Purpose

• To assess the beneficial and adverse effects of corticosteroid treatment for optic neuritis.
• To determine the natural history of vision in patients who suffer optic neuritis.
• To identify risk factors for the development of multiple sclerosis in patients with optic neuritis.

Background

In this disorder, closely linked to multiple sclerosis, prognosis for visual recovery is generally good. However, return of visual function is almost never complete. After resolution of optic neuritis, virtually all patients show some signs of optic nerve damage, and most are symptomatic. Even when a patient's acuity recovers to 20/20, abnormalities frequently remain in other measures such as contrast sensitivity, color vision, and visual field. 

Prior to the Optic Neuritis Treatment Trial (ONTT), well-established guidelines for treating optic neuritis did not exist. Although corticosteroids had been used to treat this disease, studies to demonstrate their effectiveness had not been satisfactory. Some experts advocated treatment with oral prednisone while others recommended no treatment. Anecdotal reports suggested that high-dose intravenous corticosteroids might be effective. 

The association between optic neuritis and multiple sclerosis is well established. Optic neuritis may be the first manifestation of multiple sclerosis, or it may occur later in its course. A strong case can be made for "isolated" optic neuritis being a forme fruste of multiple sclerosis, based on similarities between the two in such epidemiologic factors as gender, age, geographic distributions, cerebrospinal fluid changes, histocompatibility data, magnetic resonance imaging (MRI) changes, and family history. The magnitude of the risk of multiple sclerosis after optic neuritis is uncertain. Previous studies have reported very disparate results, with the risk being reported to be as low as 13 percent and as high as 88 percent. The importance of risk factors such as age, gender, and MRI changes in predicting which patients with optic neuritis are most likely to develop multiple sclerosis also is unclear.
 

Description

Patients were randomized to one of the three following treatment groups at 15 clinical centers:

• Oral prednisone (1 mg/kg/day) for 14 days
• Intravenous methylprednisolone (250 mg every 6 hours) for 3 days, followed by oral prednisone (1 mg/kg/day) for 11 days
• Oral placebo for 14 days

Each regimen was followed by a short oral taper. The oral prednisone and placebo groups were double masked, whereas the intravenous methylprednisolone group was single masked. 

Baseline testing included blood tests to evaluate for syphilis and systemic lupus erythematosus, a chest x-ray to evaluate for sarcoidosis, and a brain MRI scan to evaluate for changes suggestive of multiple sclerosis.

The rate of visual recovery and the long-term visual outcome were both assessed by measures of visual acuity, contrast sensitivity, color vision, and visual field at baseline, at seven followup visits during the first 6 months, and then yearly. A standardized neurologic examination with an assessment of multiple sclerosis status was made at baseline, after 6 months, and then yearly. 
 

Patient Eligibility

• Age range of 18 to 46 years
• Acute unilateral optic neuritis with visual symptoms for 8 days or less
• A relative afferent pupillary defect and a visual field defect in the affected eye
• No previous episodes of optic neuritis in the affected eye
• No previous corticosteroid treatment for optic neuritis or multiple sclerosis
• No systemic disease other than multiple sclerosis that might be the cause of the optic neuritis

Results

• Routine blood tests, chest x-ray, brain MRI, and lumbar puncture are of limited value for diagnosing optic neuritis in a patient with typical features of optic neuritis.
• Brain MRI is a powerful predictor of the early risk of multiple sclerosis after optic neuritis.
• In optic neuritis patients with no brain MRI lesions, the following features of the optic neuritis are associated with a low 5-year risk of multiple sclerosis: lack of pain, optic disc edema (particularly if severe), peripapillary hemorrhage, retinal exudates, and mild visual loss.
• Visual recovery begins rapidly (within 2 weeks) in most optic neuritis patients without any treatment, and then improvement continues for up to 1 year. Although most patients recover to 20/20 or near 20/20 acuity, many still have symptomatic deficits in vision.
• The probability of a recurrence of optic neuritis in either eye within 5 years is 28 percent. Visual recovery after a second episode in the same eye is generally very good.
• Treatment with high-dose, intravenous corticosteroids followed by oral corticosteroids accelerated visual recovery but provided no long-term benefit to vision.
• Treatment with standard-dose oral prednisone alone did not improve the visual outcome and was associated with an increased rate of new attacks of optic neuritis.
• Treatment with the intravenous followed by oral corticosteroid regimen provided a short-term reduction in the rate of development of multiple sclerosis, particularly in patients with brain MRI changes consistent with demyelination. However, by 3 years of followup, this treatment effect had subsided.
• The treatments were generally well-tolerated, and side effects during the treatment period were mild.

Chest x-ray, blood tests, and lumbar puncture are not necessary in evaluating patients with typical clinical features of acute optic neuritis (young adult with sudden visual loss, with progression of symptoms of 1 week or less accompanied by pain on eye movement, with visual improvement beginning within 1 month, with either a swollen or normal optic disc but no more than a minimal vitreous cellular reaction, and with no history of a systemic disease that might produce optic neuritis).

