With Multiple Sclerosis, 'Permanent Arrest' May be Temporary

VANCOUVER, British Columbia, Feb. 16 -- It can take more than a decade, but multiple sclerosis patients in a state of "permanent arrest" can find their relatively benign disease progressing.

Among patients who 10 years after a MS diagnosis still had only mild symptoms or no disability, nearly half had significant disease progression after another 10 years, reported Ana-Luiza Sayao, M.D., of the University of British Columbia here, and colleagues.

Approximately 21% became severely disabled and mobility restricted, requiring the use of a cane, and 23% went on to develop secondary progressive MS two decades after symptom onset, the investigators reported in the Feb. 13 issue of Neurology.

"We hoped to identify risk factors that make people more likely to progress in the disease after 10 years of a benign course, but we did not find that gender, the symptoms when the disease began, or age when the disease began were associated with either disease progression or remaining benign," said Virginia Devonshire, M.D., a co-author. "More research needs to be done to identify criteria to determine which people will remain with mild disability over the long term."

As other investigators have shown, the Expanded Disability Status Scale (EDDS) score at 10 years was the only predictor of benign disease at 20 years, yet even this marker was inadequate for describing the disease in the cohort, the authors said.

But as researchers from the Netherlands reported in a separate study in a different journal, MRI scans showing brain changes at the time of diagnosis appear to hold clues to disease progression.

"In patients with recently diagnosed multiple sclerosis, the extent of accumulated brain tissue loss and overall lesion load partly explain the subsequent rate of cerebral atrophy," wrote Bas Jasperse, M.D., and colleagues from VU University Medical Center in Amsterdam, in the February issue of Archives of Neurology.

In the Canadian study, Dr. Sayao and colleagues in Vancouver evaluated disease status after 20 years in a cohort of patients with benign MS, defined as an EDSS score of three or less 10 years after disease onset. Of 200 patients who met the criteria at 10 years, 20-year follow-up was available for 169.

"Patients for whom we were unable to obtain 20-year follow-up were analyzed through 'best-case' and 'worst-case' scenarios, with best case assuming the same EDSS score at 20 years as at 10 years, and worst case being death due to MS (EDSS score = 10)," the investigators wrote.

The primary study outcome was clinical progression in the cohort, determined by the EDSS score at 20 years, with comparisons between patients who still had benign disease and those whose disease had progressed.

The authors also conducted a regression analysis controlling for age at onset, sex, onset symptoms (optic neuritis, sensory, motor, and cerebellar/ataxia/brainstem), and EDSS score at 10 years.

They found that of the 169 patients for whom 20-years EDSS scores were available, 52.1% (88 patients) continued to have a benign course, but 21.3% (36 patients) had progressed to require the use of a cane (EDSS score > 6), and of the 196 who originally had a relapsing-remitting disease course, 23% (45 patients) had conversion to secondary progressive MS.

In the logistic regression analysis, they determined that the only variable associated with disease progression at 20 years was the EDSS score at 10 years (P<0.0005). There was no "ideal" 10-year EDDS score for predicting benign status at 20 years, however.

In addition, of the 108 patients with EDSS scores of 2 or less at 10 years, 32% (35 patients) no longer had benign disease (EDSS > 3) at 20 years.

"At 10 years from onset, neither an Expanded Disability Status Scale score < 3 nor an EDSS score < 2 adequately represented 'benign multiple sclerosis' because an appreciable proportion of patients progressed in disease severity," the investigators wrote. "Appropriate and reliable criteria to identify which patients with MS remain with mild disability over the long term have yet to be determined."

The authors noted that while there is clearly a subgroup of patients with MS who have a mild or benign disease course over the long haul, there is a lack of consensus on the definition of benign, and there may be other, undetected consequences of living with the condition.

"Patients who persist with low EDSS scores over 20 years may have cognitive symptoms, fatigue, or functional impairments not accounted for by the EDSS that can result in noteworthy disability. However, we were not able to assess these," they wrote. "Perhaps the suggested definition 'fully functional in all neurologic systems 15 years after disease onset,' despite its imprecision, may be the most suitable definition of benign MS, given current knowledge."

In an accompanying editorial, Sean J. Pittock, M.D., of the Mayo Clinic in Rochester, Minn,, noted that other trials have seen higher rates of benign disease long-term. He also suggested that many patients with mild disease may not need or benefit from immediate disease-modifying agents.

"The 'watchful waiting' approach should not be misconstrued as a 'never treat' approach," he wrote. "If the decision is made to delay treatment in a patient with a favorable disease profile, yearly clinical and radiologic surveillance is advised, with appropriate initiation of disease-modifying agents should the clinical (relapses) or radiologic (new/enhancing lesions) status or patient wishes change. The MS prognostic glass is half full for a high proportion of these most benign cases."

In the Dutch study, the researchers attempted to identify specific clues visible on MRI that could predict the rate of cerebral atrophy in patients with newly diagnosed MS.

"Knowledge of features that precede the subsequent rate of atrophy may partly elucidate pathophysiological mechanisms behind the development of atrophy and may thus have prognostic value for clinical functioning at long-term follow-up," Dr. Jasperse and colleagues wrote. "Better knowledge of factors that predispose to development of atrophy may also have implications for the interpretation of clinical trials that use atrophy rate as an outcome measure."

They compared MRI scans taken at baseline and at two years after diagnosis, looking at lesion load as determined by areas of T2 hyperintensity, black hole lesion load, the presence of contrast-enhancing lesions, and normalized brain volumes. Their purpose was to determine which of the factors, if any might be associated with the annualized percentage of brain volume change (main outcome measure).

They found that among 89 patients with MS recently diagnosed at study baseline, the mean annualized rate of cerebral atrophy was -0.9% + 0.8 %. Both baseline normalized brain volume (standardized coefficient, 0.426, P=0.001) and baseline T2 lesion load (standardized coefficient, ?0.244, P=0.02) were predictive for subsequent annualized percentage of brain volume change.

In logistic regression modeling, baseline brain volume and T2 lesion load were able to explain 31.2% of the variance in the main outcome measure.

"Because a higher rate of cerebral atrophy is predictive of worse clinical functioning at a later stage in the MS disease course, our findings suggest that these two baseline variables could have prognostic value for clinical functioning in early MS," the investigators wrote. "These findings also indicate that T2 lesion load and brain volume should be taken into account when designing and interpreting clinical trials that use cerebral atrophy rate as [an] outcome measure."

The findings suggest that the current techniques for monitoring MS disease progression tell only a part of the story, suggested J. Theodore Phillips, M.D., Ph.D., of the Multiple Sclerosis Center at Texas Neurology in Dallas, in an accompanying editorial.

"Despite clinical differences in populations studied and differences in strength of relationship among various MRI disease measures, the study of Jasperse et al and other similar studies lead to a similar, critically important conclusion; that typical MRI measures of focal disease activity (gadolinium enhancement, T2- or T1-weighted lesion load) only partly explain brain atrophy progression in MS," Dr. Phillips wrote.

One place to look for less evident changes, he said, is in so-called normal-appearing brain tissue, which may be just that: normal appearing.

"The hypothetical construct of MS beginning as a spatially limited, focal disturbance(s), whether inflammatory or noninflammatory, positioned in otherwise truly normal brain tissue that subsequently spreads to create a generally dysfunctional and inhospitable microenvironment throughout normal-appearing brain tissue is attractive and compatible with evolving views of MS pathogenesis," he wrote.

The study by Jasperse and colleagues was supported by the Netherlands Organization for Scientific Research. The authors had no financial disclosures.