MS Speaks

An article in Lancet Neurology (February 2015), "Pathological mechanisms in progressive multiple sclerosis," is available in its entirety (see link below). Here is the Introduction:

Introduction

Multiple sclerosis is a chronic inflammatory disease of the CNS that leads to focal plaques of primary demyelination and diffuse neurodegeneration in the grey and white matter of the brain and spinal cord. In most patients, the disease starts with a relapsing-remitting course (RRMS), which is followed after several years by a secondary progressive phase (SPMS)'. Patients with primary progressive disease (PPMS) miss the relapsing and remitting stage and start with uninterrupted progression from disease onset.When patients die within the first year of the disease, it is referred to as acute multiple sclerosis. Current anti-inflammatory or immunosuppressive therapies are beneficial in patients with RRMS, but are not effective in patients with progressive disease.

Although data have shown that the risk of disease development is determined partly by genetic factors related to immune function and activation, and environmental factors such as Epstein-Barr virus infections, the ultimate cause of multiple sclerosis is unknown. A commonly proposed idea is that multiple sclerosis is an autoimmune disease in which autoreactive T lymphocytes enter the CNS from the peripheral immune system in the initial stages of lesion formation (the outside-in hypothesis. So far, no multiple sclerosis-specific autoimmune reaction has been identified. However, aggressive immunomodulatory treatments not only reduce relapses of the disease, but also reduce sustained disability progression, suggesting an important role for inflammation, at least in the early stages of the disease. Alternatively, multiple sclerosis might be caused by a primary infection or neuronal disturbance within the brain, and inflammation might therefore occur as a secondary response to this initial trigger, which amplifies disease and tissue damage (the inside-out hypothesis). Although infectious agents and specific alterations in CNS components that initiate a secondary immune reaction have not been identified in the brains of patients with multiple sclerosis, cortical atrophy can occur before substantial white matter demyelination and predicts future disease progression. While this finding could be taken as support for the inside-out hypothesis of multiple sclerosis, events that occur outside and inside the CNS are likely to determine the clinical outcome of the disease.

As outlined in this Series paper, many conflicting ideas have been proposed to explain disease progression and lesion formation in multiple sclerosis, all of which seem to be supported by firm and convincing data. We aim to provide a unifying picture by defining a cascade of immunological and neurodegenerative events that act in concert to induce multiple sclerosis-specific brain damage, but change in their relevance in the course of chronic disease evolution.

[references omitted]

And the final section:

Conclusions and therap-eutic implications

As outlined in this Series paper, inflammation seems to drive a pathogenic cascade in multiple sclerosis, leading to oxidative damage and mitochondrial injury, which, particularly in the progressive stages of the disease, is further amplified by age-related changes in the human brain and microglia activation caused by accumulated brain damage. Similar mechanisms have been proposed in other human neurodegenerative diseases, but they seem to be especially prominent in multiple sclerosis because of the chronic inflammatory nature of the disease, the long-lasting accumulation of tissue damage in the brain and spinal cord, and the fact that iron accumulation occurs mainly in oligodendrocytes and myelin, the prime targets of pathology in multiple sclerosis. Although some aspects of the inflammatory component of the disease are well replicated in current experimental models, the patterns of chronic tissue injury, which are prominent in progressive multiple sclerosis, are poorly represented. Thus, new models should be developed that represent the progressive changes in multiple sclerosis, to test the effect of neuroprotective therapies.

With regard to new treatment strategies for progressive multiple sclerosis, current data define certain requirements that must be fulfilled. First, for drugs to be effective in the progressive stage of multiple sclerosis, they should be able to access the brain through a normal or repaired blood–brain barrier. Second, anti-inflammatory treatments should target the regulation of inflammation within the CNS, by blocking proinflammatory mediators produced by T and B lymphocytes within the CNS, for example, or by targeting proinflammatory mechanisms in microglia and astrocytes. Generally, newly developed oral drugs for multiple sclerosis have better access to the brain than therap-eutic antibodies or proteins. Additionally, neuroprotective strategies to inhibit oxidative damage or induce antioxidative cellular defence mechanisms should be developed and tested in patients with progressive multiple sclerosis. Mitochondrial protection and replenishment strategies might be an attractive option. Finally, therapies that target different ion channels are now being tested in patients with progressive multiple sclerosis. However, the absence of suitable animal models for the progressive stage of the disease makes difficult the reliable selection of therap-eutic approaches that have the best chance of working in patients.

The entire article is available here.

More on this article in the MSFYi Newsletter, February  27, 2015:

Documentation of MS Progression May Lead to New Treatment Options

A group of researchers have charted the progression of MS and discovered that two lines of thought about the disease actually are interrelated. This could lead to new treatment options.

 

Disease categorization has focused on two approaches. In the first, MS is seen as a disease of the nervous system that is inflammatory throughout, with the inflammation also being responsible for the subsequent neurodegenerative damage. In the second, the disease is viewed as ultimately progressing from an inflammatory condition into a neurodegenerative one.

 

However, an international team of researchers from Edinburgh, Cleveland, and Vienna, under the leadership of Hans Lassmann, Head of the Department of Neuroimmunology at the MedUni Vienna, has shown that MS is comprised of both factors. The inflammatory process acts as a "driving force" from the onset right to the end, and neurodegenerative processes also occur in the so-called progressive, late phase that damage the brain.

 

The researchers found that "amplification mechanisms" are triggered in the later stages of MS. The damage becomes amplified in a "self-contained" cycle that continues to cause damage. The neurodegenerative damage in the brain activates microglial cells that drive the disease forward, along with the formation of oxygen radicals that destroy lipids and proteins in the brain. Concurrently, damage occurs to the mitochondria – the power plants and energy providers to brain cells. This – coupled with normal brain aging and the associated deposition of iron – also causes further damage.

 

Researchers say the new discoveries may result in the development of new disease treatments. One would consist of drugs that have an anti-inflammatory effect in the brain, not just suppressing the defense response in the blood and lymphatic organs. Another would preventively block the amplification mechanisms and damage to the mitochondria.

 

Their findings have been published in the journal Lancet Neurology.