Inflammation and Neurodegeneration in MS
Nerve degeneration
Inflammatory lesions in the CNS can cause significant damage to the myelin sheath (called demyelination), which protects nerve fibres (axons), as well as to the nerves themselves. The deterioration in myelin can be repaired, although this in-built repair mechanism appears to become less effective after repeated inflammatory relapses.
More serious, however, is the damage that can be caused to the underlying nerve fibres. It is this nerve damage that is believed to result in permanent neurological deficits and disability. Numerous studies have shown that significant nerve damage occurs within active MS lesions in the CNS as a result of the effects of inflammation. During an inflammatory flare-up, many chemicals (e.g. cytokines and enzymes that degrade proteins) are released that are toxic to nerves. It is believed that this can ultimately lead to axonal transection, i.e. the severing of the nerve fibre. Axonal damage and transection can occur even in people who have had MS for only a short time.
It might be supposed that as the insulating myelin is stripped away, there would be a corresponding loss of the nerve “wiring”. However, the precise relationship between the loss of myelin and the loss of axons has not been fully worked out. In general, axonal loss is related to the amount of inflammatory activity in MS lesions, but damage can still occur in older, inactive lesions as well as in recovering lesions that are undergoing remyelination.
This suggests that neurodegeneration is an ongoing process that is somewhat independent of inflammation. Indeed, recent research has suggested that neurodegeneration begins early in the MS disease course – even before inflammation is apparent – and continues thereafter. If you imagine that MS is a forest fire, inflammation is the match that will cause the most visible flare-ups. But before the match is struck, the undergrowth may already be smouldering. Neurodegeneration is that slow burn, which will continue to smoulder long after the forest fire of inflammation has been suppressed. This would explain why strictly anti-inflammatory medications, such as steroids, do not affect the longer term process of nerve degeneration: the inflammatory flare-up is doused, but the slow burn of neurodegeneration continues. Similarly, in progressive forms of deterioration, the neurodegenerative process is rapid and severe even when there is little or no significant inflammation. No match is lit, but the forest still burns.
Ideally, a treatment would prevent this process of axonal damage. But why are axons so important? Many researchers believe that axonal loss is the principal determinant of disability. For example, one small autopsy study of five people with severely disabling MS found that in their chronic brain lesions, about two-thirds of the axons had been lost compared to people without MS. These individuals’ disabilities appeared to be due largely to this extensive loss of nerve cells in their brains.
How is neurodegeneration measured?
Researchers use a number of tools to try and assess the extent of neurodegeneration that occurs in MS. The most direct way is to examine MS lesions at autopsy after a person has passed away. New research techniques, such as magnetic resonance spectroscopy (MRS), provide a less invasive approach (and can be done while people are still alive). MRS involves imaging the brain and spinal cord to identify the presence of certain chemicals that indicate nerve damage. Of particular interest is a substance called NAA (N-acetyl aspartate), an amino acid that is fairly specific to neurons and axons; it is rarely found outside of nerves. The level of NAA has been shown to be lower in MS lesions, notably in chronic T1 lesions (called “ chronic black holes”). This indicates that there is a lower density of nerve cells, presumably because of neurodegeneration. Older MS lesions also show substantial loss of axons, as assessed by NAA levels. In addition, MRS studies have shown that there is diffuse injury to axons early in MS – even before there is any sign of disability.
A more global measure of tissue change is brain atrophy, or shrinkage. MRI can provide a good estimate of the total amount of tissue in the brain. Studies have shown that the amount of tissue in everyone’s brain declines with aging. However, this brain atrophy progresses faster in people with MS versus those without MS. Compared with other MRI metrics, the extent of brain atrophy is well correlated with clinical disability. There are several possible causes of brain atrophy in MS, including loss of myelin (demyelination) and axons. However, atrophy measures can be influenced by many things. Steroid treatments, for example, actually decrease the volume of the brain because they reduce swelling. Similarly, neurodegeneration can reduce atrophy in some cases because it may lead to overproduction of other cells.
MS disease progression
During the course of MS, inflammation and neurodegeneration cause a significant amount of axonal loss. But this loss of axons does not necessarily result in permanent deficits or disabilities – at least not right away. There are several reasons for this. Lesions may appear in what are known as “clinically silent” areas. This means that the brain region affected is not directly tied to a type of function. In contrast, damage to certain parts of the nervous system, such as the optic nerve, is more likely to produce symptoms right away.
