Multiple sclerosis

6.09.2.1.1.1 Overview

MS is a chronic disease of the CNS, characterized by cell-mediated inflammation, demyelination, and variable degrees of axonal loss.3'4 MS is also characterized by lesions in the white matter of brain, brainstem, optic nerve, or spinal cord that are visible by MRI, and formed by infiltration of CNS parenchyma by monocytes and lymphocytes. Degeneration of postmitotic oligodendrocytes and oligodendrocyte progenitors is also a hallmark of MS lesions and an impediment to remyelination. The lesions are heterogeneous in nature, and have been classified into four histopathological subtypes. MS is the most prevalent inflammatory disease of the CNS, and is far more common in females (1.6-2:1). It can occur at any age, but is most commonly diagnosed between the third and fourth decades.

It is unknown if MS is a single disease or a syndrome. There are, however, multiple subtypes, the most common being relapsing-remitting MS (RRMS), which occurs in 85% of new patients (see Table 1). Relapses are defined by a clinical episode or by subclinical activity detected by MRI. More than half of RRMS patients progress to secondary progressive MS (SPMS). Six additional subtypes have been described: PPMS and RPMS - both progressive diseases from onset, CIS, benign MS, ON, and NMO (Devic's syndrome). Axonal loss occurs early in the disease course, suggesting that all forms of MS - except benign - are progressive.

PPMS patients can present with weakness in one limb and progress without remission to total paralysis; spinal cord involvement is pronounced. Benign MS can only be diagnosed retrospectively, and is seen in a small fraction of MS patients who have no signs of physical disability even decades after diagnosis. NMO, which is generally relapsing, is distinct in that it affects only the optic nerves and spinal cord, does not progress to SPMS, exhibits distinct demographics, and exacerbations are usually severe with lasting disability.

There are no MS-specific biomarkers. However, elevated levels of immunoglobulin in cerebrospinal fluid (CSF), mostly immunoglobulin G (IgG), are sometimes used to support the diagnosis of MS. NfH, a neurofilament heavy chain phosphoform monitored in plasma or CSF, is indicative of neurodegeneration and a poor prognostic sign; it is elevated in the plasma of RRMS patients versus healthy controls. In addition, nitric oxide metabolites are elevated in CSF, but not serum, of MS patients - particularly those with milder disability - suggesting a role for nitric oxide in the early phase of MS. Finally, S100B, a marker for astrocytic activation, is often elevated in plasma of RRMS patients who respond to interferon (IFN)-b therapy compared with nonresponders or healthy controls.

6.09.2.1.1.2 Pathogenesis

The two currently favored hypotheses for the pathogenesis of MS are immunopathological and apoptotic. Histopathological data as well as the ability of immunosuppressive therapies, such as natalizumab, to reduce or stop clinical relapses and suppress MRI activity support the idea that inflammation is an important pathogenic mechanism, and thus a therapeutic target for controlling relapses in RRMS. Further, the natalizumab trials support the role of a4 integrin, and the immune cells that express it, in MS pathogenesis. The presence of autoantibodies in some patients lends additional support to the autoimmune or immunopathological hypothesis, as does the association of MS with genes of the major histocompatibility complex. On the other hand, the apoptotic theory is favored by a pathological report from a very early case of MS, and by the general failure of immunosuppressive therapies to slow disease progression. Indeed, progression seems to be independent of relapses - it occurs regardless of the presence of superimposed relapses. Poor recovery from relapses does, however, account for the acquisition of disability.

Both polygenetic and environmental factors are thought to contribute to MS etiology. Concordance rates in monozygotic twins are relatively modest (about 25%), supporting a role for environmental and polygenetic factors. One or more genes in the area of the major histocompatibility complex are thought to account for some of the genetic risk. MS is more common in Caucasian populations. Prevalence data also show a north-south gradient in the northern hemisphere that reverses in the southern hemisphere; moving to high-risk areas before the age of 15 years increases the risk of developing MS. These data suggest that a decrease in sunlight exposure or a temporal zone pathogen (such as virus) may be causative in MS. Prevalence also correlates positively with the level of socioeconomic development of a country, which can be explained by many factors, including decreased exposure to sunlight and a reduction in childhood infections.4

MS is a cell-mediated immune disorder, with strong evidence for both CD4 + and CD8 + T cells playing a role in disease pathogenesis.4 Epidemiological studies suggest that autoreactive CD4 + Th1 cells may be established for 10-20 years before they become active and contribute to disease.

While MS pathogenesis is primarily mediated by T cells, a role for B cells is also well described in MS patients. While the autoantigens in MS are unknown, most putative ones are myelin-associated antigens: myelin basic protein (MBP), proteolipoprotein, myelin-associated glycoprotein, and myelin oligodendrocyte glycoprotein (MOG); other putative autoantigens are transaldolase, 2',3'-cyclic nucleotide 3'-phosphodiesterases, and a/b-crystallin. A pathogenic role for autoantibodies has not been clearly demonstrated. However, antibodies to MOG are pathogenic in animal models, have been detected in brain parenchyma from MS patients, including lesions, and are present early in the disease. MOG is a type I membrane protein expressed exclusively in CNS. Interestingly, while antibodies from RRMS and SPMS patients bind to oligodendrocyte precursors, binding to a neuronal cell line is increased in SPMS. Many of these studies are plagued by problems and shortcomings common to antigen-antibody assays.

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