Brain MRI should be considered to assess the risk of multiple sclerosis. At present, the decision to perform an MRI scan should be made on an individual patient basis. A scan will become imperative only if, in the future, treatments are identified that have a sustained prophylactic benefit regarding the development and course of multiple sclerosis.

Treatment with oral prednisone in standard doses should be avoided, but treatment with intravenous methylprednisolone should be considered, particularly if brain MRI demonstrates multiple signal abnormalities consistent with multiple sclerosis or if a patient needs to recover vision rapidly. However, as with the decision on whether to perform a brain MRI, the decision as to whether to prescribe this treatment must be made on an individual patient basis. Prescribing no treatment for acute optic neuritis also is a viable option. 
 

Publications

• Keltner JL, Johnson CA, Spurr JO, Beck RW, Optic Neuritis Study Group: Comparison of central and peripheral visual field properties in the Optic Neuritis Treatment Trial. Am J Ophthalmol 128: 543-553, 1999.

• Cleary PA, Beck RW, Bourque LB, Backlund JC, Miskala PH: Visual symptoms after optic neuritis. Results from the Optic Neuritis Treatment Trial. J Neuro-ophthalmol 17: 18-28, 1997.

• Anderson MM, Boly LD, Beck RW, Optic Neuritis Study Group: Remote monitoring for multicenter trials. Controlled Clinical Trials 17: 407-414, 1996.

• Rolak LA, Beck RW, Paty DW, Tourtellotte WW, Whitaker JN, Rudick RA, Optic Neuritis Study Group: Cerebrospinal fluid in acute optic neuritis: Experience of the Optic Neuritis Treatment Trial. Neurology 46: 368-372, 1996.

• Trobe JD, Beck RW, Moke PS, Cleary PA: Contrast sensitivity and other vision tests in the Optic Neuritis Treatment Trial. Am J Ophthalmol 121: 547-553, 1996.

• Beck RW, Optic Neuritis Study Group: The Optic Neuritis Treatment Trial. Three-year follow-up results. Arch Ophthalmol 113: 136-137, 1995.

• Beck RW, Trobe JD, Optic Neuritis Study Group: The Optic Neuritis Treatment Trial: Putting the results in perspective. J Neuro-ophthalmol 15: 131-135, 1995.

• Beck RW, Trobe JD, Optic Neuritis Study Group: What we have learned from the Optic Neuritis Treatment Trial. Ophthalmology 102: 1504-1508, 1995.

• 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. Ophthalmology 101: 1771-1778, 1994.

• Keltner JL, Johnson CA, Spurr JO, Beck RW, Optic Neuritis Study Group: Visual field profile of optic neuritis: One-year follow-up in the Optic Neuritis Treatment Trial. Arch Ophthalmol 112: 946-983, 1994.

• 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 8: 841-846, 1993.

• Beck RW, Cleary P, Optic Neuritis Study Group: Optic Neuritis Treatment Trial: One-year follow-up results. Arch Ophthalmol 111: 773-775, 1993.

• Beck RW, Cleary PA, Optic Neuritis Study Group: Recovery from severe visual loss in optic neuritis. Arch Ophthalmol 111: 300, 1993.

• Beck RW, Cleary PA, Trobe JD, Kaufman DI, Kupersmith MJ, Paty DW, Brown CH, Optic Neuritis Study Group: The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med 329: 176-1769, 1993.

• Beck RW, Diehl L, Cleary PA, Optic Neuritis Study Group: The Pelli-Robson Letter Chart: Normative data for young adults. Clin Vis Sci 8: 207-210, 1993.

• 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 100: 691-698, 1993.

• 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 269: 2110-2112, 1993.

• 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 14: 123-142, 1993.

• 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 14: 143-159, 1993.

• 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 111: 231-234, 1993.

• Beck RW, Cleary PA, Anderson MA: A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 326: 581-588, 1992.

• Beck RW, Optic Neuritis Study Group: Corticosteroid treatment of optic neuritis: A need to change treatment practices. Neurology 42: 1133-1135, 1992.

• Beck RW, Optic Neuritis Study Group: The Optic Neuritis Treatment Trial: Implications for clinical practice. Arch Ophthalmol 110: 331-332, 1992.

• Optic Neuritis Study Group: The clinical profile of acute optic neuritis: Experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 109: 1673-1678, 1991.

• Beck RW, Optic Neuritis Study Group: The Optic Neuritis Treatment Trial. Arch Ophthalmol 106: 1051-1053, 1988.

• Optic Neuritis Study Group: The five-year risk of multiple sclerosis after optic neuritis. Experience of the Optic Neuritis Treatment Trial. Neurology (in press).

• Optic Neuritis Study Group: Visual function five years after optic neuritis. Experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol (in press).