Pathophysiology of multiple sclerosis

Overview
Multiple sclerosis is a disease in which the myelin (a fatty substance which covers the axons of nerve cells, important for proper nerve conduction) degenerates. This includes not only the usually known white matter demyelination, but also demyelination in the cortex and deep gray matter (GM) nuclei, as well as diffuse injury of the normal-appearing white matter. GM atrophy is independent of the MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS

Demyelination process
According to the view of most researchers, a special subset of lymphocytes, called T cells, plays a key role in the development of MS. Under normal circumstances, these lymphocytes can distinguish between self and non-self. However, in a person with MS, these cells recognize healthy parts of the central nervous system as foreign and attack them as if they were an invading virus, triggering inflammatory processes and stimulating other immune cells and soluble factors like cytokines and antibodies.

Normally, there is a tight barrier between the blood and brain, called the blood-brain barrier, built up of endothelial cells lining the blood vessel walls. It should prevent the passage of antibodies through it, but in MS patients it does not work. A deficiency of uric acid has been implicated in this process. Uric acid added in physiological concentrations (i.e. achieving normal concentrations) is therapeutic in MS by preventing the breakdown of the blood brain barrier through inactivation of peroxynitrite. The low level of uric acid found in MS victims is manifestedly causative rather than a consequence of tissue damage in the white matter lesions, but not in the grey matter lesions. Nevertheless, whether BBB dysfunction is the cause or the consequence of MS is still disputed,because activated T-Cells can cross a healthy BBB when they express adhesion proteins

According to a strictly immunological explanation of MS, the inflammatory processes triggered by the T cells create leaks in the blood-brain barrier. These leaks, in turn, cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins such as matrix metalloproteinases. The final result is destruction of myelin, called demyelination.

Repair processes, called remyelination, also play an important role in MS. Remyelination is one of the reasons why, especially in early phases of the disease, symptoms tend to decrease or disappear temporarily. Nevertheless, nerve damage and irreversible loss of neurons occur early in MS. Proton magnetic resonance spectroscopy has shown that there is widespread neuronal loss even at the onset of MS, largely unrelated to inflammation. Often, the brain is able to compensate for some of this damage, due to an ability called neuroplasticity. MS symptoms develop as the cumulative result of multiple lesions in the brain and spinal cord. This is why symptoms can vary greatly between different individuals, depending on where their lesions occur.

The oligodendrocytes that originally formed a myelin sheath cannot completely rebuild a destroyed myelin sheath. However, the central nervous system can recruit oligodendrocyte stem cells capable of proliferation and migration and differentiation into mature myelinating oligodendrocytes. The newly-formed myelin sheaths are thinner and often not as effective as the original ones. Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons. Under laboratory conditions, stem cells are quite capable of proliferating and differentiating into remyelinating oligodendrocytes; it is therefore suspected that inflammatory conditions or axonal damage somehow inhibit stem cell proliferation and differentiation in affected areas

Demyelination patterns
Also known as Lassmann patterns, it is believed that they may correlate with differences in disease type and prognosis, and perhaps with different responses to treatment. This report suggests that there may be several types of MS with different immune-related causes, and that MS may be a family of several diseases.

The four identified patterns are :


 * Pattern I : The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation.
 * Pattern II : The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, as before, but also signs of complement system activation can be found.
 * Pattern III : The scars are diffuse with inflammation, distal oligodendrogliopathy and microglial activation. There is also loss of myelin associated glycoprotein (MAG). The scars do not surround the blood vessels, and in fact, a rim of preserved myelin appears around the vessels. There is evidence of partial remyelinization and oligodendrocyte apoptosis.
 * Pattern IV : The scar presents sharp borders and oligodendrocyte degeneration, with a rim of normal appearing white matter. There is a lack of oligodendrocytes in the center of the scar. There is no complement activation or MAG loss.

The meaning of this fact is controversial. For some investigation teams it means that MS is a heterogeneous disease. Others maintain that the shape of the scars can change with time from one type to other and this could be a marker of the disease evolution.

Correlation with clinical courses
No definitive relationship between these patterns and the clinical subtypes has been established by now, but some relations have been established. All the cases with PPMS (primary progressive) had pattern IV (oligodendrocyte degeneration) in the original study and nobody with RRMS was found with this pattern. Balo concentric sclerosis lesions have been classified as pattern III (distal oligodendrogliopathy). Neuromyelitis optica was associated with pattern II (complement mediated demyelination), though they show a perivascular distribution, at difference from MS pattern II lesions.

Correlation with MRI findings
The researchers are attempting this with magnetic resonance images to confirm their initial findings of different patterns of immune pathology and any evidence of possible disease “sub-types” of underlying pathologies. It is possible that such “sub-types” of MS may evolve differently over time and may respond differently to the same therapies. Ultimately investigators could identify which individuals would do best with which treatments.

