MRI a Poor Disability Predictor in Secondary Progressive MS

Erik Greb

August 27, 2021

MRI results may not be effective at indicating disability for patients with secondary progressive multiple sclerosis (SPMS), new research suggests.

Analysis from the phase 3 ASCEND trial of almost 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.

The few associations that were shown between MRI measures and clinical outcomes "were with the newer and possibly more sensitive outcomes" ― the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), write the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Calgary, Canada.

However, "it is unclear if these associations are clinically meaningful," they add.

Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.

The findings were published online July 26 in the Multiple Sclerosis Journal.

ASCEND Data Analysis

Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.

However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.

In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.

Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.

The study's clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter.

In addition, 3-month confirmed disability progression was measured every 12 weeks.

Few Significant Associations

The investigators' analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.

Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.

For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little.

Of all the clinical measures, the NHPT was most consistently associated with MRI measures.

Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than amng those whose NHPT score did not worsen.

Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.

After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.

Important Disability Contributors Missed

The odds ratio (OR) of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).

Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).

Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.

From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.

"The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience," the investigators write.

The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they note.

"Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome," they add.

"Interesting and Provocative"

Commenting on the findings for Medscape Medical News, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, in Toronto, Canada, called the study "interesting and provocative."

Dr E. Ann Yeh

"Other studies previously have shown associations between disability and progression, but many have been cross-sectional," said Yeh, who was not involved with the research.

The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Yeh said.

Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population's average brain volume loss.

"When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change," said Yeh.

She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.

"We'll continue to use the EDSS, because it's what we have," said Yeh.

However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.

"We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time," said Yeh.

These measures could include specific regional brain volumes "and more advanced measures that look at axonal injury or axonal loss." Studies with longer follow-up are also necessary, she concluded.

The investigators and Yeh have reported no relevant financial relationships.

Mult Scler. Published online July 26, 2021. Abstract

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