Multiple Sclerosis Research Repository

1. “New Insights into Multiple Sclerosis Clinical Course from the Topographical Model and Functional Reserve”: Stephen C Krieger and James Sumowski

-MS-related cognitive dysfunction: this insidious but pervasive symptom has not been fully incorporated into longstanding approaches to disability assessment or conceptualizations of MS phenotypes

-presence or absence of sidious worsening of neurological function in the absence of relapses referred to as disease progression

-progression characterized by neurodegeneration

-the long-term impact of relapses on the clinical course and the accumulation of disability continues to be a matter of debate

-an increased frequency and severity of relapses early in disease course MAY also confer an unfavorable prognosis and rapid development of disability 

-older studies of long-term outcomes in MS had identified a very limited impact of early relapses to the development of disability once the progressive phase of MS has become apparent

-acute lesions seen on MRI…serve as a surrogate marker for inflammatory disease activity

-those diagnosed at an older age are at a higher risk of manifesting a PPMS course  or developing SPMS after a short interval from diagnosis

-compensatory mechanisms may not be as roust in the older-onset MS population

-it (the topographical model of MS) remains agnostic (as do the other conceptual depictions of a clinical course of disease) to pathophysiologic and cellular mechanisms of the disease

-the spinal cord and optic nerves-the simplest, most linear structure commonly affected by MS-have the least redundancy and capacity for organizational plasticity and rewiring whereas the cerebral hemispheres possess the greatest such structural and functional resilience

-new MRI lesions are a…surrogate marker for relapse

-topographical model of MS; posits that there is a distinct relationship between lesion topography and the loss of functional reserve that drives the clinical course of MS

-the recapitulation hypothesis: progression clinically recapitulates a patient’s prior relapse symptoms and unmasks previously clinically silent lesions, incrementally manifesting above the clinical threshold a patient’s underlying disease topography

-topographical model of MS; is in some respects a relapse-centric model

-the concept that the loss of reserve may yield progressive worsening through loss of compensation for lesion burden helps to explain why high lesion burden early in the course of disease-even if the lesions are initially asymptomatic-is a poor prognostic factor for disability accrued many years later; once compensatory reserve declines, those sub-clinical lesions are no longer sub-threshold

-the topographical model: depicts the loss of reserve as beginning at the outset of disease, congruent with findings at CIS and RIS supporting the concept that early treatment to prevent disease activity-keeping the disease topography flat-may forestall the development of progressive disability later in the disease course

-topographical model: further congruent with findings that progressive accumulation of disability-be it in a context of SPMS or PPMS-is an age-related phenomenon; in the model, it takes years for reserve to be lost and for the clinical threshold to decline sufficiently for the progressive unmasking of disease topography to begin

-topographical model: does prioritize the loss of reserve-the declining threshold-as the crucial driver of disability in progressive disease

-clinical-radiologic paradox: the observation that some persons are better able to withstand neurological disease without or before suffering disability

-reserve is, in essence, the difference between the actual and expected disability for a given level of disease burden

-DMTs are “modifiable factors to maintain as much reserve as possible”

-greater cognitive leisure is linked with larger hippocampal volume in MS patients

-the goals of care in MS include both preventing new disease topography as well as maximizing reserve and “keeping the tank full” to augment a person’s capacity to keep the disease submerged

-”the goal of DMT for relapsing MS: keeping the topography flat, preventing new lesions from emerging and relapses from crossing the threshold (*but what about PIRA, neurodegeneration, and so many other aspects of MS pathology and activity that drive progression and disability worsening?*)