Bottom Line:
Multiple sclerosis is a heterogeneous disease. It is, in my opinion, a syndrome like pneumonia, that is an illness with multiple possible pathways to central nervous system tissue injury. Studies of brain tissues from persons with MS show at least four different pathways of tissue damage. The changes noted in one of these pathways, called Type III, suggests that the first event in this pathway is not an attack by the immune system but a loss of myelin producing cells (oligodendrocytes). The changes noted in Type III tissues are very similar to those seen in tissues damaged due to low levels of oxygen (hypoxia). The above paper discusses the complex effects of hypoxia on the central nervous systems of both persons with MS and in animal models of MS. Depending on the timing, the effects of hypoxia can be either protective or destructive. Randomized, controlled trials of high dose oxygen administration (hyperbaric oxygen) to persons with MS failed to show any consistent benefit. However, there are data from other studies showing that particular subgroups of persons with MS respond differently to treatments. Understanding the role of hypoxia in that subgroup of persons with MS that have the Type III pattern of tissue damage may offer a new approach to therapy.
Key Points:
1. Multiple sclerosis is a very heterogeneous disease.
2. For example, the course of the illness is different in every individual and responses to disease-modifying therapies differ greatly among individuals.
3. Scientists have described at least four distinct patterns of tissue damage in the central nervous systems of persons with MS. These are called Types I to IV. Such observations suggest that MS is not a disease but a syndrome, with multiple pathways for central nervous system tissue damage.
4. Type III tissue changes in this subgroup of persons with MS show a loss of myelin proteins in oligodendrocytes, the cells that produce myelin. Eventually this loss of myelin proteins results in oligodendrocyte death. Only mild inflammation is present. Type III changes strongly resemble the pattern of tissue damage seen in persons with strokes where tissue oxygen levels also are very low, a condition called “hypoxia.”
5. Supporting the importance of hypoxia in causing Type III tissue damage is the finding that levels of a chemical called hypoxia-induced factor (HIF)-1a are increased in such lesions; this chemical is also increased in areas of stroke damage.
6. There are multiple reasons for hypoxia to occur in MS lesions. Most importantly is the presence of inflammation. Inflammation increases the metabolic demands of oligodendrocytes and nerve cells (neurons), greatly reducing the energy-producing capabilities of critical parts of these cells, the mitochondria. When the metabolic demands of oligodendrocytes and neurons are not met, levels of oxygen greatly decrease.
7. Recent studies also show there is reduced blood flow in the central nervous systems of persons with MS, and that persons with MS have a greater risk of heart and blood vessel diseases. Indeed, many MS lesions are found at the junctions of two blood vessel supply zones (“watersheds”), areas where the blood supply is weakest.
8. Studies in mice exposed to hypoxia showed that hypoxia resulted in local tissue inflammation. In humans, areas of stroke, which by definition are hypoxic, become inflamed, further contributing to the hypoxia.
9. The above data suggest a complex, intertwined relationship between hypoxia and inflammation, with either condition having the potential to induce the other.
10. Researchers have studied the effects of oxygen supplementation and hypoxia using an animal model of MS called experimental autoimmune encephalomyelitis (EAE). Results showed protective effects on the disease with oxygen supplementation, and surprisingly, using different protocols of oxygen deprivation, a protective effect of hypoxia. Reasons for such differing results are not clear but may have to do with the timing of the treatment and the stages of tissue destruction (acute or chronic) in the animals.
11. Randomized, controlled trials of hyperbaric oxygen in persons with MS did not show any sustained or substantive benefit, and treatment with hyperbaric oxygen is not recommended as a treatment for any form of MS.
12. However, there is great variability in how persons with MS respond to different treatments, with particular subgroups of persons with MS responding to a treatment while other subgroups may not; this raises the possibility of “personalizing” treatment to subgroups of persons with MS, which in the case of persons with MS with Type III patterns of tissue damage could mean treatment with higher levels of oxygen.
13. The challenge, or course, is in identifying such individuals, but new techniques in molecular biology, in particular techniques to identify genetic changes in oligodendrocytes that could result in local tissue hypoxia, may allow a truly “precision” approach to the treatment of MS.
Discussion:
Considering MS a syndrome rather than a single disease with uniform causes is controversial. There are persuasive arguments on both sides; my skew is to consider MS a syndrome, given the differences noted on examination of central nervous system tissues and the differences in response to disease-modifying therapies. Similar paradigms exist in the treatment of cancers such breast cancers, where the presence or absence of certain hormone receptors or growth factor proteins determines responses to different drugs.
Decreased blood flow and low oxygen levels are described in the central nervous systems of persons with MS. Such observations led to trials of hyperbaric oxygen as a therapy for MS. However, randomized, controlled trials of hyperbaric oxygen exposure did not show a consistent benefit and such therapy is not advised at this time. That said, energy metabolism is impaired in both normal appearing white matter and in MS lesions. This is worsened by the presence of inflammation with the release of toxic chemicals; it also affects the energy-producing components, the mitochondria, of both oligodendrocytes and neurons. Supporting the important role of altered energy metabolism in MS are the preliminary positive results of a clinical trial directed at improving energy metabolism in MS central nervous system. This was discussed in a previous blog (“Repairing an injured brain with gold”).
The Type III tissue changes noted in the central nervous systems of a subgroup of persons with MS suggest that in this subgroup hypoxia may play an important role in the tissue destructive process. There are at least three major obstacles to proceeding from this observation to treatment. First, in the absence of doing a brain biopsy, there is the difficulty in determining which persons with MS have Type III changes. This may be mitigated in part by doing genetic studies of persons with MS looking for changes that indicate abnormalities in the abilities of oligodendrocytes to produce proteins that effect their function. Second, are the observations in experimental autoimmune encephalomyelitis that the timing of oxygen administration is important in observing benefits. Since lesions in the central nervous systems of persons with MS are at different time points in their development, this could be a challenge. Finally, due to the intertwined effects of inflammation and hypoxia, with inflammation resulting in hypoxia and hypoxia resulting in localized inflammation, administration of higher levels of oxygen alone may not be sufficient to note a benefit; thus, combination therapy with another, anti-uninflammatory disease-modifying therapy could be needed.
Despite all these caveats, considering hypoxia as a component of the MS disease process in a subgroup of persons with this illness opens up a new and novel approach to treatment and suggests a pathway for “personalizing” disease-modifying therapies to such subgroups.
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