Nevertheless, there remain major unmet needs. Recently, siponimod (which modulates cell migration) was the first agent to provide a moderate benefit in secondary progressive MS, and ocrelizumab (which depletes B cells) was the first drug to be moderately effective in a subgroup of patients with primary progressive MS (PPMS) 14. DMTs predominantly curtail the migration of lymphocytes into the CNS, or deplete specific types of immune cell. Molecular effector pathways involve oxidative stress, calcium overflow, excitotoxicity and eventually mitochondrial energy failure 8, 13.Īlthough the disease remains incurable, the past three decades have witnessed the successful development of disease-modifying therapies (DMTs), predominantly for the relapsing forms 1, 13, 14, 15 (Fig. Axonal damage and neurodegeneration may be caused by collateral damage in the wake of a vigorous inflammatory response, with demyelination rendering the denuded axon susceptible to noxious mediators, lack of neurotrophic factors and retrograde degeneration 1, 2. As the disease evolves, adaptive immunity loses importance and CNS-specific innate immunity, orchestrated by microglia and astroglia, takes precedence 11, 12.

During the early stages of the disease, the ongoing damage may go unnoticed as compensatory functional mechanisms are recruited, involving supplementary neuronal circuitry and the capacity for remyelination of damaged dysfunctional axons by oligodendrocyte precursors 10.Įarly disease pathology is led by adaptive immunity outside the central nervous system (CNS).

Axonal damage detectable early in the course of the disease foretells the development of permanent disability tissue destruction gives rise to global and regional brain and spinal cord atrophy 1, 8. MS therefore places a heavy burden on patients, their families and caregivers, healthcare systems and society at large 7.Ĭardinal pathological features are multifocal inflammation, primary demyelination, oligodendroglial death, neuroaxonal degeneration, and astrocytic scarring in the brain and spinal cord 8, 9. The disease spans decades and life expectancy is shortened. Typical MS manifestations include visual, sensory, motor and sphincter disturbances, as well as incoordination, gait disorder and cognitive impairment 1. These descriptions of the course of the disease have recently been modified to classify MS into either relapsing forms, with disability occurring both in relation to and independently of relapses, or progressive forms that are active or inactive, classified according to clinical or magnetic resonance imaging (MRI) findings 6 (Box 1). 10%–15% of patients follow a primary progressive course, characterized by the continuous worsening of neurological disability from the first manifestation of disease. In two-thirds of cases, the transition from this relapsing course to secondary progressive MS usually occurs after 10–15 years and, for some time, superimposed relapses may occur, reflecting ongoing inflammatory activity 5. In addition, progression may occur independently of relapse activity. In the majority of patients, the disease takes a relapsing course with intermittent periods of neurological dysfunction that may initially completely resolve however, as the disease advances, recovery is incomplete and disability accumulates. Globally, some 2.8 million people are affected and its incidence and prevalence have been on the rise worldwide over the past few decades 3, 4. The aetiology of the disease remains elusive but a large body of evidence suggests that it is immune-mediated in nature 2. Multiple sclerosis (MS) is the most frequently occurring neuroinflammatory disease and the commonest cause of permanent disability in younger adults 1.

Mog disease life expectancy