Pathophysiology of Multiple Sclerosis - Heterogeneity of The Disease

Heterogeneity of The Disease

Multiple sclerosis has been reported to be heterogeneus in its behavior, in its underlying mechanisms and recently also in its response to medication.

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."

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. Though this pattern could be considered similar to damage seen in NMO, some authors report no AQP4 damage in pattern II lesions

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. For some researchers this pattern is an early stage of the evolution of the others.

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. Anyway, the heterogeneity could be true only for the early stage of the disease. Some lesions present mitocondrial defects that could distinguish types of lesions. Currently antibodies to lipids and peptides in sera, detected by microarrays, can be used as markers of the pathological subtype given by brain biopsy.

Several correlations have been studied:

• 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.

• With MRI and MRS 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, diffusion Tensor MRI, and VCAM-1 enhanced MRI could be able to show the pathological differences of these patterns. Together with MRI, magnetic resonance spectroscopy will allow in the future to see the biochemical composition of the lesions.

• With CSF findings: Teams in Oxford and Germany, found correlation with CSF and progression in November 2001, and hypotheses 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. Antibodies against Neurofascin–186 could be involved in a subtype of MS

• With responses to therapy: It is known that 30% of MS patients are non-responsive to Beta interferon. The heterogeneous response to therapy can support the idea of hetherogeneous aetiology. It has also been shown that IFN receptors and interleukins in blood serum predicts response to IFN therapy, specially IL-17, and interleukins IL12/IL10 ratio has been proposed as marker of clinical course. Besides:

• • 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.
  • People non-responsive to interferons are the most responsive to Copaxone
  • In general, people non-responsive to a treatment is more responsive to other, and changing therapy can be effective.
  • There are genetic differences between responders and not responders. Though the article points to heterogeneous metabolic reactions to interferons instead of disease heterogeneity, it has been shown that most genetic differences are not related to interferon behavior