Multiple Sclerosis


Multiple sclerosis is considered an autoimmune disease that affects young individuals, predominantly women, and is one of the leading causes of neurological disability in the United States and Europe.

Intense research carried over the last four decades has unveiled mechanisms underlying the disease process and although some questions remain unanswered, the role of the immune system in initiating a deregulated immune response and contributing to degenerative phenomena within the central nervous system has been elucidated.

Advances in molecular and radiological techniques have refined diagnostic accuracies and have helped define how the disease progresses. Then, in parallel with the improved understanding of the disease pathogenesis, a growing number of therapies have been developed that are capable of obtaining control of the inflammatory component of the disease and they are rewriting its natural history. Arresting neuronal degeneration, promoting remyelination, repairing tissue damage and reversing neurological deficits are the ongoing challenges for the medical science in the field.

Key Concepts

  • MS is the leading cause of neurological disability in young women in North America and Europe.
  • As for other multifactorial diseases, MS results from the interplay of a genetic background with small contribution from many different genes and environmental factors acting as triggers.
  • Although classified as a demyelinating disease, MS is a disorder of the central nervous system where there are inflammatory and degenerative phenomena. Both the myelin and the grey matter are involved, causing demyelination, axonal injury, neuronal loss and brain atrophy.
  • The pathogenesis of MS entails an aberrant autoimmune response that sees the mobilisation of both the adaptive and the innate immune systems.
  • The variability of the expression of the disease depends on lesion locations, vulnerability of oligodendrocytes, neurons and axons, as well as secondary metabolic derangements and finally the intrinsic abilities to repair and re‐myelinate.
  • Magnetic resonance imaging (MRI) has fundamentally changed our understanding of the disease and its activity. It has better defined the diagnostic criteria and has helped to characterise the disease courses.
  • As further advances of MRI techniques are offering new opportunities to visualise tissue changes in vivo, greater attention has been paid to the involvement of the cerebral cortex and the grey matter atrophy. These are strongly correlated with cognitive impairment and functional disability.
  • As a result of the better definition of the pathogenesis of MS, new and better disease‐modifying therapies continue to be made available.
  • Neurodegeneration seems to be both a direct consequence of the activity of the immune system and an indirect effect linked to neurotoxicity, neuronal injury and impaired survival of neurons. Its treatment is the ongoing challenge the neurology field is confronted with.

Keywords: multiple sclerosis; central nervous system (CNS); autoimmune disease; demyelinating disease; T lymphocytes; B lymphocytes; microglia

Figure 1. Brain specimens showing demyelinating lesions in the periventricular cerebral white matter (a) and the brain stem (c); Examples of magnetic resonance images detecting demyelinating lesions in similar regions of the periventricular white matter (b) and the brain stem (d) to the brain specimens, not from the same patient.
Figure 2. Magnetic resonance images showing classic demyelinating lesions scattered in the periventricular white matter in a patient with a 10‐year history of MS (a–c). Axial MRI sequences without contrast (d–f) demonstrating lesions with associated loss of brain volume and consequent enlargement of the lateral ventricles. In the same patient, the areas of enhancement seen after the administration of gadolinium (g–i) are due to the breakdown of the blood–brain barrier and are indicative of an aggressive form of MS in persistently active inflammatory stage.Sagittal (j) and axial (k) views of a typical demyelinating lesion involving the central and posterior aspects of the cervical cord. Section of cerebral white matter obtained with high‐resolution MRI (7 Tesla scanner) showing the bright signal of demyelinating lesions surrounding venules identified by the dark of the flow void, central vein sign (l).
Figure 3. Schematic diagrams of the natural history of MS (a). A relationship exists between frequency of MRI‐detected inflammatory activity (gadolinium‐enhanced lesions), increase in lesion volume (MRI‐detected lesion burden) and progressive increase in neurological impairment. Most CNS inflammatory events are not associated with a clear change in neurological status (subclinical activity) but these inflammatory events contribute to CNS atrophy. Schematic views of different patterns of clinical courses of MS (b).
Figure 4. Simplified diagram of the immunopathology of MS. Antigen‐presenting cells (APC) engage with naive T cells that are activated into a proinflammatory state. The Th1 and /or Th17 phenotypes of CD4+ lymphocytes produce of IL2, IL17, IFNγ and TNFα, as well as other proinflammatory cytokines. Transmigration of activated lymphocytes is facilitated by induction of adhesion molecules and matrix metalloproteinases, which disrupt the blood–brain barrier. 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). B cells (non‐shown) likely participate as APCs and by generating auto‐antibodies. Multiple factors lead to myelin and axonal injury (destruction of myelin and axons).
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

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Bomprezzi, Roberto(Jul 2020) Multiple Sclerosis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000192.pub3]