Primary Progressive Multiple Sclerosis: Putting Together the Puzzle

Abstract

The focus of multiple sclerosis research has recently turned to the relatively rare and clearly more challenging condition of primary progressive multiple sclerosis (PPMS). Many risk factors such as genetic susceptibility, age, and Epstein-Barr virus (EBV) infection may interdepend on various levels, causing a complex pathophysiological cascade. Variable pathological mechanisms drive disease progression, including inflammation-associated axonal loss, continuous activation of central nervous system resident cells, such as astrocytes and microglia as well as mitochondrial dysfunction and iron accumulation. Histological studies revealed diffuse infiltration of the gray and white matter as well as of the meninges with inflammatory cells such as B-, T-, natural killer, and plasma cells. While numerous anti-inflammatory agents effective in relapsing remitting multiple sclerosis basically failed in treatment of PPMS, the B-cell-depleting monoclonal antibody ocrelizumab recently broke the dogma that PPMS cannot be treated by an anti-inflammatory approach by demonstrating efficacy in a phase 3 PPMS trial. Other treatments aiming at enhancing remyelination (MD1003) as well as EBV-directed treatment strategies may be promising agents on the horizon. In this article, we aim to summarize new advances in the understanding of risk factors, pathophysiology, and treatment of PPMS. Moreover, we introduce a novel concept to understand the nature of the disease and possible treatment strategies in the near future.

Keywords: Epstein–Barr virus; pathophysiology; primary progressive multiple sclerosis; risk factors; treatment.

Figure 1

Sequence of events in multiple sclerosis. (1) Autoreactive B (B_Auto) cells are formed by epitopes mimicry with Epstein–Barr virus (EBV) antigens or through persistent activation of the naturally presence autoreactive B cells through the chronic EBV infection (first hit). (2) Autoreactive CD4+ T (T_Auto) cells are formed through antigen mimicry with intestinal flora (second hit). (3) The autoreactive B and CD4+ T cells interact in the peripheral lymph nodes leading further activation. (4) After releasing into blood stream, they both cross the blood–brain barrier and interact again in the perivascular space. (5) They recognize the self-antigens sequestrated in the central nervous system and release cytokines to attract other inflammatory cells (macrophages, cytotoxic CD8+) from the blood as well as to stimulate the microglia and astrocytes.(6) and (7) The inflammatory cells attack the neurons and the oligodendrocytes leading to demyelination, neuronal death with release of many sequestrated intracellular antigens (first event). (8) These antigens provoke more B and T cells reaction leading to accentuation of the inflammatory cascade (second event). (9) Other factors like mitochondrial dysfunction, glutamate cytotoxicity, and iron accumulation play import role in the demise of neurons, especially in primary progressive multiple sclerosis and SPMS.

Figure 2

Different risk factors and their effect on the clinical phenotype in multiple sclerosis (MS). The pathological process in MS occurs in genetically susceptible individuals after in presence of the Epstein–Barr virus (EBV) infection and predisposing intestinal microbiome (see below). Initially, the pathological process does not lead to clinical manifestations, but radiological changes may be present [radiologically isolated syndrome (RIS)]. The presence of vitamin D deficiency will exacerbate the inflammatory changes leading to appearance of the first relapse [clinically isolated syndrome (CIS)], which is usually followed by complete recovery. Fluctuation in vitamin D levels and eventually other unknown factors will lead to appearance of further relapses and starting of the relapsing remitting multiple sclerosis (RRMS). Another slowly inflammatory triggered neurodegenerative process takes place in the background and exhibits its clinical manifestation only after exceeding an age threshold. One possible explanation for the age threshold is known changes in the host defense to EBV infection. Other factors like age-dependent local iron precipitation may play a role.

Figure 3

Overview of the possible treatment strategies in primary progressive multiple sclerosis (PPMS). A summary of the current and possible treatment strategies in PPMS.