There are three ways of demonstrating disease activity in MS. First, pwMS can experience new neurological symptoms compatible with a relapse. Second, blood or CSF neurofilament levels can be elevated which indicates brain damage because of ongoing inflammation. Third, there can be new inflammatory lesions on a brain or spinal cord MRI. From a biological point of view, there is no hierarchy between these disease activity pillars. If disease activity is demonstrated in one of these three domains, it would be a valid reason to initiate or upscale treatment. However, some pwMS and clinicians put more weight on the first clinical pillar.
Recently, I advised two pwMS who had radiological (i.e. two enhancing brain lesions/one new brain lesion + one cord lesion) but no clinical activity to upscale towards a second line treatment. Although I discussed the relevance of these lesions, both of them decided to stay on their first line and thus less effective treatment. Undoubtedly, several factors played a role in these decisions. Not having to upscale treatment could be a coping mechanism in people who have not entirely accepted the diagnosis. For others it is difficult to grasp the impact of asymptomatic lesions, especially if they are flourishing professionally and personally. Last but not least, I failed to sufficiently clarify the concept of silent brain lesions and the clincial-MRI paradox.
Two attempts to do it better for the readers of this blog:
First attempt: topographical model of MS.
This model visualises the central nervous system as a pool divided into three basic anatomical regions with increasing amounts of functional reserve: 1. spinal cord and optic nerve lesions occupy the shallow end and carry a higher permanent disability burden, 2. brainstem and cerebellum comprises the middle, 3. cerebral hemispheres constitute the deep end of the pool as many brain regions are involved in information processing.
The water represents neurologic reserve capacity. This means the ability to compensate for damage and keep regions of damage “submerged.” Reserve might fluctuate over time during fever or concurrent illness. The water’s surface depicts the clinical threshold: peaks that cross above the threshold cause clinical relapses; peaks that remain below the surface are seen as clinically silent lesions on MRI. A peak that crosses the clinical 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 reserve capacity, and revealing clinical symptoms or peaks who had been previously under the water surface corresponding to silent lesions or partially recovered relapses.
The model design incorporates 5 variable factors which reflect the heterogeneity in MS disease course:
1. Localization of relapses and causative lesions: shallow vs. deep end of the pool
2. Relapse frequency: number of peaks above the pool surface
3. Severity: height of the peak
4. Recovery: the degree to which each peak recedes under the water surface
5. Progression rate: the rate at which water level declines
Central to this model is the observation that MS progression reflects prior relapse symptoms and unmasks previously clinically silent lesions. Most importantly, the model illustrates how, although a significant brain lesion burden may appear discordant with a favourable clinical picture early in the disease course, early disease activity or the amount of clinically silent disease seen on MRI are meaningful predictors of disability in the long term.
This model has been beautifully illustrated by the following videos:
Early secondary progressive disease: https://www.youtube.com/watch?v=RElXMiR6HtI
Relapsing MS, highly active disease: https://www.youtube.com/watch?v=MBjSckRtQD_8
Primary progressive MS: https://www.youtube.com/watch?v=uGInYEfDJLU
Relapsing MS, Benign course: https://www.youtube.com/watch?v=Yd4oUu8kB-U
Second attempt: the traffic analogy
The meaning of these asymptomatic MRI lesions can also be illustrated by something that we are all familiar with: car traffic. Roads in Western Europe are subject to regular maintenance, with or without a couple of days notice. If there is one road block (read: silent MRI lesion) because of construction works on your daily commute, there are often one or two diversions you can follow and it will hardly affect the amount of time spent on commuting. On the contrary, when there are two road blocks, it might become more difficult to reach your target destination and your new trajectory might not allow you to pick up some last-minute groceries from the local store. Nonetheless, you will still reach your destination, albeit at a slower pace. With three, four and five road blocks, there are less opportunities for efficient rerouting and you’d prefer working from home.
Although the first attempt is more refined and granular it might not always be clinic-proof and requires a considerable amount of explaining before concepts such as silent MRI lesions sip through. The second attempt definitely does not encompass the complexity of the disease course in MS but has the beauty of simplicity.
Any other ideas on how to explain the significance of asymptomatic brain lesions? Please share!
Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
The topographical model of multiple sclerosis: A dynamic visualization of disease course
Stephen C Krieger, Karin Cook, Scott De Nino, Madhuri Fletcher
PMID: 27648465, PMCID: PMC5015541, DOI: 10.1212/NXI.0000000000000279
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.