Introduction

Several reports presented at the American Neurological Association (ANA) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) added to the latest evidence that cerebral atrophy and cognitive impairment are significant components of the multiple sclerosis (MS) spectrum. Researchers are discovering that with the appropriate diagnostic tests, the occurrence of atrophy and cognitive decline can be predicted earlier in the course of disease progression.

A study in 51 relapsing-remitting multiple sclerosis (RRMS) patients from the National Institute of Neurologic Disorders and Stroke (NINDS) showed that the number of gadolinium contrast enhancing lesions (CELs) seen on initial magnetic resonance imaging (MRI) examination predicts the amount of global tissue damage 8 years later.¹

"We now know that MS isn't just a disease of the lesion itself but a global disease of the normal-appearing white matter. Using a technique called magnetization transfer ratio (MTR) that examines the whole brain, we showed for the first time that CELs predict global atrophy down the road," announced Nancy Richert, MD, PhD., who presented the findings at the ANA. Dr. Richert is a radiologist and staff clinician at the NINDS.

"We all believe that gadolinium-enhancing lesions are very sensitive outcome measures, but the problem has been that the correlation between enhancing lesions and the degree of disability down the road is notoriously poor," Dr. Richert explained. "Gadolinium enhancement is a measure of the blood brain barrier. The feeling is that we have to move from the blood brain barrier up to the level of the neuron, and measure damage to those neurons, which we can do with magnetization transfer imaging and brain atrophy [assessments]."

In the NINDS study, the correlation between the number of CELs and tissue damage was made by determining the MTR and degree of brain atrophy by the brain parenchymal fraction. Magnetization transfer imaging is an indirect measure of tissue destruction that quantitates the relative proportion of the bound water fraction. A decrease in the MTR reflects the extent of demyelination and also correlates with axonal loss.

Some patients in Dr. Richert's study had no lesions initially, some had a few lesions, and one patient actually had 60 lesions on the first MRI examination. The study aimed to determine whether the number of these CELs (the average of the first three MRI scans) predicted the MTR, indicating the amount of tissue damage seen when patients were re-evaluated after 8 years.

A very strong correlation did, indeed, emerge, Dr. Richert made clear. While the number of CELs did not directly correlate with clinical factors, CELs did correlate with the MTR, which in turn correlated well with brain parenchymal fraction and with a number of clinical measures, including the Kurtzke Expanded Disability Status Scale (EDSS), change in EDSS, Scripps Neurological Rating Scale (SNRS), and Paced Auditory Serial Addition Test (PASAT).

Histograms compiled from MTRs of MS patients-including the 51 patients in this study-show an increasing leftward shift as disability increases. This shift reflects more voxels with lower MTR values and more tissue damage, Dr. Richert pointed out.

Whether treatment affects this correlation is yet to be determined, but this question will be studied after all 187 patients in the study are re-evaluated. Most of the subjects have received disease-modifying therapy.

In terms of current therapies, Rudick et al.² conducted a post-hoc analysis on MRI data of 140 RRMS patients participating in the original Phase III Avonex trial and showed that brain parenchymal fraction was more than 5 standard deviations lower in MS patients than in healthy controls. During the second year of treatment, patients receiving Avonex had significantly less change in this parameter, versus controls, representing a 55% reduction in the rate of brain atrophy progression.

Cognitive Impairment in MS

In another study presented at the ANA, a significant correlation was found between cerebral atrophy and mild cognitive impairment.³ The study included 37 patients with either RRMS (59.5%) or secondary progressive multiple sclerosis (SPMS)(40.5%), who initially showed mild cognitive impairment on a brief screening examination and were further evaluated more extensively for cognitive impairment and brain atrophy.

These so-called "mildly impaired" patients demonstrated significant deficits on several more sophisticated measures of verbal learning/memory, spatial learning/memory, and auditory attention, reported Lauren B. Krupp, MD, from the State University of New York at Stony Brook.

Furthermore, the patients' neuropsychological summary Z score correlated with brain atrophy, as determined by the central cerebrospinal fluid proportional total volume score, which is a more specific measure of atrophy than the brain parenchymal fraction, Dr. Krupp said.

"We found a significant correlation between worse scores on neuropsychological testing and less volume in the brain," she remarked.

Treatment with disease-modifying agents may halt the progression of cognitive impairment, in her opinion. "What Dr. Rudick and others have told us is that untreated axons die out, and there is progressive atrophy even in mild patients. With treatment, atrophy is lessened," she said.

