Typically the onset of disease progression in MS is ‘silent’ and differs from person to person. Not surprisingly, attempts at defining at least clinically has not been an exact science.
In a letter to Annals of Neurology Gil-Perotin et al. (Valencia) ask an important question, whether progression during the relapsing phase of MS is the same as in secondary progression (refer to MS-EPIC Team Silent Progression in Disease Activity-Free Relapsing Multiple Sclerosis. Ann Neurol. 2019; 00:1-14), or is there what is called bout onset progressive MS (BOPMS, includes single attack progressive MS and progressive MS after RRMS onset) where pre- and post-progression relapses accelerate time to progressive disease (refer to Mateo Paz Soldan Relapses and disability accumulation in progressive multiple sclerosis. Neurology 2015; 84(1): 81–88).
In biological terms the first is the pure progressive model defined by brain volume loss, whilst the latter is the focal inflammatory model (defined by T1/T2 lesion volumes). If you focus on this, by definition there is neuro-axonal loss (defined by neurofilament release) during both processes; so the two are not disparate in occurrence i.e. at least superficially; progressive MS pathophysiologically (disordered physiological processes associated with disease or injury) is the one and same disease process. However, the temporal process of neuro-axonal loss may differ, owing to differences in the underlying pathobiology (mechanisms of disease), and this is what we don’t know. Is the focal inflammatory model therefore, purely synaptic damage, whilst brain volume loss is the loss of large myelinated axons? And, where and how does regeneration and neuroplasticity fit into all of this?
If we re-think progressive MS along these lines, we will have a better understanding of the changes occurring at a clinical level.
If you disagree, then I’d like to hear your view point.