OPHTHALMOLOGISTS PUTTING CHAMPS FINDINGS INTO ACTION

The recent CHAMPS study (Controlled High-Risk Subjects Avonex® Multiple Sclerosis Prevention Study; Jacobs LD et al: N Engl J Med, 343:898-904) underscores the important role of ophthalmologists in the diagnosis of optic neuritis, a precursor to multiple sclerosis (MS), according to speakers at the American Academy of Ophthalmology (AAO) annual meeting.

"The landmark CHAMPS study is going to change the way ophthalmologists practice. We have had a 180-degree reversal and a paradigm shift," said Steven L. Galetta, MD, Director of Neuro-Ophthalmology and the Van Meter Professor of Neurology at the University of Pennsylvania. Dr. Galetta presented the CHAMPS findings at the "Hot Topics" symposium.

CHAMPS FINDS EARLY TREATMENT PROTECTIVE

CHAMPS was a randomized, double-blind trial involving 383 patients who experienced a first acute clinical demyelinating event and had evidence of prior subclinical demyelination on MRI. For half the patients, the qualifying event was optic neuritis, with the remainder being either an incomplete transverse myelitis or brain-stem or cerebellar syndrome.

After initial treatment with corticosteroids, 193 patients were randomly assigned to receive weekly intramuscular injections of 30 micrograms of Avonex® (Biogen, Inc.) and 190 were assigned to weekly injections with placebo. The study end points were the development of clinically definite MS (CDMS) and changes in the MRI findings. The study was intended to last for 3 years, but at 24 months the data safety and monitoring committee found that all end points were significantly achieved, therefore the trial was concluded early.

Analysis showed that during 3 years of follow-up, the probability of developing CDMS (by the development of a second demyelinating event) was 44% lower in the Avonex®-treated group (p = 0.002).

"Early in the study, there were twice the number of placebo-treated patients going on to develop MS compared to the Avonex®-treated group," Dr. Galetta pointed out.

"Even more robust than the clinical findings were the MRI results," he continued, reporting that at 18 months, treatment with Avonex® was associated with:

* A 57% relative reduction in the mean number of new T2 lesions (p < 0.001) * A 67% reduction in the number of gadolinium-enhancing lesions (p < 0.001)

* A 91% reduction in T2 lesion volume (p < 0.001)

Even more significant, he added, were the MRIs of patients who remained in the placebo arm who did not develop CDMS. "You see a dramatic finding in their scans, in that 82% have ongoing new lesions appearing, suggesting that a large proportion of these high-risk patients already have subclinical MS," he noted.

Dr. Galetta stressed, in his presentation, "The ophthalmologist will be at the front line in the evaluation of these patients at high risk for MS after an episode of optic neuritis and should refer them to a neurologist or neuro-ophthalmologist because we now have a treatment that has been shown to dramatically alter the natural history of this subgroup."

HISTORY OF CHAMPS

The CHAMPS study followed the Optic Neuritis Treatment Trial (ONTT), which found that patients with MRI lesions who received intravenous steroids had only a transient delayed effect in the development of MS. CHAMPS aimed to determine if early treatment with a different approach could make a difference.

"Steroids were found to enhance visual recovery, but not to ultimately improve it. We know what IV Solu-Medrol can and cannot do, and this study tells us what we can do beyond steroids. Physicians can no longer be satisfied in just following these patients because there are bigger things at stake. These patients can develop MS, and they need to be treated early," said Eric R. Eggenberger, DO, Associate Professor, Michigan State University Department of Neurology and Ophthalmology, Director, MSU National MS Society Clinic, East Lansing.

"Now, when I see patients I can tell them that based on their MRI scan and clinical presentation, they should go on treatment, because there is science behind the data," he added. "Most patients accept treatment when you explain their risk without treatment. The watch-and-wait approach has gone by the wayside."

