ONTT
A Randomized, Controlled Trial of Corticosteroids in the Treatment of Acute Optic Neuritis
Clinical Question
Does treatment with either oral prednisone or intravenous methylprednisolone improve visual outcome in acute optic neuritis? Does either treatment speed the recovery of vision? What are the complications of treatment in relation to its efficacy?
Study Overview
Objective
To evaluate whether oral prednisone or intravenous methylprednisolone improves visual outcome in acute optic neuritis, and to assess treatment complications in relation to efficacy
Study Summary
- IV methylprednisolone followed by oral prednisone speeds visual recovery vs placebo (P=0.0001 for visual field), with slightly better visual function at 6 months
- Oral prednisone alone provides no benefit in recovery rate or 6-month outcome compared to placebo
- Oral prednisone alone increases risk of new optic neuritis episodes (RR 1.79 vs placebo; 95% CI 1.08-2.95)
Intervention
IV methylprednisolone 250mg q6h x 3 days then oral prednisone 1mg/kg/day x 11 days; OR oral prednisone 1mg/kg/day x 14 days; OR oral placebo x 14 days
Patients per Arm
151 (IV methylprednisolone), 156 (oral prednisone), 150 (placebo)
Bottom Line
Intravenous methylprednisolone followed by oral prednisone accelerates visual recovery compared to placebo, with slightly better visual function at 6 months in contrast sensitivity, visual field, and color vision (but not visual acuity). However, oral prednisone alone is ineffective—providing no benefit in recovery rate or outcome—and unexpectedly increases the risk of new episodes of optic neuritis (relative risk 1.79 vs placebo). Oral prednisone alone, as prescribed in this study, should not be used for acute optic neuritis.
Major Points
- IV methylprednisolone followed by oral prednisone significantly speeds recovery of visual function vs placebo (adjusted P=0.0001 for visual field, P=0.02 for contrast sensitivity, P=0.09 for visual acuity)
- Oral prednisone alone provides no benefit in rate of recovery or 6-month visual outcome compared to placebo (rate-of-recovery adjusted P=0.39 for VA, 0.39 for CS, 0.08 for VF)
- At 6 months, IV methylprednisolone group had slightly better contrast sensitivity (adj P=0.026), visual field (adj P=0.054), and color vision (adj P=0.033), but not visual acuity (adj P=0.664)
- Oral prednisone alone unexpectedly increased the rate of new optic neuritis episodes: 27% vs 15% placebo (RR 1.79; 95% CI 1.08-2.95; log-rank P=0.02)
- IV methylprednisolone had lowest rate of new optic neuritis episodes (13%; either-eye RR 0.81, 95% CI 0.45-1.47 vs placebo; affected-eye RR 0.86, 95% CI 0.42-1.76)
- Multiple sclerosis developed in 14% IV methylprednisolone, 24% oral prednisone, and 20% placebo groups during 6-24 month follow-up (RR for MS with IV methylprednisolone vs placebo: 0.65; 95% CI 0.37-1.16; RR for oral prednisone vs placebo: 1.17; 95% CI 0.71-1.93)
- Maximum treatment benefit occurred during first 15 days; differences between groups decreased over time
- Patients with worse baseline visual acuity (20/50 to 20/200 or worse) showed greater relative benefit from IV methylprednisolone (Table 5)
- 6% (9/151) of IV methylprednisolone patients had visual acuity 20/50 or worse at 6 months vs 7.1% (11/156) oral prednisone vs 5.3% (8/150) placebo (similar poor outcomes across groups)
- This trial established that oral prednisone alone should not be used for optic neuritis
Design
Study Type: Multicenter, randomized, controlled, partially double-blind trial
Randomization: 1
Blinding: Partially blinded. Personnel assessing visual function were always unaware of whether patient was assigned to placebo or prednisone group, and as often as possible unaware of whether patient was receiving IV methylprednisolone. Patients in oral-prednisone and placebo groups were blinded to their treatment assignment; those in IV methylprednisolone group were not masked.
Enrollment Period: July 1, 1988 to June 30, 1991
Follow-up Duration: 6 months primary; 6-24 months for new episodes and MS development
Centers: 15
Countries: USA
Sample Size: 457
Analysis: Stratified by baseline visual acuity. Results adjusted for baseline visual loss. Univariate Wilcoxon rank-sum test for 6-month outcomes. Wei-Lachin test for stochastic ordering combining all four measures. Rate of recovery analyzed by Mantel-Haenszel method with Kruskal-Wallis test for censored data. New episodes and MS development analyzed by Kaplan-Meier product-limit method with Mantel log-rank test. Sample size: 145 patients/group for 90% power at α=0.02 to detect 30% reduction in abnormal contrast sensitivity at 6 months; increased by 20% for withdrawal/noncompliance.
