Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is the leading cause of neurological disability in young women in the USA and Europe and the second leading cause of such disability in young men. Major advances have been made in the past two decades in understanding the pathogenesis and immunobiology of MS resulting in major advances in the treatment of the disease over the past 15 years. These advances are the consequence of advanced neuroimaging, molecular biology and immunological techniques. However, the disease remains generally incurable. Further advances will depend on developing more selective immunotherapeutic strategies, particularly involving B cells and regulatory T cells as well as developing therapeutic strategies to prevent neurodegeneration and to induce repair in the central nervous system (CNS) of patients with MS.

Key Concepts:

  • MS is the leading cause of neurological disability in young women in North America and Europe.

  • Although there is good evidence that MS results from both genetic and environmental factors, the exact nature of those factors remains uncertain.

  • Although often classified as a disease of myelin, recent research clearly demonstrates the immune attack on the CNS destroys neurons, axons and oligodendroglia; therefore MS is more properly considered an inflammatory disease of the CNS.

  • Although classically considered an autoimmune disease driven by autoaggressive T cells, clinical data suggests B lymphocytes also play a key role in the pathogenesis of MS.

  • Mechanisms of immune attack on the CNS may vary from patient to patient but in general include both cellular and humoral mechanisms.

  • Brain magnetic resonance imaging (MRI) has fundamentally changed our understanding of disease activity in MS patients. It is now known that much of the damage to the CNS is not apparent clinically in the early phase of the disease, but contributes to the longā€term disability of the disease.

  • Recently, major advances have been made in developing therapies that can slow the progression of MS. However, no cure has yet been found.

  • Neurodegeneration appears to be a consequence of the immune attack on the CNS and may result in continued progression of disability even if the immune attack on the CNS is inhibited.

  • Recently it has become clear that the brain in MS patients is constantly attempting to repair the damage done by the immune attack both through remyelination and cortical remodelling. In fact, these processes appear to explain the clinical appearance of stability in MS patients at a time when the MRI demonstrates ongoing inflammation and damage.

  • Advances in our understanding of the pathogenesis and treatment of MS has significant implications for other inflammatory diseases of the nervous system.

Keywords: multiple sclerosis; central nervous system (CNS); autoimmune disease; demyelination; T lymphocytes

Figure 1.

Demyelination of white matter of cerebral hemispheres in multiple sclerosis. Note the extensive periventricular demyelination.

Figure 2.

Magnetic resonance images from a 26‐year‐old woman with a 2‐year history of laboratory‐supported definite multiple sclerosis. The only new symptom is decreased vision in both eyes, which began four months before this investigation and may be explained by the left optic radiation lesion (c). Note the gadolinium‐enhancing lesion in the left occipital area which represents a currently active but clinically asymptomatic lesion (d).

Figure 3.

Natural history of multiple sclerosis: magnetic resonance imaging (MRI) and clinical pattern. The relationship between frequency of MRI‐detected inflammatory events (gadolinium‐enhanced MRI), the progressive increase in multiple sclerosis plaque volume (MRI‐detected burden of disease) and neurological impairment. As can be seen, most exacerbations of neurological impairment in patients with multiple sclerosis are associated with an inflammatory event of the central nervous system (CNS). Most CNS inflammatory events, however, are not associated with a clear change in neurological status. These inflammatory events do contribute to the total volume of demyelination, which correlates generally with progression of disability.

Figure 4.

Diagram showing the immunopathology of multiple sclerosis. Multiple sclerosis is a T cell‐mediated disease. Antigen presenting cell (APC) engages with naive T cell. Autoreactive T cells are activated into a proinflammatory state. The T helper (TH) type 1 phenotypes of CD4+ T lymphocytes are characterized by the production of interleukin (IL) 2, interferon (IFN)γ and tumour necrosis factor (TNF)α, as well as other proinflammatory cytokines. This phenotype mediates cell‐mediated cytotoxicity (activation). Transmigration of activated lymphocytes is facilitated by induction adhesion molecules and matrix metalloproteinases, which disrupt the blood–brain barrier (transmigration). Autoreactive T cells engage again with protein molecules of myelin, which leads to the attraction of a second wave of immune cells into the brain (reactivation). Multiple factors lead to myelin and axonal injury (destruction of myelin and axons). MBP, myelin basic protein.

Figure 5.

Demyelination and axonal degeneration in multiple sclerosis. (a) Normal myelinated fibre. The action potential travels (thin arrow), with high velocity and safety factor, to the postsynaptic neuron (green). (b) In acutely demyelinated axons, conduction is blocked. (c) Conduction is restored in some chronically demyelinated axons, which acquire a higher than normal density of sodium channels. (d) Axonal degeneration interrupts action potential propagation in a permanent manner.

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Further Reading

Vollmer TL and Waxman SG (1998) Multiple sclerosis and other demyelinating disorders. In: Comprehensive Neurology, 2nd edn, pp. 795–825. New York: Wiley.

Waxman SG (1982) Current concepts in neurology: membranes, myelin and the pathophysiology of multiple sclerosis. New England Journal of Medicine 306: 1529–1533.

Waxman SG (2008) Sodium channels and neuroprotection in MS: current status. Nature Clinical Neurology 4: 159–170.

Waxman SG and Kocsis JD (1998) Functional repair of myelinated fibers in the spinal cord by transplantation of myelin‐forming glial cells. In: Juurlink BHJ, Devon RM, Doucette R et al. (eds) Cell Biology and Pathology of Myelin, pp. 283–299. New York: Plenum Press.

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Preiningerova, Jana, Bomprezzi, Roberto, Vollmer, Timothy L, and Waxman, Stephen G(Sep 2009) Multiple Sclerosis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000192.pub2]