The past two decades have seen a profound change in the treatment of multiple sclerosis. With recent regulatory approvals, 12 disease-modifying treatments are available in many countries for relapsing-remitting multiple sclerosis (RRMS) and there is a robust pipeline of experimental treatments at various stages of clinical development. Such progress should be a cause for celebration; however, much still needs to be done to make available a similar range of treatments to people living with progressive forms of multiple sclerosis.
Few neurological disorders have seen so great a transformation in public perception as multiple sclerosis. Over the past 20 years, the disease has moved from being an untreatable disorder with few management options to one with active management underpinned by a wide range of oral and injectable treatments, at least for patients with the relapsing-remitting form of the disease (RRMS). The effect that this development has had on people affected by RRMS is difficult to overstate, but these improvements overshadow a less palatable fact: for a sizeable proportion of patients—those with progressive multiple sclerosis—almost no treatment options are available.
A better understanding of the pathological mechanisms that drive neurodegeneration in individuals with multiple sclerosis is needed to develop therapies that will effectively treat patients in the primary and secondary progressive stages of the disease. We propose that the inflammatory demyelinating disease process in early multiple sclerosis triggers a cascade of events that lead to neurodegeneration and are amplified by pathogenic mechanisms related to brain ageing and accumulated disease burden. Key elements driving neurodegeneration include microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, and age-related iron accumulation in the human brain. Altered mitochondrial function in axons might be of particular importance. This process leads to chronic cell stress and imbalance of ionic homoeostasis, resulting in axonal and neuronal death. The evidence suggests that treatment of progressive multiple sclerosis should be based on a combination of anti-inflammatory, regenerative, and neuroprotective strategies.
Disease-modifying drugs have mostly failed as treatments for progressive multiple sclerosis. Management of the disease therefore solely aims to minimise symptoms and, if possible, improve function. The degree to which this approach is based on empirical data derived from studies of progressive disease or whether treatment decisions are based on what is known about relapsing-remitting disease remains unclear. Symptoms rated as important by patients with multiple sclerosis include balance and mobility impairments, weakness, reduced cardiovascular fitness, ataxia, fatigue, bladder dysfunction, spasticity, pain, cognitive deficits, depression, and pseudobulbar affect; a comprehensive literature search shows a notable paucity of studies devoted solely to these symptoms in progressive multiple sclerosis, which translates to few proven therapeutic options in the clinic. A new strategy that can be used in future rehabilitation trials is therefore needed, with the adoption of approaches that look beyond single interventions to concurrent, potentially synergistic, treatments that maximise what remains of neural plasticity in patients with progressive multiple sclerosis.