegroup), or oral placebo for 14 days (the placebo group). Thefirst two regimens were each followed by a tapering regimenof prednisone consisting of 20 mg on day 15 and 10 mg on days16 and 18. Treatment was begun within 8 days of the onset ofvisual symptoms, after a mean (±SD) interval of 5.0 ±1.6days. The patients in the methylprednisolone group were hospitalizedfor the three days of intravenous treatment. Oral doses, roundedto the nearest 10 mg, were prescribed as single morning doses.Whereas the patients in the oral-prednisone and placebo groupswere not informed of their treatment assignments, those in theintravenous-methylprednisolone group were aware of their assignments.
Base-Line Evaluations and Determination of Outcome
At study entry, the patients underwent ocular and neurologicexaminations, visual-function testing, and brain MRI accordingto standardized protocols. Follow-up neurologic examinationswere performed after 6 and 12 months and then yearly. Althoughthey were not formally kept unaware of the patients' treatment-groupassignments, the study neurologists were generally not awareof these assignments at the time of the follow-up visits.
The development of probable or definite multiple sclerosis wasdetermined solely on the basis of clinical criteria. A demyelinatingattack was defined as an episode of symptoms, documented onexamination, that was indicative of a neurologic abnormalityattributable to acute demyelination in one or more regions ofthe central nervous system; the symptoms had to last more than24 hours and had to be separated from a previous attack by atleast four weeks18. The optic neuritis present at entry intothe study was considered to constitute one attack and clinicalevidence of one lesion. Definite multiple sclerosis was diagnosedwhen there was a second attack with a new neurologic abnormalitythat was confirmed by examination. Probable multiple sclerosiswas diagnosed when symptoms consistent with a new demyelinatingevent occurred for which there was no confirmatory examination.Recurrent episodes of optic neuritis in either eye were notconsidered in the diagnostic criteria for multiple sclerosis.All records of neurologic examinations were evaluated by a reviewerunaware of the patients' treatment assignments, in order toverify the character and dating of neurologic events. A newattack of optic neuritis was diagnosed if a patient reportednew visual loss in either eye that was documented on visual-functiontesting and verified by a masked review of the records.
Unenhanced MRI scans obtained at study entry for 352 of the389 patients were classified at a single center with a maskedgrading system2. As previously described,2 each signal abnormalitywas characterized by its size ( 3 or <3 mm), location (periventricularor nonperiventricular), and shape (ovoid or nonovoid). Scansshowing no signal abnormalities were classified as grade 0;those showing one or more focal signal abnormalities, all ofwhich were either smaller than 3 mm or nonperiventricular andnonovoid, as grade 1; those showing one periventricular or ovoidsignal abnormality at least 3 mm in size, as grade 2; thoseshowing two such abnormalities as grade 3; and those showingthree or more such abnormalities as grade 4.
Statistical Analysis
The assumptions used in the calculation of sample size havebeen described elsewhere14. All reported P values are two-tailed.
The cumulative incidence of the development of definite multiplesclerosis was calculated for each treatment group with use ofKaplan-Meier estimates. Incidence rates were compared by a generalizedWilcoxon test for the first two years of follow-up and, in aseparate analysis, for the entire follow-up period (up to fouryears in the case of some patients)19,20. Unadjusted rate ratiosand test-based confidence intervals for the development of definitemultiple sclerosis within two years were based on person-timeof follow-up21,22. Adjusted rate ratios were determined froma proportional-hazards model23. The assumption of proportionalhazards was tested for the treatment groups with use of a time-dependentcovariate and found to be appropriate.
Results
Of the 389 patients included in the study, 134 were randomlyassigned to the intravenous-methylprednisolone group, 129 tothe oral-prednisone group, and 126 to the placebo group. Thenumber of patients enrolled at each clinical center ranged from12 to 40 (median, 27). The patients' mean (±SD) age was31.7 ±6.7 years; 77 percent were women, and 85 percentwere white (Table 1).
