The Optic Neuritis Treatment Trial (ONTT), which has been following a cohort of patients with acute unilateral optic neuritis since 1988, is over. The release of 15-year follow-up data this spring marked the finale of a trial that began by looking at the effect of corticosteroid treatment on optic neuritis and ended with data for the prognosis of optic neuritis, the use of steroids to treat it and the subsequent risk of developing multiple sclerosis.
The original ONTT, along with three follow-up studies at five-year intervals, generated more than three dozen papers in scientific journals. Collectively they show what happens to an individual over the course of 15 years following a bout of optic neuritis.
Essentially, for most patients, the vision loss from the neuropathy is transient, but the neuropathy itself may represent the first of multiple episodes for patients who will subsequently develop MS. “As you go along in life,” said M. Tariq Bhatti, MD, “your vision doesn’t change [from the optic neuritis], but your risk of MS increases.” Dr. Bhatti is associate professor of neuro-ophthalmology and orbital disease at Duke University and was an ONTT principal investigator.
Several findings stand out, said Roy W. Beck, MD, PhD, who conceived the trial, which he called “a major advance, in terms of having a better understanding of the natural untreated disease course and of understanding the effects of high- and low-dose corticosteroids.” Dr. Beck is director of the Jaeb Center for Health Research Clinical Trials Coordinating Center in Tampa, Fla.
Combination drugs speed recovery. ONTT helped define the role of corticosteroids in the treatment of acute optic neuritis. When the study originated, many doctors were treating the condition with oral corticosteroids. The study looked at oral prednisone vs. high-dose intravenous methylprednisolone vs. placebo and found that the IV methylprednisolone followed by a tapering course of oral prednisone accelerated visual recovery by a few weeks.
Recovery of vision occurs with or without treatment. The investigators found that the choice of regimen has no effect on final visual outcome. Most patients in the placebo group recovered vision, on average, in six to eight weeks. Oral prednisone alone was no better than placebo with respect to visual recovery and, in fact, was associated with twice the risk of recurrent optic neuritis. It is no longer recommended for an initial episode of typical, presumed demyelinative optic neuritis. The therapy should include either high-dose methylprednisolone or nothing, Dr. Beck explained.
White matter lesions predict MS. The initial findings, published 16 years ago, in 1992, still apply today, said Dr. Beck. But in addition to determining a therapeutic regimen, the ONTT defined the risk factors for development of MS among patients with optic neuritis. The presence of asymptomatic white matter lesions on the MRI scan is the strongest predictor for MS. Few patients at the start of the study had any history of MS, but over time the numbers grew.
Outcome favorable and stable. For the majority of patients, even those with MS, the visual outcome is good. Those who develop MS are more likely to exhibit abnormal visual function findings, but their vision is normal about 60 percent of the time.
There was little or no change in visual acuity in the affected eye between the 10- and 15-year examinations, in most patients. After 15 years, 72 percent of patients with optic neuritis had visual acuity of 20/20 or better; and 66 percent had acuity of 20/20 or better in both eyes.
Short-term considerations. Treating the patient with active optic neuritis involves weighing the benefits and risks. “Keeping in mind that high-dose steroids merely alter the rate of recovery and not the ultimate recovery, I typically will discuss the risk, benefits, side effects and alternatives with each patient in light of their unique medical history and individual preferences,” said Andrew G. Lee, MD, professor of ophthalmology, neurology and neurosurgery at the University of Iowa in Iowa City. “I tend to offer high-dose methylprednisolone, 1 g IV qd for three days followed by oral prednisone, 1 mg/kg qd for 11 days, followed by a four-day taper, to most patients unless there is a contraindication or patient preference dictates otherwise.” He added that short-term side effects in young, otherwise healthy people are unlikely but may include hyperglycemia, gastrointestinal symptoms, mood alteration, insomnia and weight gain.
