ONTT
(1992)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
• 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
Inclusion Criteria
Age 18-46 years, acute unilateral optic neuritis with visual symptoms ≤8 days, relative afferent pupillary defect, visual-field defect in affected eye, no prior optic neuritis in same eye, no systemic disease other than MS that could cause optic neuritis
Study Design
Arms: 1) IV methylprednisolone + oral prednisone (n=151); 2) Oral prednisone alone (n=156); 3) Oral placebo (n=150)
Patients per Arm: 151 (IV methylprednisolone), 156 (oral prednisone), 150 (placebo)
Outcome
• At 6 months: IV methylprednisolone slightly better contrast sensitivity (P=0.026), visual field (P=0.054), color vision (P=0.033); visual acuity similar (P=0.66)
• New optic neuritis episodes (6-24 mo): 27% oral prednisone vs 15% placebo vs 13% IV methylprednisolone (RR 1.79 for oral prednisone)
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 (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
- At 6 months, IV methylprednisolone group had slightly better contrast sensitivity (P=0.026), visual field (P=0.054), and color vision (P=0.033), but not visual acuity (P=0.66)
- 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)
- IV methylprednisolone had lowest rate of new optic neuritis episodes (13%)
- 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)
- 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
- 6% of IV methylprednisolone patients had visual acuity 20/50 or worse at 6 months vs 7% oral prednisone vs 5% placebo (similar poor outcomes across groups)
- This trial established that oral prednisone alone should not be used for optic neuritis
Study Design
- Study Type
- Multicenter, randomized, controlled, partially double-blind trial
- Randomization
- Yes
- 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.
- Sample Size
- 457
- Follow-up
- 6 months primary; 6-24 months for new episodes and MS development
- Centers
- 15
- Countries
- USA
Primary Outcome
Definition: Visual field (assessed with Humphrey Field Analyzer) and contrast sensitivity (assessed with Pelli-Robson chart) at 6 months. Recovery defined as return to normal function.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Placebo: Contrast sensitivity median 14 (13, 15); Visual field median 14 (13, 15) | IV Methylprednisolone: Contrast sensitivity median 15 (14, 15); Visual field median 15 (14, 16) | - | Contrast sensitivity: P=0.026; Visual field: P=0.054 (IV methylprednisolone vs placebo at 6 months) |
Limitations & 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
Citation
N Engl J Med 1992;326:581-588