By Jai S. Perumal, MD
Assistant Professor of Neurology, Weill Cornell Medical College; Assistant Attending Neurologist, New York-Presbyterian Hospital
SYNOPSIS: In a long-term, 30-year follow-up study of a cohort of patients with multiple sclerosis who presented with clinically isolated syndrome, the investigators found that, among the variables assessed, the presence of cortical lesions had the highest association with long-term physical and cognitive disability.
SOURCE: Haider L, Prados F, Chung K, et al. Cortical involvement determines impairment 30 years after a clinically isolated syndrome. Brain 2021;144:1384-1395.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that is diagnosed predominantly in young adults. The clinical course of MS is variable, with a spectrum of relatively mild disease with no significant disability, even years after the diagnosis, on one end, and other patients with significant impairment at the other end. Studies that have attempted to predict long-term disability at the time of diagnosis encountered several hurdles, including inadequate length of time for follow-up, patient drop-out, treatment effects, and patient enrollment at various time points after their diagnosis. Investigators also have examined the factors that best correlate with disability, such as magnetic resonance imaging (MRI) lesion volume and lesion location. Cortical pathology has been an area of immense interest with regard to studies looking at long-term disability.
The current study has one of the longest follow-up periods ever reported — 30 years. These patients were enrolled at onset when they presented with an initial clinically isolated syndrome (CIS), which provides a homogenous population observed from early disease onset. Patient demographics, including age, sex, disease duration, MRI metrics, and neurological examination, were collected. Subsequent regular assessments also included Expanded Disability Status Scale (EDSS), timed 25-foot walk, Paced Auditory Serial Addition Test (PASAT), and the Brief International Cognitive Assessment for MS (BICAMS) for measurement of cognitive function. The goal of the study was to evaluate MRI correlates of disability in this cohort at 30 years from disease onset. MRI was obtained using a 3T Phillips scanner. Linear regression models were used to correlate MRI metrics to clinical measures.
Sixty-three patients, from among 132 patients with CIS who were recruited for prospective longitudinal follow-up at the study site between 1984 and 1987, were included in the analysis. By year 30, out of the 63 patients, 27 patients developed relapsing-remitting multiple sclerosis (RRMS), 15 developed secondary progressive multiple sclerosis (SPMS), and 21 patients remained in the CIS category. The RRMS patients in this cohort had EDSS scores between 0 and 2, which indicates a less disabled population with no limitations in their ability to walk.
From all the MRI metrics analyzed, the variable that revealed the greatest difference between the RRMS and SPMS groups was the number of cortical
lesions. Cortical lesions were present in three of the 27 patients with RRMS and all of the SPMS patients. None of the patients in the CIS category had cortical lesions. Cortical lesions correlated with both physical disability and cognitive impairment.
The limitations of this study include the relatively smaller number of patients who were followed for the full 30 years, and the few patients who were recruited initially but not followed to completion because of death. Some of the deaths were related to the MS diagnosis, and this could have biased the study toward those with less disability. Also, the cognitive impairments observed in this study were not predictive of future disability and were a contemporaneous correlate of current impairment.
COMMENTARY
In this 30-year, long-term follow-up study of patients who presented initially with CIS, the authors showed that cortical pathology correlated the most with physical and cognitive disability. Traditionally, MS was believed to be predominantly be a white matter disease, but the role of gray matter lesions is being increasingly recognized as a vital component of disease pathogenesis and progression. More studies examining gray matter involvement, particularly early in the disease course, might help identify a subset of patients who may have a worse long-term prognosis. A focus on developing more sensitive MRI sequences would help identify gray matter injury that currently is not evident on our present clinical scans.
