1. Chapter 8 Multiple Sclerosis
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

2. Figure 1 Jean-Martin Charcot (1825–1893) was a French neurologist often regarded as the founder of modern neurology. He is generally credited with defining multiple sclerosis as an independent neurological disease. (public domain).
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 2

3. Figure 2 Geographic distribution of MS color coded for prevalence by country per 100,000 inhabitants. Disease prevalence is greatest toward the poles and lowest near the equator.
Reproduced from the World Health Organization (WHO), Atlas, Multiple Sclerosis Resources in the World, 2008.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 3

4. Figure 3 Graphical depiction of the four patterns in which MS progresses over time: RRMS, relapsing–remitting; PPMS, primary progressive; SPMS, secondary progressive; PRMS, primary relapsing.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 4

5. Reproduced with permission from Ref. 1.
Figure 4 Typical MRIs from four different patients with MS. Multiple lesions are found throughout (A) the white subcortical matter cortex, (B) the corpus callosum, and (C) the spinal cord. (D) Blood infusion of the contrast medium gadolinium reveals breaches of the blood–brain barrier primarily associated with lesions in the white matter.
Reproduced with permission from Ref. 1.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 5

6. Reproduced with permission from Ref. 4.
Figure 5 Examples of the typical histopathology seen in MS lesions. (A) Example of an active MS lesion surrounded by macrophages at the rim. The lesion is stained for myelin oligodendrocyte glycoprotein (MOG), which, due to myelin loss, is absent in the lesion. (B) 700× magnification of an active lesion stained with an antigen for myelinated fibers, showing both myelinated fibers and ones that have lost their myelin.
Reproduced with permission from Ref. 4.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 6

7. Reproduced with permission from Ref. 5.
Figure 6 Hypothetical view of immune response in an acute MS lesion. Blood-derived CD4+ T and B cells enter the brain by crossing the endothelial wall of the cerebral blood vessels. Once inside the brain, they recognize their respective myelin antigen(s) on microglia or astrocytes. T cells release proinflammatory cytokines that direct CD8+ killer T cells or microglial cells toward myelin, oligodendrocytes, or axons, which they destroy.
Reproduced with permission from Ref. 5.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 7

8. Figure 7 Saltatory conduction refers to action potentials jumping along the axon from one node of Ranvier to the next. This greatly enhances signal conduction even in small-caliber nerve fibers. Each myelin segment separating two nodes is provided by the processes of one oligodendrocyte, yet each oligodendrocyte can produce myelin for up to 50 axons myelin segments.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 8

9. Figure 8 Myelin. (A) An individual oligodendrocyte (yellow) can form myelin segments for up to 50 axons (red). (B) Myelin wraps are continuous with the processes of an oligodendrocyte, as shown by electron microscopy (EM). (C) EM reveals the tight stacking of adjacent myelin wraps, which (D) are separated by myelin basic protein acting as extracellular spacers and proteolytic protein (PLP) anchoring adjacent membrane wraps. (A, kindly provided by Dr Partizia Casaccia, B & C by Dr Cedric S. Raine as used in Basic Neurochemistry 5th edition, reproduced with permission).
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 9

10. Reproduced with permission from Ref. 8.
Figure 9 Degeneration of chronically demyelinated axons (green, axon; red, myelin). Most axons survive demyelination and redistribute Na+ channels to recover signal conduction. Others, like the ones seen with the large green bulbous expansion in (A), are transected with accumulating organelles as their distal axon degenerates and is eaten by microglial cells, as schematically depicted in the cartoon in (B). Owing to loss of myelin trophic support, chronically demyelinated axons exhibit slowly progressive swelling and cytoskeletal disorganization.
Reproduced with permission from Ref. 8.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 10

11. Reproduced with permission from Ref. 9.
Figure 10 Remyelination produces thinner myelin sheaths with a reduced g-ratio. The g-ratio is a measure to compare myelin thickness by dividing the circumference of the axon by the circumference of the myelin.
Reproduced with permission from Ref. 9.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 11

12. Reproduced with permission from Ref. 8.
Figure 11 White matter atrophy visualized by MRI. (A) Normal brain, (B) the brain of a patient with relapsing–remitting MS, and (C) the brain of a patient with secondary progressive MS with end-stage disease. The progressive increase in ventricular volume indicates brain atrophy.
Reproduced with permission from Ref. 8.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 12

13. Figure 12 A multitude of signaling cascades contribute to axonal injury in MS. Central to all of them is depolarization of the axon causing influx of Ca2+, which in turn causes destructive enzymes in the axolemma to be activated.8
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 13

14. Reproduced with permission from Ref. 10.
Figure 13 Axonal degeneration can also result from impairment of axonal transport, which causes the aggregation of organelles, depicted schematically in (A) as bulbous expansions. On electronmicrographic sections in B–E, intracellular accumulations of organelles can be visualized along the axon.
Reproduced with permission from Ref. 10.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 14

15. Reproduced with permission from Ref. 16.
Figure 14 Schematic depiction of the sites of action where currently available drugs that treat MS are presumed to work.
Reproduced with permission from Ref. 16.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 15

16. Reproduced with permission from Ref. 17.
Figure 15 Role of Na+ channels in MS. On the axon, energy failure, that is, loss of production of ATP, causes the Na+/K+ ATPase to decrease its function, thereby depolarizing the cell membrane. This in turn causes persistent Na+ influx through Nav1.6 channels, leading to a rise in intracellular Na+. As a consequence, the Na+/Ca2+ exchanger now runs in reverse, thereby taking in Ca2+ rather than removing it. Na+ channels on microglial cells are involved in microglial activation.
Reproduced with permission from Ref. 17.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 16

17. Reproduced with permission from Ref. 19.
Figure 16 K+ channel block with 4-AP (now clinically used as fampridine-SR) broadens the action potential, allowing it to jump across a demyelinated axonal segment. The Control trace illustrates an experimentally demyelinated axon stimulated proximally at the electrode labeled S1 and recorded at S2 where the action potential fails to travel. In 4-AP the action potential bridges the demyelinated gap.
Reproduced with permission from Ref. 19.
From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 17