Secondly, the brain is able to adapt to the loss of tissue by shifting the work of those lost axons to other nerve cells. The responsibility for a given task may be moved to adjoining brain regions, or even to a region on the opposite side of the brain. A “left-brain” task may become a “right-brain” task, and vice-versa. This ability to adapt how functions are performed is called brain plasticity.
While the brain can compensate for some degree of injury, it loses some of this ability as time passes. Brain plasticity appears to decline with time in everyone, not just people with MS. In addition, as the brain experiences repeated injuries caused by relapse after relapse, its capacity to repair and adapt may become exhausted. In other words, the slow accumulation of damage reaches a “tipping point”: once a certain threshold of tissue loss has been reached, the cumulative effect results in permanent neurological deficits that begin to progress thereafter. The effect is not unlike an avalanche: snow gradually builds up until there is one snowflake too many, and the whole mass begins to fall.
This may be what occurs in secondary-progressive MS. During the relapsing-remitting phase of the disease, damage slowly accumulates over many years. Then a critical point is reached, and the progressive phase begins. Thereafter, the development of disability is much more rapid than during the relapsing-remitting phase.
One large study of an MS population found that there was a very wide variation in the amount of time it took for people to develop moderate disability (an EDSS score of 4.0). Some people reached that point within a year of diagnosis, others only reached it 33 years later. However, once that threshold was reached, the steady march of progressive disability after that was very similar in everyone.
Factors that influence neurodegeneration
MS is a remarkably individual disease. Unlike other illnesses, it is impossible for doctors to predict the symptoms that will occur, the severity of the disease course, and if and when disability will occur. Every person is different. As mentioned above, some people may have relapsing-remitting MS for thirty years or more before they begin to progress while others experience early disabilities.
Many factors appear to influence how MS will develop during the course of one’s lifetime. Disease-specific factors, such as the extent of disease activity, and the size and location of CNS lesions, also appear to be important in determining the types of disabilities that may occur and the pace at which MS will progress.
As discussed in the previous chapter, genetic susceptibility seems to play a role. There is no single MS gene – at least one hasn’t been isolated – that causes MS but genetics factors do influence the immune systemhyperresponse seen in MS, the amount of disease activity, how damaging the inflammatory attacks will be, and how quickly and how well that damage is repaired.
While these genetic factors are notoriously difficult to identify, further research into these factors may provide some guide posts for treatment approaches that may be beneficial in the future. These concepts will be discussed in the next chapter.
Shifting the goal posts
The idea that there is a disease process – neurodegeneration – underlying the development of disability in MS is less than a decade old but it has already received intense interest from the research community. Neurodegeneration is a complex process and at this stage there are more questions than answers. How does nerve degeneration occur? How are axons transected and can this process be influenced? How do oligodendrocytes, the cells responsible for producing new myelin, repair damaged myelin and why are they less able to do the job as time passes? Are there ways to stimulate the body’s natural repair mechanisms to restore nerve functioning? Some of these issues will be addressed in the next chapter.
To conclude this chapter, it’s important to know that the traditional way of thinking of MS as solely an inflammatory disease of the CNS has provided researchers with the two principal approaches to treatment: reduce inflammation and/or prevent some of the damage that is done during inflammatory flare-ups.
Steroids and immunosuppressants act primarily by targeting inflammation. Immunomodulatory drugs, as the name implies, modulate (or alter) the inflammatory response rather than suppressing it. Glatiramer acetate (Copaxone®) shifts the immune response so the activated T cells entering the CNS are less likely to cause damage, while beta-interferons (Avonex®, Betaseron®, Rebif®) make the blood-brain barrier less “porous”, so fewer of these activated T cells can enter the CNS. Similarly, new MS medications are being developed that will selectively suppress inflammation or target one or more components of the inflammatory process.
Thus far, the reduction of inflammation has been the main goal of treatment. But as we have seen in this chapter, the ability of a medication to prevent or reduce neurodegeneration is becoming the truer measure of treatment success. The new goal post for therapy is whether a medication can protect the nerves in the brain and spinal cord from deteriorating and causing disability during the course of MS.