Table 1. Demographic and Clinical Characteristics of the Patients at Study Entry.
As reported elsewhere, compliance with medication was excellentand side effects of treatment generally mild14,24. Two patientsin the intravenous-methylprednisolone group had serious adverseeffects, an acute psychosis and acute pancreatitis. Both conditionsresolved without sequelae.
Missed Visits and Loss to Follow-up
The aggregate rate of completed six-month, one-year, and two-yearvisits was 91 percent (90 percent in the intravenous-methylprednisolonegroup, 93 percent in the oral-prednisone group, and 90 percentin the placebo group).
Outcome Assessments
The data on 50 patients were censored without the patients'having completed the two-year visit. This group included 21patients in the intravenous-methylprednisolone group, 14 inthe oral-prednisone group, and 15 in the placebo group. Thebase-line characteristics of these patients were similar. Subsequentexamination of 8 of these patients and telephone contact with26 others revealed that only 1 patient in each group had symptomsof a neurologic event consistent with multiple sclerosis withinthe first two years.
Comparisons of Treatment Groups
Definite multiple sclerosis developed within two years in 50patients (12.9 percent): 16.7 percent of the placebo group,7.5 percent of the intravenous-methylprednisolone group, and14.7 percent of the oral-prednisone group (Table 2). The unadjustedtwo-year rate ratio for the development of definite multiplesclerosis in the intravenous-methylprednisolone group as comparedwith the placebo group was 0.43 (95 percent confidence interval,0.21 to 0.89), and the rate ratio in the oral-prednisone groupas compared with the placebo group was 0.86 (95 percent confidenceinterval, 0.37 to 2.00).
Table 2. Percentage of Patients in Whom Multiple Sclerosis Developed or Who Had New Attacks of Optic Neuritis within Two Years of Study Entry.
Most of the treatment effect was observed in the patients withabnormal MRI scans at study entry. Among patients with grade3 or 4 scans, definite multiple sclerosis developed within twoyears in 35.9 percent of 39 patients in the placebo group, 32.4percent of 37 patients in the oral-prednisone group, and only16.2 percent of 37 patients in the intravenous-methylprednisolonegroup (Table 3). Regardless of treatment assignment, the rateof development of definite multiple sclerosis in patients withgrade 0 or 1 MRI scans was so low that therapeutic efficacycould not be determined.
Table 3. Estimates of the Effect of Treatment on the Development of Definite Multiple Sclerosis within the First Two Years of Follow-up, According to MRI Grade.
Life-table analysis of the interval before the development ofdefinite multiple sclerosis revealed that the two-year cumulativeincidence of definite multiple sclerosis was lower in the intravenous-methylprednisolonegroup than in the placebo group (P = 0.03) but was not significantlydifferent between the oral-prednisone group and the placebogroup (P = 0.54) (Figure 1). The difference between the curvesfor the intravenous-methylprednisolone group and the placebogroup appeared to lessen after two years. This trend was alsofound when the life-table analysis was limited to patients (71in the intravenous-methylprednisolone group and 79 in the placebogroup) who completed three years of follow-up, indicating thatthis finding was not due to a cohort effect.
Figure 1. Kaplan-Meier Curves Showing the Cumulative Incidence of Definite Multiple Sclerosis, According to Treatment Group.
The numbers of patients still at risk for definite multiple sclerosis at the beginning of each six-month period are shown below the figure for each treatment group. P = 0.09 and P = 0.12 by the Wilcoxon test for the comparison of the curves for the three groups, evaluated together, for the first two years and the entire follow-up period, respectively. The two-year cumulative incidence of definite multiple sclerosis was lower in the intravenous-methylprednisolone group than in the placebo group (P = 0.03), but the value in the prednisone group did not differ significantly from that in the placebo group (P = 0.54).