It seems that Pulsed magnetization transfer imaging [PMID 16964602], diffusion Tensor MRI [PMID 16385020] and VCAM-1 enhanced MRI could be able to show the pathological differences of these patterns.

Correlation with CSF findings
Teams in Oxford and Germany, [PMID 11673319] found correlation with CSF and progression in November 2001, and hypothesis have been made suggesting correlation between CSF findings and pathophysiological patterns. In particular, B-cell to monocyte ratio looks promising. The anti-MOG antibody has been investigated but no utility as biomarker has been found, though this is disputed. High levels of anti-nuclear antibodies are found normally in patients with MS. Antibobies against Neurofascin–186 could be involved in a subtype of MS

Response to therapy
The heterogeneous response to therapy can support the idea of hetherogeneous aetiology.
 * Pattern II lesions patients are responsive to plasmapheresis, while others are not.
 * The subtype associated with macrophage activation, T cell infiltration and expression of inflammatory mediator molecules may be most likely responsive to immunomodulation with interferon-beta or glatiramer acetate.[PMID 12027786]
 * People non-responsive to interferons are the most responsive to Copaxone

Blood-brain barrier disruption
A healthy blood-brain barrier shouldn't allow T-cells to enter the nervous system. Therefore BBB disruption has always been considered one of the early problems in the MS lesions. Recently it has been found that this happens even in non-enhancing lesions, and it has been found with iron oxide nanoparticles how macrophages produce the BBB disruption.

Abnormal tight junctions are present in both SPMS and PPMS. They appear in active white matter lesions and in NAGM in SPMS. They persist in inactive lesions, particularly in PPMS

Apart from that, activated T-Cells can cross a healthy BBB when they express adhesion proteins.

Haemodinamics of the lesions has been messured and distortion has been found related to plaques distribution. It was meassured through transcranial color-coded duplex sonography (TCCS).

Neural and axonal damage
The axons of the neurons are damaged by the attacks or its byproducts. Currently no relationship has been established with the relapses or the attacks.

A relationship between neural damage and N-Acetyl-Aspartat concentration has been stablished, and this could lead to new methods for early MS diagnostic through magnetic resonance spectroscopy. 

Spinal cord damage
Cervical spinal cord has been found to be affected by MS even without attacks, and damage correlates with disability.

Normal appearing brain tissues abnormalities
Brain normal appearing white matter (NAWM) and grey matter (NAGM) show several abnormalities under MRI. This is currently an active field of research with no definitive results. It has been found that grey matter injury correlates with disability and that there is high oxidative stress in lesions, even in the old ones.

Cortical lesions also appear. They can be detected by double inversion recovery MRI. They have been observed specially in people with SPMS but they also appear in RRMS and clinically isolated syndrome. They are more frequent in men than in women. These lesions can partly explain cognitive deficits.

Research
Until recently, most of the data available came from post-mortem brain samples and animal models of the disease, such as the experimental autoimmune encephalomyelitis (EAE), an autoimmune disease that can be induced in rodents, and which is considered a possible animal model for multiple sclerosis. However, since 1998 brain biopsies apart from the post-mortem samples were used, allowing researchers to identify the previous four different damage patterns in the scars of the brain.

History
The National MS society launched The Lesion Project to classify the different lesion patterns of MS.

Claudia F. Lucchinetti, MD from Mayo Clinic and collaborators from the U.S., Germany and Austria were chosen to conduct this study for their previous contributions in this area. They have amassed a large collection of tissue samples from people with MS through brain biopsies or autopsy. Claudia Lucchinetti was appointed director of this project. The group has reported promising findings on samples from 83 cases. They found four types of lesions, which differed in immune system activity. Within each person, all lesions were the same, but lesions differed from person to person.

The first article about pathophysiological heterogeneity was in 1996 [PMID 8864283] and has been confirmed later by several teams. Four different damage patterns have been identified by her team in the scars of the brain tissue. Understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more accurate treatment decisions.

According to one of the researchers involved in the original research "Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity."

Apart of this, recent achievements in related diseases, like neuromyelitis optica have shown that varieties previously suspected different from MS are in fact different diseases. In neuromyelitis optica, a team was able to identify a protein of the neurons, Aquaporin 4 as the target of the immune attack. This has been the first time that the attack mechanisme of a type of MS has been identified.

The investigators are now trying to identify the types of cells involved with tissue destruction, and examining clinical characteristics of the individuals from whom these tissues were taken.

The MS Lesion Project has just been renewed with a commitment of $1.2 million for three years. It is now part of the Promise 2010 campaign.