ARTICLE IN BRIEF
Investigators reported that 34 percent of subjects who had “radiologically isolated syndrome” (RIS) — T2 hyperintense white-matter anomalies without clinical signs of multiple sclerosis — evolved to either a first acute or progressive demyelinating event within five years of their scan.
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SAN DIEGO—At least one third of people with the “radiologically isolated syndrome” (RIS) will go on to develop clinical signs of multiple sclerosis within five years, according to the largest longitudinal study of the syndrome to date.
Darin Okuda, MD, who first described RIS in 2009, discussed the results of the study in a plenary session here at the AAN annual meeting in March. Dr. Okuda is chief of neuroimmunology at the Barrow Neurologic Institute in Phoenix, AZ.
RIS is defined as the presence of T2 hyperintense white-matter anomalies more than 3 millimeters in size, which are ovoid, well-circumscribed, homogeneous, and periventricular; involving regions of the brain and spinal cord commonly affected in MS, but without clinical manifestations of MS. They typically come to attention when the individual has a scan for other reasons, such as headache.
While RIS cases meet the MS diagnostic criteria of spatial dissemination, and occasionally time dissemination when a second scan is performed, they don't meet the criteria for MS since, by definition, they lack symptoms of the disease.
Despite the interest in RIS since it was first identified, there have not been any large, multicenter longitudinal studies to better understand its implications. “These data are important not only in our understanding of the general evolution of RIS to differing MS subtypes,” Dr. Okuda said, “but for the design and calculation of power estimates for future prospective trials, especially those aimed at extending the time to first symptom onset through the introduction of approved disease-modifying therapies.”
To fill that void, Dr. Okuda and colleagues of the Radiologically Isolated Syndrome Consortium set out to study the five-year risk for the development of a first symptomatic demyelinating event in a multinational cohort of RIS subjects. The study retrospectively identified subjects fulfilling RIS criteria in 20 clinical databases in the US, France, Spain, Italy, and Turkey, and then followed them prospectively to determine how long it took for the development of the first acute symptomatic demyelinating event followed by at least partial remission, or alternatively, for the development of a progressive neurological event.
Dr. Okuda noted that both MRI protocols and machine field strength differed among the centers, although they limited cases to those with scans after 1989. Imaging was not interpreted by a central facility, reducing the consistency of the diagnosis. Finally, he said, there may have been some recall bias regarding past symptoms in some participants.
In all, they found 451 RIS cases meeting their criteria, most from the US and France. Eighty-six percent were white, and 78 percent were female. Forty percent received their scan for diagnosis of headache. While only 3 percent sought a scan because of a family history of MS, 10 percent actually proved to have MS in the family. The average clinical follow-up was 4.4 years.
PROBABILITY AND RISK FACTORS
Thirty-four percent of subjects evolved to either a first acute or progressive event within five years of their scan. That probability varied by date of the scan, with more recent scans associated with higher percent of subjects experiencing a clinical event. Forty-five percent of those who were scanned in 2008 or after experienced a clinical event within five years, versus 22 percent of those scanned before 2003. “But we feel that that observation was principally due to a selection bias or the fact that there may have been more awareness over the past 5 years regarding RIS itself,” Dr. Okuda noted.
A younger age at RIS diagnosis was associated with an increased risk for developing an initial symptomatic event, Dr. Okuda said, with an estimated risk of developing an event decreasing by 2 percent for every additional year of age. He also found that male sex and the presence of a lesion within the cervical or thoracic spine also predicted development of a first clinical event.
Fourteen individuals, mostly white men, developed the primary progressive form of MS. Predictors of this subtype were a very high lesion load within the cervical and thoracic spine, and an abnormal cerebrospinal fluid profile. These results suggest there is a subclinical phase of primary progressive MS, Dr. Okuda said.
“Future worldwide efforts are needed to capture prospective biological, clinical, and radiologic data,” Dr. Okuda concluded. “And given these data, should we make plans to develop prospective studies aimed at preventing clinical symptom onset or radiological progression?”
IS A PROSPECTIVE STUDY FEASIBLE?
David Miller, MD, professor of clinical neurology at the Institute of Neurology of the University College London, who was not involved with the study, sought to address that question. Dr. Okuda's study clearly showed “that about one-third of these patients have had a clinical event characteristic for MS in five years,” he said. “It is an important finding and does indicate that the group has a significant risk of MS. On the other hand, bear in mind that two thirds did not have any clinical event in five years.”
Some portion of these individuals are likely to have been misdiagnosed, he said, given that similar MRI findings may be seen in cerebrovascular disease, CNS infections, and other conditions. “It may not be that much, but it is significant,” he said. “So there are some caveats in applying the MRI criteria to support the diagnosis of multiple sclerosis.”
Secondly, he said, “there is undoubtedly a higher probability of diagnosing MS that will follow a benign course. So what to do in this situation? Well, it is clear that these are people that have a high risk for MS, but on the other hand, they may have a good long-term prognosis. My own general view of the situation would be to adopt a ‘wait and watch’ approach to management.”
Dr. Miller also pointed out that the study included individuals from areas of high or moderate prevalence. “It is important that these data are not extrapolated to regions of low MS, where the risk for MS is less and where the possibility of misdiagnosis may be higher.”
He also noted that while spinal lesions appeared to be associated with a higher risk for both relapsing-remitting and progressive MS, a spinal MRI was not done in all cases. “This could be relevant, because unless investigations were performed systematically in every individual there could be a selection bias that in some way affects the final risk,” Dr. Miller said.
“With regard to research, there is an opportunity to study pathogenic mechanisms of MS at the very earliest stage that may result in new insights that lead to new therapeutic strategies,” Dr. Miller continued. “There's undoubtedly a potential to treat MS before the development of significant pathological damage or clinical episodes.”
However, Dr. Miller said, for larger studies to be performed cost-effectively, “I think we would like to identify a higher-risk subgroup, perhaps near the 80 percent risk that is now achievable in clinically isolated syndrome patients.”
But screening to identify such subjects remains problematic, without either dramatic cost reductions in imaging technology or identifying other biomarkers to enrich the pool of potential RIS subjects. Population-based prospective studies might be the definitive way of establishing the prevalence and prognostic importance of RIS, “but whether they are actually feasible is a different question,” Dr. Miller said.
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