In the proportional-hazards model, the two-year adjusted rateratio for the development of definite multiple sclerosis inthe intravenous-methylprednisolone group as compared with theplacebo group was 0.34 (95 percent confidence interval, 0.16to 0.74), and in the oral-prednisone group as compared withthe placebo group it was 0.90 (95 percent confidence interval,0.48 to 1.71). For the combined outcomes of probable or definitemultiple sclerosis, definite multiple sclerosis or a new attackof optic neuritis in the other eye, and definite multiple sclerosisor a new attack of optic neuritis in either eye, the rate inthe intravenous-methylprednisolone group was consistently lowerthan that in either of the other groups (Table 4).
Table 4. Comparisons of Treatment Groups with Regard to Combined Outcomes in the First Two Years of Follow-up.
New attacks of optic neuritis within two years occurred morefrequently in the oral-prednisone group than in the other twogroups (Table 2 and Table 4).
Base-Line Covariates
Signal abnormalities of the brain, expressed as the grade ofthe MRI scans, were the strongest indicator of risk for thedevelopment of definite multiple sclerosis within two years(Table 5). Among the 202 patients with a normal or grade 1 scanat entry into the study, definite multiple sclerosis developedin only 5.0 percent, as compared with 24.7 percent of the 150patients with grade 2, 3, or 4 scans.
Table 5. Unadjusted and Adjusted Rate Ratios for the Development of Definite Multiple Sclerosis within the First Two Years of Follow-up for Base-Line Covariates.
Other variables that had high rate ratios for the developmentof definite multiple sclerosis included a history of optic neuritisin the other eye, ill-defined neurologic symptoms, a familyhistory of multiple sclerosis, and white race, although the95 percent confidence intervals for the last two of these variablesincluded 1.0. Age and sex were not important indicators of risk.
Discussion
In this controlled study, patients treated with intravenousmethylprednisolone followed by oral prednisone had a reductionin the risk of new clinical manifestations of multiple sclerosiswithin the next two years, as compared with patients receivingeither placebo or oral prednisone. This protective effect wasmost apparent in the patients at highest risk for multiple sclerosis-- namely, those with multiple focal brain MRI abnormalities.Patients treated with oral prednisone alone, in dosages typicalof those prescribed in clinical practice, had a higher rateof new attacks of optic neuritis than patients in the othertwo groups.
Inasmuch as the clinical and demographic characteristics ofour patients conformed to the profile accepted for acute, isolatedoptic neuritis25,26 and the two-year risk of definite multiplesclerosis in our placebo group was approximately the same asin previous studies,8,9,10,11,12 we believe our findings canbe generally applied to patients with this diagnosis. Interpretationof the results must, however, be tempered by the fact that evaluatingthe randomized treatments with regard to the development ofmultiple sclerosis was not the primary study objective, and14.2 percent of the originally randomized patients were notpart of the current analysis because they were diagnosed ashaving multiple sclerosis at entry.
Nevertheless, the probability is high that the strong protectiveeffect of intravenous methylprednisolone followed by oral corticosteroidsfound in this study is real and unlikely to have resulted fromchance, confounding, or bias. The magnitude of the treatmenteffect was consistent among most of the base-line covariates,and the direction of the effect was consistent among clinicalcenters (data not shown). Both unadjusted and adjusted analysesyielded similar estimates of effect and similar confidence intervals.Missing data for patients who did not complete the two yearsof follow-up did not appear to be an appreciable source of bias.
Although the patients in the intravenous-methylprednisolonegroup were aware of their treatment, it is doubtful, for threereasons, that this awareness caused bias. Visual recovery wasexcellent in all three treatment groups, and there was no previousinformation to suggest that corticosteroid treatment would reducethe rate of new attacks of multiple sclerosis. Thus, neitherthe patients nor the neurologists evaluating them had reasonto believe that intravenous methylprednisolone treatment wassuperior. Furthermore, a survey of the study neurologists atthe conclusion of the two years of follow-up, while they remainedunaware of the results, found no sentiment to indicate thatthat treatment would be superior. Second, the neurologic assessmentwas recorded in a structured format that resulted in a standardizedexamination. Third, patients were classified as having definitemultiple sclerosis only after a masked independent review.
