Article In Brief
A review of outcomes 30 years after clinically isolated syndrome shows that prognostic features predicting more auspicious longer-term outcomes include an early age at symptom onset, an initially remitting-relapsing course, optic neuritis or a predominantly sensory clinical isolated syndrome, complete remission after this episode, and a more extended time span between the first and second relapse.
Recognizing significant variance in the long-term course of multiple sclerosis (MS), a new prospective study attempts to predict outcomes by identifying early prognostic features on MRI in patients who had clinically isolated syndromes (CIS).
Subsequent to a CIS—an episode of neurological symptoms with at least partial resolution—investigators noted that higher initial brain lesion load and greater lesion accumulation over the first five years were associated with a heightened probability of developing disability within two decades.
Early lesions within the infratentorial and deep white matter regions also seemed to portend an elevated risk of ensuing disability, according to the findings published in the November 6 in Annals of Neurology.
In analyzing outcomes 30 years after a CIS, the investigators—led by a team at the University College London Institute of Neurology in the UK—observed a divergence in the largely untreated cohort. Some individuals accrued considerable disability early in their disease trajectory, while others fared relatively well over the long term.
“This cohort provides a unique perspective on the long-term clinical and MRI evolution of relapse-onset MS,” the study's lead author, Karen K. Chung, MBBS, MSc, clinical research associate at the university's Queen Square MS Centre, told Neurology Today. “As MRI first became available in the 1980s, and disease-modifying therapies in the 1990s, it is highly unlikely that such long-term, essentially natural history data can be obtained again.”
Prognostic features predicting more auspicious longer-term outcomes include an early age at symptom onset, an initially remitting-relapsing course, optic neuritis or a predominantly sensory CIS complete remission after this episode, and a more extended time span between the first and second relapse.
Clinical follow-up of 20 years or longer is needed because mobility restrictions arise more than a decade after onset in the majority of patients with relapsing-remitting MS (RRMS), the study authors wrote. They noted that it takes more than two decades for immobility without aids to occur.
The authors recommended a personalized risk-benefit analysis, ideally early in a patient's disease trajectory, to assess early use of MS disease-modifying therapies (DMTs) that may bring about extended remission.
“A key goal of future research is to determine what pathologically differentiates progressive from persistently non-progressive MS, with a view to targeting treatments that would substantially increase the chances a person with MS follow a less-disabling clinical course,” the authors wrote.
Study Design, Findings
Investigators asked two main questions: How variable are clinical outcomes at 30 years after a CIS? Is it possible to determine early on (within five years) which patients will develop progressive MS or have their lives curtailed by MS?
To answer these queries, the researchers utilized data from a unique cohort of 140 individuals enrolled in the prospective study after a CIS between 1984 and 1987 at the National Hospital of Neurology and Neurosurgery in Queen Square, and Moorfields Eye Hospital, both in London. Of these patients, eight received alternative diagnoses.
The remaining 132 individuals underwent clinical and MRI follow-up at one, five, 10, 14, 20, and 30 years. This cohort was mostly untreated because the study's recruitment pre-dated the advent of DMTs. The definition of MS was based on 2010 McDonald criteria. CIS classification was stratified to optic neuritis, transverse myelitis, or brainstem syndrome, according to clinical features.
At 30 years, clinical outcome data were available for 120 participants, of whom 80 were known to have developed MS. Expanded disability status scale (EDSS) scores in 107 participants, 77 of whom had MS: 42 percent—all of whom has RRMS— were still completely; 4 percent had RRMS, and EDSS >3.5, indicating moderate disability 34 percent had secondary progressive MS with more than moderate disability, and MS contributed to death in 20 percent. Of those with MS, 11 received DMTs.
The strongest early predictors (within five years of presentation) of secondary progressive MS (SPMS) at 30 years were presence of baseline infratentorial lesions and deep white matter lesions at one year.
The authors acknowledged some limitations to their analysis. EDSS and occupational status dominated outcome measures, while common MS symptoms, such as fatigue and low mood, were not evaluated. An EDSS of 3.5 was the threshold cutoff for “non-disabling” MS. Although this denotes fully ambulatory status (without the need for a walking aid), an individual may have ill effects and MS symptoms. Patient-reported measures were not considered, Dr. Chung told Neurology Today.
In addition, “at the inception of this cohort, MRI was a new technique, and image quality was not as good as is achievable now,” she added. As a result, “analyses of the earlier images will be less reliable than later ones. Spinal cord images were also not routinely obtained, in keeping with clinical practice back in the 1980s and 1990s.” Finally, the cohort size was small and a modest number of participants were lost to follow-up.
