Anti-inflammatory drugs that reduce inflammatory (immune) attacks in patients with RRMS fail to prevent disease progression in the SPMS phase. No animal models are available that mimic this behaviour and it does not fix into the autoimmune model. Three hypotheses have been proposed:
1) Inflammation in the relapsing-remitting and progressive phases is driven by the same mechanisms, but during progressive MS the central nervous system does not respond to currently available anti-inflammatory drugs (maybe because a closed blood-brain barrier)
2) Microglia, which are under the control of intact neurons, may become chronically active due to primary neurodegeneration, axonal degeneration, and some other processes.
3) Multiple sclerosis may be primarily caused by cytodegenerative processes/infections, which are amplified by inflammation
Which one of these theories do you think is the right one? and, why?