Inclusion Criteria
- Age 18 to 46 years
- Acute unilateral optic neuritis with visual symptoms lasting 8 days or less
- Relative afferent pupillary defect in the affected eye
- Visual-field defect in the affected eye on examination
- No prior optic neuritis in the same eye
- No clinical evidence of systemic disease other than multiple sclerosis that might cause optic neuritis
Exclusion Criteria
- Previous optic neuritis in the same eye
- Prior treatment with corticosteroids for current episode
- Clinical evidence of systemic disease (other than MS) that might cause optic neuritis (e.g., sarcoidosis, systemic lupus erythematosus, syphilis)
- Compressive optic neuropathy
- Connective-tissue diseases
Arms
| Field | Control | Intravenous Methylprednisolone | Oral Prednisone |
|---|---|---|---|
| Intervention | Oral placebo for 14 days, followed by an oral taper (20 mg on day 15, 10 mg on days 16 and 18) | Intravenous methylprednisolone (Solu-Medrol) 250 mg every 6 hours for 3 days (hospitalized), followed by oral prednisone (Deltasone) 1 mg per kilogram of body weight per day [rounded to nearest 10 mg] for 11 days, then an oral taper (20 mg on day 15, 10 mg on days 16 and 18) | Oral prednisone 1 mg per kilogram of body weight per day [rounded to nearest 10 mg] for 14 days, with tapered dose (20 mg on day 15, 10 mg on days 16 and 18) |
| Duration | 14 days full dose + 4 days taper | 14 days total (3 days IV + 11 days oral) + 4 days taper | 14 days full dose + 4 days taper |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Visual field (Humphrey Field Analyzer, mean deviation dB) and contrast sensitivity (Pelli-Robson chart, line number) at 6 months; recovery to normal function (CS ≥ line 15; VF mean deviation ≥ -3.00 dB) also analyzed as rate over follow-up | Primary | Placebo (Total): Contrast sensitivity median 14 (14, 15); Visual field mean deviation -2.18 dB (-4.48, -0.62) | IV Methylprednisolone (Total): Contrast sensitivity median 15 (14, 15); Visual field mean deviation -1.81 dB (-2.91, -0.46) | 6-month distributions (Wilcoxon, adjusted): Contrast sensitivity P=0.026; Visual field P=0.054 (IV methylprednisolone vs placebo) | |
| Visual acuity at 6 months (Snellen ETDRS letter chart) | Secondary | Placebo (Total): 20/16 (20/20, 20/13) | IV Methylprednisolone (Total): 20/16 (20/20, 20/13); Oral Prednisone (Total): 20/16 (20/20, 20/13) | adj 0.664 (IV vs placebo); adj 0.350 (oral prednisone vs placebo) | |
| Color vision at 6 months (Farnsworth-Munsell 100-hue error score) | Secondary | Placebo (Total): 94 (182, 50) | IV Methylprednisolone (Total): 82 (119, 44); Oral Prednisone (Total): 100 (220, 37) | adj 0.033 (IV vs placebo); adj 0.576 (oral prednisone vs placebo) | |
| Rate of recovery of visual field to normal (Kruskal-Wallis, life-table) | Secondary | Placebo reference | IV methylprednisolone: chi-square 12.68 (P=0.0004) unadjusted, chi-square 16.27 (P=0.0001) adjusted; Oral prednisone: chi-square 2.34 (P=0.13) unadjusted, chi-square 3.16 (P=0.08) adjusted | 0.0001 (IV vs placebo adjusted); 0.08 (oral prednisone vs placebo adjusted) | |
| Rate of recovery of contrast sensitivity to normal | Secondary | Placebo reference | IV methylprednisolone: chi-square 3.27 (P=0.07) unadjusted, chi-square 5.91 (P=0.02) adjusted; Oral prednisone: chi-square 0.27 (P=0.61) unadjusted, chi-square 0.75 (P=0.39) adjusted | 0.02 (IV vs placebo adjusted); 0.39 (oral prednisone vs placebo adjusted) | |
| Rate of recovery of visual acuity to normal | Secondary | Placebo reference | IV methylprednisolone: chi-square 1.45 (P=0.23) unadjusted, chi-square 2.93 (P=0.09) adjusted; Oral prednisone: chi-square 0.03 (P=0.61) unadjusted, chi-square 0.06 (P=0.39) adjusted | 0.09 (IV vs placebo adjusted); 0.39 (oral prednisone vs placebo adjusted) | |
| Stochastic-ordering summary statistic (all 4 measures combined at 6 months) | Secondary | 0.029 (IV vs placebo); 0.87 (oral prednisone vs placebo) | |||
| Relative risk of recovery to normal within 6 months (IV methylprednisolone vs placebo, Total, from Table 5) | Secondary | Placebo reference | Adjusted RR: Contrast sensitivity 1.17 (95% CI 0.98-1.41); Visual field 1.09 (0.97-1.23); Visual acuity 1.07 (0.90-1.28); Color vision 1.21 (1.02-1.44) | Adjusted RRs above | |