This study adds to the body of scientific evidence amassed in several prior clinical trials, several independent MS experts said. “Its 30-year follow-up is impressive and unlikely to be repeated,” said Jonathan Howard, MD, associate professor of neurology at NYU Langone Health.
The number of brain lesions on MRI is considered a “high-impact prognostic factor” in patients with CIS, Dr. Howard said. In these patients, spinal cord lesions are a particularly strong factor for predicting conversion to clinically definite MS.
Furthermore, in patients with optic neuritis, white matter lesions on baseline MRI are the most significant predictor for future risk of MS, even up to 15 years later, he said. One study found that patients with new lesions on MRI after a year of interferon-beta treatment had a higher risk of disability progression over a mean follow-up period of nearly five years.
While several DMTs have been successful in delaying conversion to clinically definite MS in patients with CIS, the fact that only 80 of 120 individuals with CIS developed MS in this study suggests that “there are a not insignificant number of patients who will have a benign prognosis in the absence of any treatment,” Dr. Howard said.
“It may be reasonable to follow such patients closely and monitor for clinical or radiographic changes,” he added. “Conversely, neurologists may reasonably choose to initiate a high-efficacy treatment in patients with CIS and the MRI findings (infratentorial and deep white matter lesions) identified in this study that portend a poor prognosis.”
As the authors indicated, the diagnostic criteria for MS and CIS have changed slightly, with the 2017 McDonald Criteria superseding the 2010 version. A CIS diagnosis, based on the latest revision, is currently uncommon, as most patients now meet the criteria for RRMS at initial presentation, Dr. Howard said.
Other neurologists expressed caution in classifying a patient as having a favorable outcome. As the authors noted, “even a relatively low EDSS, qualifying as a good outcome in this analysis, may have significant quality-of-life implications for the individual, and doesn't translate to ‘benign MS,’” said Claire Riley, MD, assistant professor of neurology at Columbia University Vagelos College of Physicians and Surgeons.
“So, while not all individuals with CIS went on to have secondary progressive MS in this largely untreated cohort, many may have been significantly affected by relapsing-remitting MS and may have benefited from immunotherapy,” Dr. Riley said. “We would not watch and wait in a CIS patient now, like those followed in this paper. The preponderance of evidence supports early treatment.”
Mirroring to some extent the rationale behind early stroke treatment, “the ‘MS world’ is tipping toward the concept of ‘time is brain’ and that MS needs to be treated aggressively from the beginning in every patient,” said Brian G. Weinshenker, MD, FAAN, professor of neurology at Mayo Clinic College of Medicine in Rochester, MN. “Many would argue that ‘there is no such thing as benign MS,’ and that even in the patients without significant motor/gait disability, there is significant cognitive impairment.”
This study emphasized that a sizeable subgroup, roughly 26 percent, developed further attacks of demyelinating disease after their initial CIS, but 30 years from the initial symptoms have “non-limiting” motor/gait and cognitive abilities (EDSS<3.5), Dr. Weinshenker said.
The investigators also confirmed many previously recognized predictors of disability, including clinical indicators, particularly the development of early impairment on examination, but MRI findings are even more foretelling. However, the study did not confirm that patients with optic neuritis at initial presentation had a more favorable outcome, even though there were many participants with this inflammatory symptom.
“This is contrary to the findings of many other studies, and the reasons for the discrepancy are not entirely clear,” he said.
Key modifications in the revised McDonald criteria can help expedite and refine the diagnostic process while decreasing the odds of misdiagnosis, Dr. Weinshenker said.
“Dissemination of lesions in the nervous system in space and time are required, but the revisions provide additional avenues for obtaining supporting evidence of dissemination,” according to the 2017 update of the McDonald criteria published in The Lancet Neurology.
For instance, when patients present with typical CIS, the new criteria allows for the existence of oligoclonal bands in the spinal fluid to stand in place of lesion dissemination in time in some contexts, noted Carrie Hersh, DO, MSc, staff neurologist and director of the MS wellness program at Cleveland Clinic's Lou Ruvo Center for Brain Health in Las Vegas.
“This is a very different therapeutic landscape currently” than what was available to MS patients who participated in the 30-year study. “We understand very clearly that early treatment will help forestall future inflammatory events and prolong accumulation of disability and then conversion to a more progressive disease course,” Dr. Hersh said.
Drs. Chung, Howard, and Riley had no relevant disclosures. Dr. Weinshenker receives royalties from RSR Ltd, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen GbR for a patent of neuromyelitis optica-IgG as a diagnostic test for NMO and related disorders. He has served on adjudication committee for clinical trials in NMO being conducted by MedImmune and Alexion, and consulted for Chugai, Mitsubishi-Tanabe regarding a clinical trial for NMO.