It is apparently not only ProfG’s pastime spent dreaming but also some of his colleagues like to do this.
With global warming we are expecting a rise in sea level, but it can make the pond disappear as the water evaporates so here we have the draining lake model or is it the down the plug hole model
The topographical model of multiple sclerosis:A dynamic visualization of disease courseStephen C. Krieger, Karin Cook, Scott De Nino, and Madhuri Fletcher doi: http://dx.doi.org/10.1212/NXI.0000000000000279Neurol Neuroimmunol Neuroinflamm October 2016 vol. 3 no. 5 e279
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.
ProfG has a length dependent hypothesis with amounts to influences related to length of a nerve tract and has mentioned the iceberg effect with most of the mass under the surface, but in this scenario the influence is from the top to the bottom of a pond/lake with a few volcanoes for lesions reaching the surface
This is open source so you can read it yourself. (Click here)
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.
This idea is based on the influence of 5 factors
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
Lesions arising from the more eloquent shallow end cross the clinical threshold more readily than those arising from the deep end. This is consistent with the relative predilection for partial myelitis, optic neuritis, and brainstem syndromes that typify MS relapses. A top view of the model emphasizes lesion location and distribution, akin to an MRI (figure 2).
FIGURE 2 Lesion localization visualized in the top view of the model
In this view, the topographical distribution of lesions is shown in the anatomical grid, grouped across the 3 key regions with lateralization, replicating a distilled MRI perspective. Both T2 lesions and a representative T1 black hole are shown. (A) Top (clinical) view: water is opaque, only above-threshold peaks are visible. (B) Top (subclinical) view: water is translucent, subthreshold lesions are visible.
It takes into account that some lesions have more prognostic significance than others on the basis of localization.
Lesions in the shallow end are more apt to cause the long tract motor or sensory symptoms that contribute disproportionately to MS disability accumulation.
This is congruent with recent data that spinal cord MRI may better discriminate between levels of disability than conventional brain MRI
Conversely, lesions in the cerebral hemispheres, such as prototypical MS periventricular lesions, are depicted as arising in the deep end of the pool, as they are least likely to cause discrete symptoms by virtue of the depth of cerebral functional reserve and compensatory ability.
This elucidates the “clinical/MRI paradox” in MS, in which the clinical picture often appears more favorable than the lesion burden seen on conventional brain MRI would suggest
While focal inflammatory lesions are depicted as topographical peaks rising from the pool base, the diffuse neurodegenerative process is depicted in this model by the water level’s gradual decline. This is congruent with emerging data on diffuse tissue loss and brain atrophy, which may be present from the outset of disease course,and may be the principal driver of disability during progressive disease. The model also incorporates the beneficial effect of large baseline brain volume, which has been shown to exert a protective influence in both cognitive and physical manifestations of the disease.
It is important to note that the water in this model is indeed a depiction of functional capacity—physiology and structure—and not literally CNS parenchymal volume.
As the relationship between focal inflammation and diffuse neurodegeneration, at the mechanistic level, has not been conclusively determined, in the model, the rate of water decline can be varied independently from lesion formation. However, as the recapitulation hypothesis of this model posits: even if relapse rate and lesion burden have no direct effect on the rate of loss of functional reserve, the topographical peaks, which are incrementally revealed as reserve is lost, are the loci of clinical progression. Thus, the model suggests that development of these lesions would more readily yield a progressive clinical course even without a direct effect on neurodegeneration itself. The crucial variable is the rate at which the threshold declines, as the loss of reserve determines whether these topographical peaks are revealed above the clinical threshold to a great or trivial degree.
Conceptualizing MS as a unified continuum has implications for bench research. Studies seeking to identify biological differences between RRMS and SPMS, or primary progressive MS (PPMS) and SPMS, are inherently methodologically predicated on the assumption of discrete clinical phenotype categorizations. Thus, these studies may be looking for biological differences between categories that were not drawn along biological lines.
The topographical model depicts both PPMS and SPMS clinical course patterns by varying these 5 factors, and thus argues that the clinical manifestation framework is not demonstrably different between patients with primary and secondary progressive forms of the disease
It is worth noting that the depiction of PPMS in this model is concordant with the observation that the mean age at PPMS diagnosis is approximately 10 years later than in RRMS.
The model does not, however, take a position on the primacy of inflammation or neurodegeneration: the model depicts topographical peaks beginning to form (“base effects”) and the water level beginning to decline (“surface effects”) simultaneously from the outset of disease.
Considering progressive MS as part of a continuum may also have clinical implications: the topographical model suggests that patients with relapsing forms of MS may also have evidence of progression, and that those with PPMS or SPMS warrant vigilance for relapses or inflammatory activity
Clinical trial outcomes of disease-modifying therapies could be evaluated through the lens of the topographical model on the basis of their distinct “base effects” (preventing new lesions and the relapses they cause) and their “surface effects” (preventing the decline of functional reserve and potential imaging correlates thereof)
From a clinical research perspective, this could have bearing on how combination treatment strategies are designed, with a focus on combining therapeutics that work differentially on the “base” and on the “surface.
What do you think?