Longitudinal Optic Neuritis Study (LONS)

• 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.

Optic neuritis is an inflammatory disease of the optic nerve that typically affects young adults. Women are affected more often than men. It is second only to glaucoma as the most common acquired optic nerve disorder in persons younger than age 50.

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.

The treatment phase of the study was called the Optic Neuritis Treatment Trial (ONTT), whereas the current long-term followup phase is called the Longitudinal Optic Neuritis Study (LONS). The study is being conducted at 15 clinical centers in the United States. Resource centers include a data coordinating center and a visual field reading center.

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.

The major eligibility criteria for enrollment into the ONTT included the following:

• 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

No longer recruiting. Comments: Completed.

Ongoing. Comments: Ongoing followup.

The study has defined the value of baseline ancillary testing, the typical course of visual recovery with and without corticosteroid treatment, the risks and benefits of corticosteroid treatment, and the 5-year risk of the development of multiple sclerosis after optic neuritis. These results are briefly summarized below:

• 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.