The topographical model of multiple sclerosis A dynamic visualization of disease course

Stuart SchlossmanMS Research Study and Reports

. 2016 Oct; 3(5): e279.
Published online 2016 Sep 7. doi: 10.1212/NXI.0000000000000279
PMCID: PMC5015541
PMID: 27648465

The topographical model of multiple sclerosis

A dynamic visualization of disease course
This article has been cited by other articles in PMC.

Abstract

Relapses and progression contribute to multiple sclerosis (MS) disease course, but neither the relationship between them nor the spectrum of clinical heterogeneity has been fully characterized. A hypothesis-driven, biologically informed model could build on the clinical phenotypes to encompass the dynamic admixture of factors underlying MS disease course. In this medical hypothesis, we put forth a dynamic model of MS disease course that incorporates localization and other drivers of disability to propose a clinical manifestation framework that visualizes MS in a clinically individualized way. The topographical model encapsulates 5 factors (localization of relapses and causative lesions; relapse frequency, severity, and recovery; and progression rate), visualized utilizing dynamic 3-dimensional renderings. The central hypothesis is that, like symptom recrudescence in Uhthoff phenomenon and pseudoexacerbations, progression clinically recapitulates prior relapse symptoms and unmasks previously silent lesions, incrementally revealing underlying lesion topography. The model uses real-time simulation software to depict disease course archetypes and illuminate several well-described but poorly reconciled phenomena including the clinical/MRI paradox and prognostic significance of lesion location and burden on disease outcomes. Utilization of this model could allow for earlier and more clinically precise identification of progressive MS and predictive implications can be empirically tested.

CONTEMPORARY CONCEPTUALIZATION OF MS DISEASE COURSE

Multiple Sclerosis (MS) is a disease characterized by both relapses and insidious progression, and is notably heterogeneous in clinical course, symptomatology, and severity. The accepted MS clinical course phenotypes have been foundational in clinical practice and are utilized to inform the eligibility requirements and outcomes of clinical trials, which shape regulatory approvals and indications for MS therapeutics.
While relapsing and progressive processes contribute to MS disease course,, neither the relationship between them, nor the spectrum of clinical heterogeneity has been fully characterized., Although the contemporary phenotypes, revised in 2013, have been refined with subdescriptors based on the presence or absence of inflammatory activity and disease progression, they maintain distinctions between relapsing and progressive disease as separate core disease subtypes at a given time point. These phenotypes have focused on clinical manifestations, yet by design, they do not directly represent the diversity of symptoms, relapse severity, and the pattern and manner of accumulation of disability.
Furthermore, uncertainties remain regarding the biological underpinnings of the disease. Perhaps relapsing-remitting MS (RRMS) is also progressive from onset, as atrophy is known to begin early in the disease., Perhaps progressive MS is inflammatory throughout the course, as there is evidence of inflammation even late in progressive disease. A contemporary view is that MS is a single disorder with an intermingling of acute focal recurrent inflammation and diffuse chronic neurodegeneration from the outset of the disease. In clinical practice, the line between relapsing and progressive MS is not always discrete. In one study, we found a mean period of diagnostic uncertainty of 4.3 years during the transition from RRMS to secondary progressive MS (SPMS), highlighting that there is no way to clinically determine a precise moment of transition between these 2 categories. A dynamic model of MS disease course must visualize this admixture of relapsing and progressive aspects of the disease in a way that remains true to MS clinical phenomenology, while also capturing the clinical variability manifested by individual patients.

THE TOPOGRAPHICAL MODEL OF MS AND THE RECAPITULATION HYPOTHESIS

The topographical model of MS described in this medical hypothesis builds directly on the 2013 clinical course revisions’ delineation of relapse activity and progression as distinct processes coexisting in parallel. As a unified visualization of disease course, this new model illustrates the interplay of relapses and progression in MS across the entire range of disease course depictions, including the transitions between clinical phenotypes. The model provides a clinical manifestation frameworkthrough which disease course may be better understood.
Central to this model is the observation that 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.” The recapitulation hypothesis central to this new clinical framework may better elucidate the drivers of disability accumulation and could allow for earlier and more clinically precise identification of progressive MS. A novel contribution of this model is to depict both the location and severity of an individual patient’s lesions in the form of a topographical map of MS disease burden, explicating the clinical heterogeneity inherent to the disease. It is important to acknowledge that this model does not attempt to address or answer unresolved questions about the underlying immunologic or pathologic bases of the disease. Indeed, the model is designed to encapsulate and depict clinical course while remaining agnostic to, and not predicated on assumptions regarding, currently unreconciled questions of MS pathogenesis and etiology.

Fundamental assumptions and variables.

The topographical model of MS visualizes the CNS as a pool divided into 3 basic anatomical regions with increasing amounts of functional reserve. MS lesions are represented as topographical peaks that rise up from the pool base. Localization of lesions is visualized by plotting lesions on an anatomical grid with lateralization grouped across the 3 key regions: (1) the spinal cord and optic nerves occupy the shallow end, (2) the brainstem and cerebellum comprise the middle; and (3) the cerebral hemispheres constitute the deep end of the pool.
The water itself represents neurologic functional capacity: in essence, the compensatory ability of the nervous system that keeps regions of damage “submerged.” Functional reserve is thus a “fluid” construct, variable over time, and subject to periods of depletion (during fever or concurrent illness), renewal, and decline over the long-term disease course to a variable degree. The water’s surface depicts the clinical threshold: those peaks that cross above the threshold upon formation cause clinical relapses; those topographical peaks below the surface are seen as clinically silent lesions on MRI. Depending on extent of relapse recovery, a topographical peak that crosses the threshold may recede again beneath the water’s surface, or remain above the clinical threshold, leaving residual deficits. Progression is depicted as the slowly declining water level, representing a gradual depletion of functional capacity, and revealing clinical symptoms referable to the underlying disease topography.
To express the heterogeneity of clinical course and varied prognostic outcomes, the model design encapsulates 5 variable factors: localization of relapses and causative lesions; relapse frequency, severity, and recovery; and progression rate (table).

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