The CHAMPS trial also calls into question the current definition of clinically definite MS (CDMS), based on two separate demyelinating attacks. "Clearly, there is a large group of patients who have a single attack who probably have underlying MS, which was verified by CHAMPS," Dr. Galetta continued. "Of placebo-treated patients, 82% demonstrated a new lesion 18 months later. This may indicate that these high-risk patients may have MS and are declaring it early-on."

NEURO-OPHTHALMOLOGIC MANIFESTATIONS OF MS

Visual difficulties are the presenting complaints in approximately 30-40% of persons who are diagnosed with MS. The diagnosis of optic neuritis is fairly straightforward, based on loss of central vision and color vision, afferent pupil defect, and pain on eye movement, according to Nicholas J. Volpe, MD, Associate Professor of Ophthalmology at the University of Pennsylvania Scheie Eye Institute. "Vision loss with pain on eye movement is 'over the center-field fence' for the diagnosis of MS," noted Dr. Volpe, who taught an instructional course at the AAO Annual Meeting.

While optic neuritis is the most common finding, other disturbances, especially double-vision, are seen with some frequency as well. Internuclear ophthalmoplegia is the most characteristic and commonly recognized motility lesion associated with MS, affecting 35-50% of patients. Abducens palsy is the most common isolated ocular motor cranial neuropathy, and cerebellar system derangements may be present in a large percentage of patients.

OPHTHALMOLOGISTS' CHALLENGE

Most ophthalmologists have little difficulty diagnosing optic neuritis, but like any other disorder, the diagnosis is occasionally missed and also mismanaged, said Bradley K. Farris, MD, Professor of Ophthalmology and Adjunct Professor of Neurology and Neurosurgery, University of Oklahoma School of Medicine, Oklahoma City.

With optic neuritis, especially the mild cases, physicians can miss the diagnosis if they don't listen to the patient and ask the right questions, such as whether there was pain on eye movement, how long it has been progressing, and whether other problems have been noticed, he said. "I have ended up with patients who have seen 7 or 8 doctors, and every one has been interested only in his or her own subspecialty area," Dr. Farris remarked. He added that physicians should be concerned about the outcome of the disease, not just the visual problem. "We cannot be consumed by their vision only, but need to consider the overall consequence of the illness and get the patient referred quickly and adequately."

Dr. Volpe agreed. "When I diagnose optic neuritis, in my heart I believe this patient is at great risk for developing MS," he said. "What is different now, versus 5 years ago, is that we used to have a condition that would get better on its own. When the patient returned later on, you would bring up the possibility that they could get other neurological symptoms and ask them to call you if these develop. But with the results of the CHAMPS study, at this first interaction we tell patients we are doing an MRI scan, not because we don't know what they have but because we want to look for brain lesions, which are predictors of MS. It's these patients that were shown benefit from treatment with Avonex®."

Dr. Eggenberger reiterated that it is not only patients with optic neuritis but also those with internuclear ophthalmoplegia or sixth nerve palsy who are at risk for MS and should be started on treatment. "Avonex® is the only agent that has been studied in this [early treatment] setting. No other study says that any other drug affects this group of patients at this point."

Though the mechanisms of action are unclear, Dr. Galetta believes that Avonex® most likely works by favorably altering the imbalance in the immune system that is driving the demyelination. Recent studies have verified that there is a significant axonal component in which nerve "cables" are destroyed. Even in new active lesions, axonal destruction occurs and ultimately correlates with disability, hence, it makes sense to prevent attacks, he said.

Dr. Galetta said he has been impressed with the response by ophthalmologists to the CHAMPS findings. "I have presented the data at several meetings, and it has been met with unbelievable enthusiasm and concern. People seem to be in a very aggressive mood regarding the treatment of these patients." Persons suspected of having MS warrant the ophthalmologist's full time and attention and should never be hurried through the consultation, Dr. Farris stressed. "You should not see so many patients in a day that you won't have time to spend with patients who have unique problems, such as optic neuritis and MS. They need help processing this information," he remarked.

© 2000 Millennium Medical Communications, Inc.

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