Corroborating data on cognitive impairment has previously been illustrated where Avonex has been shown to exhibit a significant beneficial effect on information processing and learning/memory and a trend toward benefit in visuospatial ability and problem solving in patients with the relapsing form of MS.⁴

In addition to current therapies, Dr. Krupp speculated that other neuropharmacologic agents targeted for Alzheimer's disease patients may also help preserve cognitive function in MS, and she is evaluating this in an NIH-funded placebo-controlled study.

Predictive Value of MSFC

At the ANA's Neurology Research Outcomes session, Richard Rudick, MD, described the usefulness and predictive value of the Multiple Sclerosis Functional Composite (MSFC) in disease assessment.⁵ The MSFC, which is now being used in clinical trials includes the 25-foot timed walk, the 9-hole peg test, and the 3-second version of the PASAT, averaged to produce a single composite score. Emerging data suggest that the MSFC may prove to be superior to other assessment instruments in predicting long-term disability, according to Dr. Rudick, The Cleveland Clinic Foundation, Director of the Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland, Ohio.

A number of recent studies have shown excellent correlation between the MSFC and the EDSS presence of MRI lesions (T2 lesion load and T1 black holes), brain atrophy, and quality of life. The correlation coefficients and p values of these relationships have been impressive, Dr. Rudick said.

"In fact, the MSFC predicts as well as, or even better than, traditional cardiovascular risk factors predict for heart disease," he added. Studies have shown a 1.9 risk ratio for the development of heart disease among persons in the worst quintiles for blood pressure and serum cholesterol [J Chronic Dis 1978, Vol. 3(4)]. When the MSFC data are fitted into the same schema, a risk ratio of 3.7 emerges for poor ambulatory status among patients in the worst quintiles of the MSFC, he said.

Indeed, in 160 patients from the original Avonex study re-evaluated 8 years after randomization, the 2-year change in the MSFC score independently and significantly predicted ambulatory status at 8 years, conversion to secondary progressive MS, degree of brain atrophy, and quality of life,⁶ he reported.

In the best initial MSFC quartile, 18% of patients required a cane for ambulation 8 years later, compared to 57% in the worst quartile. Conversion to SPMS occurred in 18% of patients demonstrating the least change in MSFC but in 66% of those in the worst quartile.

In the recent IMPACT study of 436 secondary progressive MS subjects from 42 sites,⁷ the MSFC intraclass correlation was 0.93, suggesting excellent reliability of the test. "This was even more remarkable because it was delivered in six different languages at 42 sites, and most [test administrators] had no prior experience with the use of this measure," he added.

In IMPACT, patients treated with Avonex had 27% better mean and 40% better median scores on the MSFC compared to placebo (p = .033). Significant treatment effects were also seen in relapse rate reduction and MRI metrics.

Fred Lublin, MD, of Mount Sinai School of Medicine, New York, commented in a presentation at ACTRIMS on the use of the MSFC in the IMPACT study. "Recent data suggests that the MSFC is a very sensitive indicator of change in MS and has predictive value for the EDSS," he said. IMPACT did not show a change in EDSS because the study was not powered to show this (since the MFSC is a more sensitive instrument and therefore fewer patients were needed). "But I think [treated] patients would have shown a change in EDSS over time," he remarked.

References

1. Contrast-enhancing lesions predict magnetization transfer ratios and cerebral atrophy in relapsing-remitting multiple sclerosis patients: preliminary results of an 8-year follow-up study. Richert et al. American Neurological Association 126th Annual Meeting, September 30 - October 3, 2001, Chicago, Illinois. Presented October 1, 2001, Poster Session I - #108.

2. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Rudick et al. Neurology 1999 Nov 10;53(8):1698-1704.

3. Clinical features of multiple sclerosis patients with mild cognitive impairment. Krupp et al. American Neurological Association 126th Annual Meeting, September 30 - October 3, 2001, Chicago, Illinois. Presented October 2, 2001, Poster Session II - #190.

4. Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Multiple Sclerosis Coolaborative Research Group. Fischer et al. Ann Neurol 2000 Dec;48(6):885-892.

5. How well does the MSFC predict neurologic outcome in Relapsing Remitting Multiple Sclerosis. Rudick, R. American Neurological Association 126th Annual Meeting, September 30 - October 3, 2001, Chicago, Illinois. Neurology Outcomes Research: Current Science & Future Directions, Presented September 30, 2001, Platform Presentations II.

6. Use of the Multiple Sclerosis Functional Composite to predict disability in relapsing MS. Rudick et al. Neurology 2001;56:1324-1330.

7. Use of the multiple sclerosis functional composite as an outcome measure in a phase 3 clinical trial. Cohen et al. Arch Neurol 2001 Jun;58(6):961-967.