The Natural History of Multiple Sclerosis: A Geographically Based Study

Weinshenker, Brian G.; Bass, B.; Rice, George P.; Noseworthy, John H.; Carriere, W.; Baskerville, J.; Ebers, G. C.

doi:10.1093/brain/112.1.133

Cited by 1,334 publications

(731 citation statements)

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“…At 16.8 years after onset, 10.7% (95% CI 7.2 to 14%) of patients had reached an EDSS ≥6 whereas in some natural history studies 50% of the cohort had reached an EDSS 6 by 15–16 years, albeit it with wide confidence intervals. 42,5 …”

Section: Discussionmentioning

confidence: 99%

Long‐term evolution of multiple sclerosis disability in the treatment era

Team:

2016

Annals of Neurology

362

167

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Objectives To characterize the accrual of long-term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and MRI data used in clinical trials have long-term prognostic value. Methods This is a prospective study of 517 actively managed MS patients enrolled at a single center. Results More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit. At this last assessment, neurologic disability as measured by the Expanded Disability Status Score (EDSS) was stable or improved compared to baseline in 41% of patients. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first two years had long-term outcomes that were no different from those of the cohort as a whole. 25-OH vitamin D serum levels were inversely associated with short-term MS disease activity; however, these levels had no association with long-term disability. At a median time of 16.8 years after disease onset, 10.7% (95% CI 7.2 to 14%) of patients reached an EDSS ≥6 and 18.1% (95% CI: 13.5 to 22.5%) evolved from relapsing MS (RMS) to secondary progressive MS (SPMS). Interpretations Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies. Notably, the NEDA 2-year endpoint was not a predictor of long-term stability. Finally, the data call into question the utility of annual MRI assessments as a treat-to-target approach for MS care.

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Section: Discussionmentioning

confidence: 99%

Long‐term evolution of multiple sclerosis disability in the treatment era

Team:

2016

Annals of Neurology

362

167

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“…A large proportion of RRMS patients eventually convert to a secondary progressive stage (SPMS) within 6 -10 years. 1,2 The hallmark of this stage is a progressive worsening of disability in the absence of relapses, and a shift from inflammatory to degenerative activity, apparent on MRI as fewer contrast-enhancing lesions and accelerated brain parenchymal atrophy (FIG. 1).…”

Section: The Repair Potential Hypothesismentioning

confidence: 99%

“…Baseline MRI for patients with an initial attack (i.e., clinically isolated syndrome, or CIS) is predictive of conversion to clinically definite MS, 9 long-term progression, 10 and failure to recover from an initial demyelinating event. 11 Similarly, frequency and duration of early relapses and time to second episode 12 all have predictive quality for future progression. 11 However, such variables lose their predictive quality once an EDSS score of 4 is reached, 11 which seems to be a landmark from which progressive disability measured by EDSS appears to accelerate.…”

Section: Fig 1 Repair-capacity Disease Progression Model For Multipmentioning

confidence: 99%

Time-Series Modeling of Multiple Sclerosis Disease Activity: A Promising Window on Disease Progression and Repair Potential?

Meier

Weiner

2007

Neurotherapeutics

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Summary:This article discusses and reviews advanced forms of serial morphometry in the context of a disease progression model in multiple sclerosis (MS). This model of disease activity distinguishes between overall disease activity and the proportion thereof that becomes permanent damage. This translates into a progression model that features a repair potential, which, when exhausted, marks the conversion or progression from relapsing to progressive disease. The level of repair capacity at a given time determines the rate of progression. Both clinical and MRI variables appear to be in support of such a model. We examine possible MRI markers for this repair capacity, particularly the short-term behavior of new MRI lesions, quantified by methods of time-series analysis-that is, capturing lesion dynamics in the form of MRI intensity change directly, rather than shape or volume change. Lower rates of individual lesion recovery may represent lower repair and greater proximity to a progressive stage. Individuals with low transient lesion turnover appear to undergo more rapid progression and atrophy. Because disease-modifying therapies aim to alter the pathophysiological chain of inflammation, demyelination, and axonal loss, a therapeutic effect may therefore be more readily apparent as a change in lesion dynamics and recovery rate and level, rather than a change in total lesion burden or enhancing lesion number. Key Words: Multiple sclerosis, disease modeling, serial MRI, morphometry, lesion evolution, repair. THE REPAIR POTENTIAL HYPOTHESISMore than 80% of newly diagnosed cases of clinically definite multiple sclerosis (MS) fall into the relapsingremitting (RRMS) category. A large proportion of RRMS patients eventually convert to a secondary progressive stage (SPMS) within 6 -10 years. 1,2 The hallmark of this stage is a progressive worsening of disability in the absence of relapses, and a shift from inflammatory to degenerative activity, apparent on MRI as fewer contrast-enhancing lesions and accelerated brain parenchymal atrophy (FIG. 1). The etiology of this progression is not known, but a premise commonly offered is that of a threshold effect and the exhaustion of structural and functional redundancy, leading from inflammatory and relapsing to more diffuse and accelerated accrual of damage.Here we review and discuss this progression model, focusing on the concept of a hypothesized repair potential as a marker for progression. Of particular interest is the possibility of obtaining early MRI markers of this repair potential from advanced forms of serial quantitativ MRI. As new therapies with alternative mechanisms (other than broad or targeted immune suppression) become available to MS patients, specific markers that reliably predict long-term progression early in the disease are becoming increasingly critical.A growing body of evidence is congruent with a repair potential model: histopathological analyses have revealed a shift from focal inflammatory activity in RRMS to diffuse damage in SPMS 3 and overall reduced...

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“…The clinical course of MS is relapsing remitting (RRMS) in about 70-80% of patients. However, after a disease duration of 10 years, almost half of the affected individuals experience a deterioration of symptoms independently of relapses and enter into the secondary progressive phase of the disease [2]. Many hypotheses have been put forward on the etiology of MS and all of them have been disproved except for one: the autoimmune hypothesis that argues in favor of the idea that the myelin sheath is attacked by autoantigen specific immune cells [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Cytokines and effector T cell subsets causing autoimmune CNS disease

2011

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a b s t r a c tAlthough experimental autoimmune encephalomyelitis (EAE) is limited in its potency to reproduce the entirety of clinical and histopathologic features of multiple sclerosis (MS), this model has been successfully used to prove that MS like autoimmunity in the CNS is orchestrated by autoantigen specific T cells. EAE was also very useful to refute the idea that IFN-c producing T helper type 1 (Th1) cells were the sole players within the pathogenic T cell response. Rather, ''new'' T cell lineages such as IL-17 producing Th17 cells or IL-9 producing Th9 cells have been first discovered in the context of EAE. Here, we will summarize new concepts of early and late T cell plasticity and the cytokine network that shapes T helper cell responses and lesion development in CNS specific autoimmunity.

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The Natural History of Multiple Sclerosis: A Geographically Based Study

Cited by 1,334 publications

References 0 publications

Long‐term evolution of multiple sclerosis disability in the treatment era

Long‐term evolution of multiple sclerosis disability in the treatment era

Time-Series Modeling of Multiple Sclerosis Disease Activity: A Promising Window on Disease Progression and Repair Potential?

Cytokines and effector T cell subsets causing autoimmune CNS disease

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