Demyelination, in multiple sclerosis

Shields, D.C., Schaecher, K.E., Saido, T.C., Banik, N.L., 1999, A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain, Proc. Natl. Acad. Sci. USA 96,11486-11491 Shollmeyer, J., 1986, Possible role of calpain I and calpain II in differentiating muscle, Exp. Cell. Res., 163, 413 122... 

In multiple sclerosis, which is a demyelinating disease, there is loss of both phospholipids (particularly ethanolamine plasmalogen) and of sphingolipids from white matter. Thus, the lipid composition of white matter resembles that of gray matter. The cerebrospinal fluid shows raised phospholipid levels. 

Oligodendrocytes are present in the CNS as well and wrap around axons to form a myelin sheath. Myelin wraps into concentric layers that spiral around the axon. Gaps in the oligodendrocytes are the nodes of Ranvier, where the membrane maintains contact with extracellular fluid. The nodes serve to propagate the action potential in myelinated axons. Schwann cells perform an analogous function, myelinating axons in the peripheral nervous system. Not all neurons are myelinated, but myelination increases the metabolic efficiency of action potentials. Demyelination of neurons produces deficits in neuronal conduction, as is seen in multiple sclerosis. 

Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownschei-dle CM, Murray TJ et al. Intramuscular interferon beta-1 a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000 343(13) 898-904. 

In addition to the effect of increased VLCFA on membrane and possibly cellular function, the rapid cerebral form of X-ALD is characterized by an inflammatory response that is believed to contribute to the demyelination that characterizes this phenotype and which is similar to that seen in multiple sclerosis. These cerebral lesions are characterized by breakdown in myelin with sparing of the axons accompanied by the accumulation of cholesterol ester in the neurons. A perivascular inflammatory response with infiltration of T cells, B cells, and macrophages also is present. Therefore, it is believed that the rapid cerebral disease has an im-munologically-mediated component. It has been suggested that the inflammatory response occurs in response to the elevated levels of VLCFA in lipids, which elicits an inflammatory cascade that may be mediated in part by cytokines. Once this cascade begins, it may be more difficult to intervene in the disease process, and in general therapeutic interventions studied to date have been most effective when initiated early. Therefore, prevention of the initiation of the immune response is important for improving outcome. 

An inconvenient but more descriptive name for this MS is intermittent, patchy demyelination. This clumsy term makes clear that multiple sclerosis is unlikely to be a single entity in terms of cause (etiology) or disease mechanisms (pathophysiology). In principle, any conditions or combination of conditions that lead to intermittent, patchy demyelination are forms of multiple sclerosis. If a clear cause can be identified, the condition is by convention not referred to as multiple sclerosis. The disease is therefore by definition of unclear etiology. The neurology literature of the last 100 years contains confident declarations that multiple sclerosis has been proven to be a viral disease, that it has been proven not to be a viral disease, that it has been proven to be an immune disease, that immune mechanisms in multiple sclerosis have been shown to be secondary to the disease process, and so on. 

Howell OW, Falser A, PoUto A, Melrose S, Zonta B, Scheiermeinn C, Voia AJ, Brophy PJ, Reynolds R (2006) Disruption of neurofascin localization revetils early changes preceding demyelination and remyelination in multiple sclerosis. Brain 129 3173-3185 Ilyas AA, Chen ZW, Cook SD (2003) Antibodies to sulfatide in cerebrospintil fluid of patients with multiple sclerosis. J Neutormmunol 139 76-80... 

Balashov KE, Rottman JB, Weiner HL, Hancock WW (1999) CCR5(-r) and CXCR3(-i-) T cells are increased in multiple sclerosis and then-ligands MIP-lalpha and IP-10 are expressed in demyelinating brain lesions. Proc Natl Acad Sci USA 96 6873-6878. 

Fowler, R. C., Durbetaki, A. J. (1952). Cyanide and thiocyanate determination in multiple sclerosis and allied demyelinizing disorders. American Journal of Physiology, 171, 724. 

Lassmarm, H. (2002) Mechanisms of demyelination and tissue destruction in multiple sclerosis. Clinical Neurology and Neurosurgery, 104, 168-171. 

Gray, E., T. L. Thomas, S. Betmouni, N. Scolding, and S. Love. 2008. Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis, 18( 1) 86-95. 

Yanagihara,TandCumingsJN(1969)Alterationsofphosphohpids,particularlyplasmalogens, in the demyelination of multiple sclerosis as compared with that of cerebral oedema. B rain, 92, 59-70. 

Multiple sclerosis (MS) is a complex inflammatory disease of the central nervous system (CNS) that is variable in terms of symptoms and presentation. The name refers to two features of the disease multiple describes the number of CNS lesions and sclerosis refers to the demyelinated lesions. Today, these lesions are usually called plaques, rather than scleroses. Although scientific understanding of MS has progressed at a rapid pace, there are still many areas of evolving knowledge. 

Biologic response modifiers (BRMs) are indicated in patients who have failed an adequate trial of DMARD therapy.1 BRMs may be added to DMARD monotherapy (i.e., methotrexate) or replace ineffective DMARD therapy.22 The decision to select a particular agent generally is based on the prescriber s comfort level with monitoring the safety and efficacy of the medications, the frequency and route of administration, the patient s comfort level or manual dexterity to self-administer subcutaneous injections, the cost, and the availability of insurance coverage.23 In general, BRMs should be avoided in patients with serious infections, demyelinating disorders (e.g., multiple sclerosis or optic neuritis) or heart failure.21... 

The functional significance of myelin is revealed by the neurological deficits observed in patients with multiple sclerosis. This disorder is caused by the demyelination of neurons in the brain, spinal cord, and optic nerve. The loss of myelin disrupts the normal conduction of impulses along the axons of these neurons and results in weakness, numbness, loss of bladder control, and visual disturbances. 

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