It is difficult to explain why such a strong and long-lastingprotective effect against the development of new demyelinatingevents would result from a 3-day course of intravenous methylprednisolonefollowed by an 11-day course of oral prednisone, particularlysince a 14-day course of oral prednisone alone had no such effect.Since oral prednisone is well absorbed and produces physiologiceffects similar to those of methylprednisolone, the efficacyof intravenous therapy may be ascribed to the higher dosage.The explanation for the prolonged protective effect of the high-doseintravenous therapy is uncertain, considering that the antiinflammatoryeffects of corticosteroids on the immune response15 and on reductionof the permeability of the blood-brain barrier27 are believedto be short-lived. Treatment administered at or near the onsetof clinical disease may have interfered with the elaborationof the immune response, perhaps by causing depletion and delayedreconstitution of activated lymphocyte subgroups.
Four smaller studies5,28,29,30 support our finding that signalabnormalities present on brain MRI at the time of the developmentof optic neuritis markedly increased the likelihood that newclinical signs of multiple sclerosis would develop. In the aggregate,in patients with optic neuritis, clinical evidence of multiplesclerosis developed after a mean follow-up of 0.9 to 4 yearsin only 4 percent of 80 patients with normal MRI scans, as comparedwith 30 percent of 108 patients with abnormal scans.
Two other factors that were found in our study to confer increasedrisk for the development of definite multiple sclerosis -- namely,a history of optic neuritis in the contralateral eye and ill-definedneurologic symptoms -- have not previously been well documented8,9,10,11.The risk associated with previous attacks of optic neuritisin the same eye cannot be determined from our study, becausepatients with this condition were excluded from entry. Femalesex, considered a risk factor for multiple sclerosis in a long-termstudy of patients with optic neuritis,10 was not confirmed assuch in our study.
On the basis of this trial, the beneficial effect of the intravenousmethylprednisolone regimen in reducing the rate of new demyelinatingevents over a two-year period justifies consideration of thistreatment, even though it has only a marginal effect on visualrecovery. Although brain MRI may not be needed to diagnose opticneuritis, scanning is valuable in establishing the two-yearrisk of additional manifestations of multiple sclerosis. Patientswith multiple signal abnormalities on brain MRI were those whomost clearly benefited from treatment. Because the rate of developmentof definite multiple sclerosis was so low in patients with normalMRI scans, the value of treating this group could not be assessed.
To our knowledge, apart from the present study, only in therecent controlled trials of interferon beta-1b,31,32 which reducedthe rate of exacerbation over a two-year period in patientswith well-established multiple sclerosis, has the natural historyof this disease been convincingly altered. Although a reductionin the development of new demyelinating attacks in patientswith optic neuritis may not be the same as a reduction in thenumber of exacerbating events in patients with clearly establishedmultiple sclerosis, the similarities between the two are likelyto be greater than the differences. This increases the needto investigate pulsed-dose corticosteroids further, not onlyin patients with isolated optic neuritis but also in those withestablished multiple sclerosis.
Supported under cooperative agreements (EY07212, EY07460, EY07461,EY07659, EY07671, EY07673, EY07674, EY07675, EY07676, EY07678,EY07679, EY07680, EY07683, EY07685, EY07687, EY07689, EY07694,EY07695, EY09435, and EY00316) with the National Eye Institute,National Institutes of Health.
We are indebted to the Upjohn Company, Kalamazoo, Mich., forsupplying all the study medications, and to the following personswho served on an advisory panel that reviewed the study resultsand assisted in the preparation of the manuscript: Marian Fisher,Ph.D., George Ebers, M.D., Kenneth Johnson, M.D., Henry McFarland,M.D., Roy Milton, Ph.D., Stephen Reingold, M.D., Daniel Seigel,Ph.D., and John Whitaker, M.D.
