When the Optic Neuritis Treatment Trial (ONTT) was launched in 1988, findings that linked brain lesions in patients with optic neuritis to an increased risk of multiple sclerosis proved fascinating—but frustrating. How useful were these results when effective MS medications remained elusive?
“Fifteen years ago, if I saw patients who presented with pain, sudden visual loss, visual field defect, decreased central vision and a clinical diagnosis of optic neuritis, that would be that. There was nothing I could do,” recalled Steven A. Newman, MD, professor of ophthalmology at the University of Virginia.
But times have changed. “With information attained from the 10-year follow-up of the ONTT study and other studies, including CHAMPS,1 combined with the advent of new medications that may change the natural course of MS, our roles have radically changed. It is now our responsibility as ophthalmologists to discuss MS up front as well as provide referrals to neurologists,” he said.
Dr. Newman noted that optic neuritis is the most common cause of sudden visual loss in young patients (15 to 45 years of age), and it is a problem seen “not infrequently” by ophthalmologists.
Tale of Two Trials
ONTT. Planning for the ONTT began in 1985—a time when the only treatment option was corticosteroids, with many ophthalmologists prescribing high doses intravenously, noted Roy W. Beck, MD, PhD, executive director of the Jaeb Center for Health Research in Tampa, Fla. The trial was launched in 1988 and included 457 patients at 15 centers randomly assigned to oral prednisone (1 milligram per kilogram daily for 14 days), intravenous methylprednisolone sodium succinate (250 mg four times daily for three days followed by oral prednisone for 11 days), or oral placebo for 14 days. The patients were between 18 and 45 years old and had a history of acute optic neuritis with visual symptoms lasting eight days or less.
Results showed that patients treated with oral prednisone did not recover more quickly or have a better outcome than patients receiving placebo. Patients receiving IV treatment did have a significantly more rapid visual recovery than those on placebo, but by 30 days, this difference was no longer clinically significant and by 12 months there were no significant differences. There was an increased incidence of recurrent optic neuritis episodes in the oral prednisone group, compared with the other groups.
In addition, in those patients with brain MRI lesions at the time the study was launched, the IV treatment regimen reduced the rate of development of clinically definite MS for two years.
A decade later, the ONTT continued to provide key clinical findings for ophthalmologists. “From the follow-up data, we learned that obtaining an MRI in patients with optic neuritis was important because this could predict the risk of a patient to develop MS,” Dr. Newman said.
Specifically, patients with at least one brain lesion on MRI at the time of the optic neuritis episode had a 56 percent risk of developing MS within 10 years, while those with no brain lesions had only a 22 percent risk of developing MS within 10 years.
For Dr. Beck, the success of obtaining long-term follow-up data has perhaps been one of the most rewarding aspects of the ONTT. “It has not been without diligence that we have been able to follow these patients for so long,” he said. “We did the 10-year follow-up in 2001 and plan to conduct a 15-year follow-up exam in 2006. The patients themselves are key to our success in gathering these data. They realize that they are part of an important endeavor.”
CHAMPS. As for CHAMPS, it involved 383 patients, 50 percent of whom presented with optic neuritis.
These patients had experienced a first acute clinical demyelinating event and also had evidence of prior demyelination on brain MRI. All patients received initial treatment with corticosteroids, and then were randomly assigned to receive injections of 30 micrograms of interferon beta-1a (Avonex) or placebo. The results showed that the cumulative probability of developing MS during the three-year follow-up period was 35 percent in the interferon group, and 50 percent in the placebo group—translating into a 44 percent reduction in the rate of development of MS in patients treated with interferon.
“In addition,” noted Dr. Newman, “the MRI scans showed significantly fewer lesions in those treated with Avonex.” Specifically, Avonex treatment was associated with a 57 percent relative reduction in the mean number of new T2 lesions, a 67 percent reduction in the number of gadolinium-enhancing lesions and a 91 percent reduction in T2 lesion volume.
Steven L. Galetta, MD, noted that the importance of the CHAMPS findings cannot be overstated. “This study emphasized the importance of making an early and accurate diagnosis of optic neuritis and then establishing the patient’s risk of MS by doing an MRI scan,” said Dr. Galetta, professor of neurology and ophthalmology at the University of Pennsylvania Medical Center. “If the findings indicate that the patient is at risk of developing MS, then discussions of IV steroids and immunomodulatory therapy need to be addressed.”
He added that extension data of the CHAMPS study (the CHAMPIONS study) have shown that those patients who were randomized to placebo and then placed on Avonex—when the trial was terminated early because the findings met the stopping guidelines for showing efficacy of treatment—never caught up to those who were immediately started on Avonex. Five years later, the conversion to clinically definite MS was still 35 percent less in the group that received Avonex from the start of the trial.
Current Treatment Guidelines
Results from these studies, along with advances in MS treatment, have led to new treatment guidelines for ophthalmologists and neuro-ophthalmologists. “The bottom line is, obtain a scan on patients who present with classical optic neuritis—e.g., a normal optic nerve, loss of vision [usually in one eye], a relative afferent pupillary defect and eye pain with movement in a young patient,” said Andrew G. Lee, MD, professor of ophthalmology, neurology and neurosurgery at the University of Iowa. “If the MRI results show white matter lesions suggestive of MS [presence of at least one brain lesion on MRI at the time of the episode of optic neuritis], strong considerations should be made for a referral to a neurologist for discussion of the diagnostic and treatment options. CHAMPS and ONTT have shown that intervention can change the course of the disease.”
Dr. Lee also noted that the more atypical the optic neuritis presentation, the less likely the patient will develop MS. “Atypical features such as a lack of pain, marked disc swelling or extensive hemorrhages or exudates lower the risk of developing MS.” Dr. Newman added, “When patients present with these atypical features, an MRI scan may be unnecessary and I may modify my approach to these individuals.”
The preferred MRI technology to detect brain lesions is whole-brain imaging with pulse sequences that are designed to maximize detection of white matter lesions. “However,” warned Dr. Galetta, “some of our enthusiasm regarding MRI findings should be tempered with the fact that MRI scans are not 100 percent specific for MS. There are many things that could cause white spots, including early viral infections, Lyme disease and lupus. We need to exclude these possibilities before jumping to the conclusion that a white matter lesion is indicative of dymyelination. Once we feel sure that a patient is at high risk of developing MS, we need to take action and consider immunomodulatory therapy.”
A Promising Future
“With the availability of new medications, an early diagnosis of MS is more important than ever,” said Dr. Newman. Ophthalmologists can play a key role in counseling and educating these patients, serving as an advocate because we now know that it may be possible to change the natural history of the disease.”
1 Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study.
Next Up in the Pipeline
A new drug called natalizumab (Antegren) is causing excitement in the neurology community, said Dr. Galetta. Antegren is a molecule designed to interfere with movement of potentially damaging immune cells from the bloodstream, across the blood-brain barrier and into the brain and spinal cord. This monoclonal antibody attaches to a protein called alpha 4-integrin on the surface of white blood cells, which serves to block such immune cell movement.
“If the results from the Phase 2 studies—which showed a 50 percent reduction in relapses during six months of treatment vs. placebo, and a 90 percent reduction in new enhancing lesions detected by MRI activity—are upheld, this will represent a dramatic advance when compared with the immunomodulatory drugs currently available. Furthermore, we are now studying various drugs on the market in combination with each other, and I believe that the combinations may be additive.”
Dr. Galetta is a consultant for and has received research support and speaking honoraria from Biogen. Drs. Beck, Lee and Newman have no related financial interests.