Multiple Sclerosis Subtypes May Have Common Pathogenesis

The theory that multiple sclerosis, which has widely varying symptoms and progression in different patients, is nonetheless a single disease with common underlying mechanisms, has gotten more supporting evidence from a new study.

Multiple sclerosis (MS) is an autoimmune disease in which the immune system disrupts the function of nerve cells in the spinal cord and brain. This can cause a variety of problems, including blurred vision, memory problems, paralysis, and more.

Symptoms and patterns of disease progression over time can vary between patients, leading to suggestions that MS may actually consist of two or more different diseases or subtypes.

Single Disease, Different Symptoms

Ekaterina Kotelnikova of the IDIBAPS – University of Barcelona, and colleagues hypothesized that MS is a single disease with multiple results in patients, all driven by the same underlying biological mechanism – immune system attack of the protective fibers shielding nerve cells and loss of the axons used by nerve cells to communicate with each other.

To explore this hypothesis, the researchers developed a mathematical model of MS based on experimental data from 66 patients who had been followed for up to 20 years. Using the model, they were able to perform computational simulations of the different known biological processes involved in the disease.

ODE model MS CNS damage

The ODE model of CNS damage in MS.
A) The model represents the volume occupied by axons and myelin: Right, the healthy CNS is composed of myelinated axons (Am);
Center, inflammatory attack is represented by the time-dependent parameter λ(t), which arises from the Generalized Extreme Value (GEV) distribution of the EDSS time-series, producing either demyelination (right) or degeneration of axons (bottom);
Left, demyelinated axons (Ad) can be remyelinated with myelin produced by oligodendrocytes (M), as a function of the parameters km and q; Bottom, myelinated or demyelinated axons can be lost by either acute axon transection or degeneration (D), according to the parameters kmd or kd respectively.
B) Clustering MS patients based on the EDSS time series. The horizontal axes correspond to the time in months (maximum = 16 months), while the vertical axes correspond to the patients. Each line represents the EDSS of a given patient over time, using a color scale to reflect the EDSS.
Clusters 1 and 2 include patients that maintain an intermediate short term EDSS and that reach a high EDSS in the long term.
Cluster 3 includes patients that maintain a low short term EDSS and that achieve an intermediate EDSS in the long term.
Cluster 4 represents a more heterogeneous group.
Credit: Kotelnikova E, et al.

To test the validity of the model, the scientists ran simulations using data from a second group of 120 MS patients. They found that, by changing the intensity of the underlying biological processes involved in MS at distinct times, they were able to successfully reproduce the variability of disease courses seen in these patients.

The results support the concept of a common pathogenesis, i.e., that all the symptoms and disease courses observed in MS patients are produced by the same underlying mechanisms that damage nerve cells over time. This implies that, even though it may follow different patterns, MS will worsen over time for all patients.

Therapeutic Implications

Co-author Dr. Pablo Villoslada, Head of the IDIBAPS research group in Pathogenesis and new treatments in multiple sclerosis and coordinator of the study, said:

“This concept has significant therapeutic implications and will drive the development of new therapies because it implies that MS will produce significant disability if suffered for enough time in all patients. Indeed, preventing relapses, although very important, will be not enough to achieve good control of the disease.”

Relapses in MS have been modeled statistically to a negative binomial distribution. Moreover, relapses have been mathematically modeled from a mechanistic point of view that focuses on the negative feedback between pro- and anti-inflammatory responses, and as a probabilistic response to self-antigen presentation.

However, how damage to the central nervous system (CNS) advances and how clinical disability accumulates over decades, defining the clinical phenotype of the disease and its prognosis, are issues that are still poorly understood. Several hypotheses have been proposed to explain the heterogeneity and different courses of the disease.

One model characterizes it as different diseases with relapse-remitting MS (RRMS) being defined as an autoimmune disease (the outside-in hypothesis) and primary-progressive MS (PPMS) a primary neurodegenerative disease (the inside-out hypothesis).

Funding support for the work came from The European Union Seventh Framework Program, the Spanish Ministry of Economy and Competitiveness and FEDER, and the Swedish Research Council (3R).

Kotelnikova E, Kiani NA, Abad E, Martinez-Lapiscina EH, Andorra M, Zubizarreta I, et al. (2017)
Dynamics and heterogeneity of brain damage in multiple sclerosis
PLoS Comput Biol13(10): e1005757. https://doi.org/10.1371/journal.pcbi.1005757

Top Image: Chronic autoimmune inflammatory damage to the brain produces waves of demyelination (blue line in the graph) and cumulative axonal loss (green line in the graph) in different intensities along time leading to all MS phenotypes. Credit: Dr Santiago Ortiz-Perez, from the Institute of Ophthalmology and Center of Neuroimmunology, IDIBAPS – Hospital Clinic, University of Barcelona.

Portions of this article © 2017 Kotelnikova et al. republished via Creative Commons.