Where understanding stands | MS in depth

Where understanding stands today

For decades MS was described as relapsing disease that later, in some people, became progressive. Current evidence supports a different picture: inflammation that causes relapses and new lesions, and slower processes that cause progression, are both present from the earliest stages. Disability can accumulate without relapses, a pattern now measured as progression independent of relapse activity (PIRA).

Within the brain, some lesions remain chronically active at their edges, where activated microglia sustain a slow, “smouldering” injury. Some of these lesions contain iron-laden cells at their edges, which appear as paramagnetic rims on specialised MRI and can support diagnosis in specified situations under the revised criteria. Treatments that act mainly on circulating immune cells have limited effect on this compartment, which is why progression remains the central research problem.

The causes are increasingly well defined. Epstein-Barr virus infection appears to be nearly necessary, while more than 200 genetic variants, low vitamin D and other environmental factors modify risk. Taken together, these findings support the description of MS as one disease along a spectrum, in which a person’s course reflects the balance of these processes at a given time rather than a fixed type.

This shift is also a reason for optimism. Relapsing disease can now often be controlled effectively, a treatment has been shown to slow primary progressive MS, and progression, repair and remyelination are important research priorities.

For decades MS was described as relapsing disease that later, in some people, became progressive. Current evidence supports a different picture: inflammation that causes relapses and new lesions, and slower processes that cause progression, are both present from the earliest stages. Disability can accumulate without relapses, a pattern now measured as progression independent of relapse activity (PIRA).
Within the brain, some lesions remain chronically active at their edges, where activated microglia sustain a slow, “smouldering” injury. Some of these lesions contain iron-laden cells at their edges, which appear as paramagnetic rims on specialised MRI and can support diagnosis in specified situations under the revised criteria. Treatments that act mainly on circulating immune cells have limited effect on this compartment, which is why progression remains the central research problem.
The causes are increasingly well defined. Epstein-Barr virus infection appears to be nearly necessary, while more than 200 genetic variants, low vitamin D and other environmental factors modify risk. Taken together, these findings support the description of MS as one disease along a spectrum, in which a person’s course reflects the balance of these processes at a given time rather than a fixed type.
This shift is also a reason for optimism. Relapsing disease can now often be controlled effectively, a treatment has been shown to slow primary progressive MS, and progression, repair and remyelination are important research priorities.

Recent consensus papers describe MS as a disease in which inflammation and nerve damage are present from its earliest stages. This article summarises that view and the questions it leaves open.

What we still do not know

Several large questions remain open.

Open questions

Why only some people infected with EBV develop MS, and what turns the immune response against the virus into an attack on the nervous system.
What drives progression in each person, and whether it is the same process in everyone.
Whether lost function can be restored, by repairing myelin or by protecting the nerve fibres that remain.
How to measure progression early and reliably enough to test new treatments quickly.

Research and treatments

The Research section follows the work on each of these questions, and the Treatments section explains what the medicines developed so far have taught researchers about the disease.

In the research now

Loading current research…

Key terms

Myelin: The fatty sheath wrapped around many nerve fibres in the brain and spinal cord. It lets signals jump quickly along the fibre. MS damages it.
Axon (nerve fibre): The long extension of a nerve cell that carries its signal. Losing axons, rather than myelin alone, is thought to cause most lasting disability.
Remyelination: The brain's own repair of lost myelin, by new oligodendrocytes. It happens in MS but often falls short.
Microglia: The resident immune cells of the brain and spinal cord. In MS they sustain slow inflammation at the edges of chronic lesions.
Lesion (plaque): An area of damage where myelin has been lost and the tissue scarred.
Relapse (attack): New or worsening symptoms lasting at least 24 hours, without fever or infection to explain them.
PIRA: Progression independent of relapse activity: disability that worsens without a relapse to explain it.
Epstein-Barr virus (EBV): A common herpes virus that causes glandular fever. Infection appears to be almost necessary for MS, but most infected people never develop it.

References

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