Long-term considerations. Dr. Bhatti said that physicians can now speak with some confidence about a patient’s risk of developing MS at five, 10 and 15 years. For example, a doctor can tell the patient with optic neuritis and an abnormal brain MRI (one lesion or more) that her/his risk of MS within 15 years is 72 percent. Armed with this information, the physician may offer disease-modifying drugs such as beta-interferon or glatiramer acetate to reduce the risk of a second demyelinating event that could result in MS.
“If you can delay those attacks and decrease inflammation early, we think we can prolong good neurological function,” said Dr. Bhatti. “For the record, I use interferon for my optic neuritis patients, but there is nothing wrong with using glatiramer. I don’t think I can definitely advise physicians to use either interferon or glatiramer for optic neuritis, but patients with high risk of developing MS should be considered for one of these therapies.” He added that high-risk patients should be referred to a neurologist or neuro-ophthalmologist familiar with treating patients with MS.
Researchers are now investigating a potential role for OCT (see “OCT Enhances MRI”) in treatment decisions for optic neuritis, as well as possible neuroprotective agents that might reduce or prevent axonal loss. Dr. Beck hopes for an eventual treatment that allows regeneration of nerve fibers once they’ve been damaged. He added that while he’d enjoy following the ONTT cohort for another five years, gathering more data over a longer time span isn’t likely to yield any surprises. “At some point, you have to say, ‘Enough is enough.’ And we felt like we’d reached that point. We felt we came close to maximizing what we’d learn.” Drs. Beck and Lee report no related financial interests. Dr. Bhatti receives honoraria, speaker fees or consulting fees from Bayer Health Care, Biogen, EMD Serono and Teva Neurosciences. Dr. Eggenberger has received grant, lecture or research support from Allergan, Bayer, Biogen, Serono and Teva Neurosciences.
OCT Enhances MRI
Though the presence of asymptomatic white matter lesions on an MRI brain scan is the strongest predictor for a diagnosis of MS in patients with optic neuritis, the MRI doesn’t tell the whole story, said Eric Eggenberger, DO, MSEpi, professor of neurology and ophthalmology at Michigan State University in East Lansing.
Dr. Eggenberger is looking at what role OCT might play in the clinical evaluation of patients with optic neuritis. “The MRI, which can look at the whole brain, is very good for showing inflammation and scarring. But it’s not as good at showing axonal loss. We have to use indirect inference measures for that,” said Dr. Eggenberger. “The typical MRI T2 hyperintensities don’t correlate all that well with how the person is doing.” T2 lesions, as indicated on the MRI, aren’t correlated with a person’s functioning, he said. “You can’t tell how a patient is doing, from standard, garden-variety MRI.”
Another window to look through. OCT, on the other hand, has the potential to show things that the MRI can’t show. “It may give you a window to general axonal health of the brain,” said Dr. Eggenberger, who used OCT to evaluate 120 patients in the 15-year ONTT follow-up. “The other thing it shows us, for example, after optic neuritis, is the results or effects of having that disease.”
Some patients, said Dr. Eggenberger, may have a normal vision exam following optic neuritis. It’s not uncommon, he added, for a person to test 20/20, have a normal field and pass all the color plates. Still, the patient may complain of issues with depth perception, color judgment and motion, and say that one eye isn’t as good as the other. “Our traditional measures of visual function don’t tell the whole story, yet the OCT will show they lost axons from that insult.”
Dr. Bhatti agrees. “We can use OCT to follow patients and monitor how much axonal loss they have and potentially provide therapy to reverse that loss,” he said.
Yet OCT is still in its infancy, said Dr. Beck, who noted there’s a lot of uncertainty regarding its use for diagnosis and subsequent treatment. Dr. Eggenberger acknowledged that viewpoint. While OCT can show that the anatomy is not normal, he said, it’s not clear what that information means. “How this will correlate in terms of what this means to a person’s prognosis is still a work in progress.” He added that OCT has the potential to be a quick, noninvasive method that could correlate with axonal health within the whole central nervous system. “It truly may be a way that the eye can be a window to the brain—in a physical and metaphysical sense.”