Source Information
From the Jaeb Center for Health Research, Tampa, Fla. (R.W.B.); the Departments of Ophthalmology (R.W.B.), Neurology (R.W.B.), and Epidemiology and Biostatistics (R.W.B., C.H.B.), University of South Florida, Tampa; the Biostatistics Center, George Washington University, Rockville, Md. (P.A.C.); the Kellogg Eye Center, University of Michigan, Ann Arbor (J.D.T.); the Division of Visual Science, Michigan State University, East Lansing (D.I.K.); the Department of Ophthalmology, New York University, New York (M.J.K.); and the Department of Neurology, University of British Columbia, Vancouver, Canada (D.W.P.). The major participants in the Optic Neuritis Study Group are listed in the Appendix.
Address reprint requests to Dr. Beck at the Jaeb Center for Health Research, 3010 E. 138 Ave., Suite 13, Tampa, FL 33613.
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Appendix
A complete listing of the members of the Optic Neuritis TreatmentTrial Study Group has been published previously17. In additionto the study authors, the following are the major participantsin the study group.
University of South Florida, Tampa: B.J. Sellers, L. Zajac,P. Moke, C. Newman, R. Murtagh, and J. Arrington; George WashingtonUniversity, Rockville, Md.: J.C. Backlund, D. Kenny, N. Loring,S. Campbell, P. Gilbert, W. Watson, and J. Zablotny; Universityof California, Davis: J. Keltner, C. Johnson, J. Spurr, andH. Hakim; National Eye Institute, Bethesda, Md.: C. Atwell andR. Mowery; University of Arkansas, Little Rock: M. Brodsky,S. Nazarian, B. Lam, B. Lyon, and S. Cain; Baylor College ofMedicine, Houston: L. Rolak, J. McCrary, S. Orengo-Nadia, R.Gross, B. Slight, and M. McMaster; California Pacific MedicalCenter, Smith-Kettlewell Eye Research Institute, San Francisco:B. Katz and T. Ambrosio; Duke University, Durham, N.C.: E. Buckley,W. Massey, S. Pollock, M. Anderson, and G. Valentine; Universityof Florida, Gainesville: J. Guy, S. Zam, D. Shamis, and R. Watson;Center for Sight, Georgetown University, Washington, D.C.: G.Chrousos, J. Kattah, E. Burt, and S. Lauber; University of Illinois,Chicago: J. Goodwin, J. Nichols, and E. Sullivan; Universityof Iowa, Iowa City: S. Thompson, J. Corbett, M. Wall, R. Kardon,and C. Musser; Wills Eye Hospital, Thomas Jefferson University,Philadelphia: P. Savino, R. Sergott, T. Bosley, S. Ward, andM. Devlin; Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore:N. Miller, M. Repka, D. Buchholz, S. Reich, and C. Krich-Putzulo;Kellogg Eye Center, University of Michigan, Ann Arbor: W. Cornblathand C. Caudill; Michigan State University, East Lansing: J.Kokinakis, J. Froehlich, and T. Moore; New York University,New York: F. Warren, A. Addessi, and J. Weinman; Devers EyeInstitute, Good Samaritan Hospital, Portland, Oreg.: W. Shults,L. Diehl, R. Wilson, and R. Herndon; University of Washington,Seattle: C. Smith, D. Kuder, C. Wredberg, and P. Ernst.
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3 or <3 mm), location (periventricular or nonperiventricular), and shape (ovoid or nonovoid). Scans showing no signal abnormalities were classified as grade 0; those showing one or more focal signal abnormalities, all of which were either smaller than 3 mm or nonperiventricular and nonovoid, as grade 1; those showing one periventricular or ovoid signal abnormality at least 3 mm in size, as grade 2; those showing two such abnormalities as grade 3; and those showing three or more such abnormalities as grade 4. 
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