'Paramagnetic Rim Sign' May Help Identify Early MS

March 12, 2020

A new marker has been discovered that may give prognostic information about patients with radiologically isolated syndrome ― a condition characterized by incidental MRI abnormalities suggestive of multiple sclerosis (MS) but that occur before any symptoms have developed.

The new marker is known as the paramagnetic rim sign (PRS). It is described as an increase in magnetic susceptibility along the rim of the MS lesion that represents the presence of iron inside phagocytes and the presence of chronic, active inflammation and demyelination.

In a letter to JAMA Neurology published online March 9, researchers report results from a cohort of 28 patients with radiologically isolated syndrome of whom 61% had at least one white matter lesion with a PRS.

"Our findings are provocative in that a significant proportion of these patients with radiologically isolated syndrome had signs of active disease," senior author Jiwon Oh, MD, St. Michael's Hospital, University of Toronto, Canada, told Medscape Medical News.

"We don't yet have any markers to tell us which patients with radiologically isolated syndrome need to be treated or managed more aggressively. This may be something that can help with that," she added.

Oh noted that specific MRI sequences can detect PRS on MS white matter lesions, which is representative of activated microglia and smoldering inflammation.

"From a pathological standpoint, these chronic smoldering lesions are seen in greater numbers in advanced MS and progressive MS," she said.

Typically, a patient with radiologically isolated syndrome has not shown any MS symptoms, but a possible MS lesion has been identified on an MRI scan conducted for an unrelated reason, such recurrent headaches or head trauma, Oh explained.

"But when lesions are seen in completely asymptomatic patients, we would not expect them to be chronic active smoldering lesions, so we were surprised to see radiologically isolated syndrome patients with one or more of these lesions.

"We don't really know what to do with radiologically isolated syndrome patients ― they are not very common and quite a recent phenomenon, and there are no studies of treatment or management strategies for these patients. But many of them are probably at risk of developing MS," Oh commented.

Noting that this was a cross-sectional study based on one set of MRI results, she said it would be necessary to follow this cohort of patients closely longitudinally.

"This may be a biomarker which could help prognosticate patients. It may be that a chronic smoldering lesion like the ones we have identified in these patients is a sign of active disease and the patient needs treatment now."

Patients with radiologically isolated syndrome are a unique population, she said. "They window into the earliest stages of MS, as they have not yet developed symptoms. They could give us information as to what causes the onset of symptoms," she added.

"But although these patients are at the earliest stage of MS, these paramagnetic rim sign–positive lesions look exactly like what we see in patients with established MS, suggesting that this cohort is not just people who happen to have lesions that may or may not be MS but rather that most of them are likely to develop MS," Oh commented.

For the current analysis, three reviewers independently assessed MRI scans from 28 individuals with radiologically isolated syndrome for lesions showing PRS, defined as a complete/incomplete rim of hypointense signal identified on phase images.

Of 1068 white matter lesions assessed, 129 (12%) were positive for PRS, and 17 patients had at least 1 PRS-positive lesion. The median number of PRS-positive lesions per patient was 1 (range, 0 – 23).

The researchers also found that 26 of the patients with radiologically isolated syndrome (93%) also had many lesions in which the central vein sign was present. That sign is thought to distinguish MS-associated lesions from other white matter disorders.

"These findings collectively suggest that most white matter lesions observed in radiologically isolated syndrome develop from perivenous inflammation and demyelination and, surprisingly, that most patients with radiologically isolated syndrome experience chronic, active inflammation," they say.

They also report that white matter lesions with PRS correlated with white matter lesion volume and brain volume and with spinal cord lesion counts.

"These findings collectively raise the possibility that the paramagnetic rim sign may have useful clinical implications regarding prognostication and disease-monitoring in radiologically isolated syndrome," they conclude.

Commenting on the study for Medscape Medical News, Jeffrey Cohen, MD, director of the Mellen MS Center at the Cleveland Clinic and current president of Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), said: "Besides T2 hyperintense lesions that resemble those of MS, patients with radiologically isolated syndrome have many other features of MS when one looks closely.

"This is not surprising, as most in fact have MS but cannot yet be diagnosed at the time," Cohen added. "Paramagnetic rim sign is another one of those features. To the extent the paramagnetic rim sign helps prognosticate in established MS, I expect it also could be used in radiologically isolated syndrome."

The study was funded by the MS Society of Canada, the St. Michael's Hospital Foundation Barford & Love Multiple Sclerosis Fund, and the Intramural Program of the National Institute of Neurological Disorders and Stroke. Oh reports receiving grants and personal fees from Biogen-Idec, Roche, and Sanofi-Genzyme and personal fees from Celgene, Novartis, and EMD-Serono.

JAMA Neurol. Published online March 9, 2020. Full text

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