| Poor visual acuity (20/50 or worse) at 6 months | Secondary | Placebo: 8 (5.3%) | IV Methylprednisolone: 9 (6.0%); Oral Prednisone: 11 (7.1%) | NS (similar across groups) | |
| New episodes of optic neuritis in either eye (6-24 months follow-up) | Secondary | Placebo: 24 (15%) | IV Methylprednisolone: 20 (13%); Oral Prednisone: 42 (27%) | RR 1.79 (oral prednisone vs placebo); RR 0.81 (IV methylprednisolone vs placebo, 95% CI 0.45-1.47) | 0.02 (oral prednisone vs placebo by Mantel log-rank test); 0.51 (IV MP vs placebo) |
| New episodes of optic neuritis in affected eye | Secondary | Placebo: 16 (10%) | IV Methylprednisolone: 14 (9%); Oral Prednisone: 23 (15%) | RR 1.40 (oral prednisone vs placebo); RR 0.86 (IV MP vs placebo) | |
| New episodes of optic neuritis in contralateral eye | Secondary | Placebo: 11 (7%) | IV Methylprednisolone: 8 (5%); Oral Prednisone: 25 (16%) | RR 2.50 (oral prednisone vs placebo); RR 0.65 (IV MP vs placebo) | |
| Development of multiple sclerosis (6-24 months follow-up, Poser criteria) | Secondary | Placebo: 28 (20%) | IV Methylprednisolone: 20 (14%); Oral Prednisone: 35 (24%) | RR 0.65 (IV methylprednisolone vs placebo); RR 1.17 (oral prednisone vs placebo) | NS |
| General tolerability | Adverse | Well tolerated | Generally well tolerated; IV methylprednisolone group had more weight gain (P<0.001) | ||
| Serious adverse effects (IV methylprednisolone group) | Adverse | 0 | 2 patients: 1 acute transient depression requiring psychotropic drugs, 1 acute pancreatitis; both resolved without sequelae | ||
| Weight gain | Adverse | Less weight gain | Greater weight gain in both steroid groups vs placebo (P<0.001 for each comparison) | <0.001 | |
| Minor side effects (both steroid groups) | Adverse | Mild mood change, stomach upset, facial flushing; more common than placebo | |||
| Sleep disturbance | Adverse | More frequent in steroid groups |
Subgroup Analysis
Results stratified by baseline visual acuity (20/40 or better; 20/50 to 20/190; 20/200 or worse). The relative risk of recovery was lowest among patients whose vision was 20/40 or better at baseline, higher among those whose vision ranged from 20/50 to 20/190, and highest among those whose vision was 20/200 or worse. This suggests patients with worse baseline visual acuity may derive greater benefit from IV methylprednisolone treatment. At 6 months, poor visual outcome (20/50 or worse) occurred similarly across groups regardless of baseline severity.
Criticisms
- IV methylprednisolone group was not masked due to hospitalization requirement, introducing potential bias in outcome assessment despite blinded assessors
- No true IV placebo control - cannot fully separate IV methylprednisolone effect from oral prednisone that followed it
- Oral prednisone dose (1 mg/kg) may have been too low; higher doses were not tested
- Increased rate of new optic neuritis with oral prednisone was unexpected and has no clear biologic explanation - may represent chance finding
- 6-month follow-up may be insufficient to assess long-term visual outcomes and MS risk
- Results may not apply to patients presenting >8 days after symptom onset
- Trial not designed to evaluate subgroups - baseline stratification analyses are hypothesis-generating only
- Cannot determine if IV methylprednisolone alone (without subsequent oral prednisone) would be equally effective
- Cost and inconvenience of hospitalization for IV treatment is a practical consideration
- Study conducted before current MS diagnostic criteria and MRI predictors were established
Funding
National Eye Institute, National Institutes of Health (cooperative agreements EY07212, EY07460, EY07461, EY07659, EY07671, EY07673, EY07674, EY07675, EY07676, EY07678, EY07679, EY07680, EY07683, EY07685, EY07687, EY07689, EY07694, and EY07695); Upjohn Company (supplied study medications)
Based on: ONTT (The New England Journal of Medicine, 1992)
Authors: Roy W. Beck, Patricia A. Cleary, Malcolm M. Anderson Jr., ..., Constance W. Atwell; and the Optic Neuritis Study Group
Citation: N Engl J Med 1992;326:581-588
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