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**The Pathophysiology of Multiple Sclerosis** //By: Alanna Bridgman//

Multiple Sclerosis (MS) is an autoimmune, inflammatory disease that affects approximately 2 million people worldwide. The pathophysiology of multiple sclerosis is largely unknown and still under thorough investigation. MS is a biphasic disease, whereby lesions occur in specific areas of the brain and spinal cord, causing disruption of the blood-brain barrier. This leads to the infiltration of leukocytes, causing inflammation. When lesions occur in the brain, axons will eventually undergo demyelination by immune cells, and the efficacy of action potential conduction will be affected. Remyelination can occur in the early stages of the disease, but recurring lesions prevent sufficient repair** [1] **. This leads to the degeneration of axons and neurons, resulting in various levels of damage to the nervous system, including motor and sensory impairment.

=**1. Lesion Occurrence and Distribution** =

1.1 Cause of Lesions
  There are multiple theories considering the cause of lesions in patients with MS. It has been shown that T helper cells, specifically Th1 and Th17, play a significant role in the development of the brain lesion. Overproduction of the protein Interleukin 12 has been found to transform CD4+ autoreactive T cells into inflammatory Th1 and Th17 cells in the brain ** [1] **. Normally, T cells can distinguish between harmful and harmless cells, but in the case of MS patients, these cells recognize healthy tissues of the Central Nervous Systems (CNS) and begin attacking them as if they were of a foreign nature. This process triggers inflammation and the formation of subsequent lesions. Another theory describing the cause of lesions in MS patients examines the role of oxidative mitochondrial damage. Active MS lesions show substantial alteration of mitochondrial proteins, as well as mitochondrial protein deletion in some neurons with progressive damage** [3] **. Since mitochondria are acutely susceptible to oxidative damage, free radical-mediation mechanisms may contribute significant damage to tissues, which could be a causal factor of lesion occurrence.

1.2 Distribution of Lesions
 Magnetic Resonance Imaging (MRI) is so far the only imaging technique available to patients with MS. Although some lesions do appear in grey matter, most lesions appear in the white matter of the brain, most notably in the optic nerves, the brainstem, the spinal cord, and in the periventricular zones ** [2] **. Grey matter lesions tend to occur in the motor cortex, spinal cord, thalamus, cerebellum, and cingulate gyrus ** [2] **.

<span style="color: #808080; font-family: 'Times New Roman',Times,serif; font-size: 13pt;">1.3 Types of Lesions
<span style="color: #808080; font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> The categorization of lesions in MS patients varies according to source. However, the most accepted categorization includes mixed grey and white matter (type I), and intracortical (types II-IV), which can be subdivided into subpial (type III) and juxtacortical (type IV) lesions.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> **Type I:**Mixed grey and white matter lesion. This type of lesion is not particularly common, as it overlaps both the grey matter and the white matter of the cortex. <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> **Type II:**Intracortical lesion. These types of lesions can only be seen with magnetic resonance double inversion recovery imaging, as they are not usually distinguishable by MRI alone. These lesions occur within the cerebral cortex ** [5] **<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">. <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> **Type III:**Subpial lesion. Subpial refers to the space underlying the pia mater of the brain, separating it from the glia limitans of the underlying neural tissue. These are the most frequent types of cortical lesions in MS patients, and are closely associated with a poor clinical outcome. <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> **Type IV:**Juxtacortical lesion. These lesions occur in the white matter and always are in contact, but not invading, the grey matter outer cortex.

<span style="color: #808080; font-family: 'Times New Roman',Times,serif; font-size: 13pt;">1.4 Normal-Appearing White and Grey Matter
<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> Normal-appearing white and grey matter typically appear around the border of lesions. Lesions borders are very discrete and specific, and the surrounding white or grey matter seeems to be unaffected, but there are in fact small, relatively indistinguishable lesions in these areas. There is growing evidence to suggest that normal-appearing white matter (NAWM) and cortical grey matter have more of an involvement in the disease process than focal white matter lesions. Chard et al (2002) have demonstrated that metabolite concentrations of N‐acetyl‐aspartyl‐glutamate (tNAA) are reduced in NAWM and cortical grey matter, myo-inositol levels are elevated in NAWM, and that choline-containing compounds (CHO) and glutamate/glutamine levels are reduced in cortical grey matter compared to healthy controls** [9] **<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">. Reductions in CHO indicate reduced cellular density and metabolic function as a result of demyelination, and reductions in tNAA indicate a specific loss of neuronal densities in the area of the lesion ** [9] **<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">. This study shows a relationship between neuronal metabolic dysfunction and clinical impairment, which is representative of the varying degrees of severity of multiple sclerosis.

=<span style="font-family: 'Times New Roman',Times,serif;">2. Blood-Brain Barrier Disruption =

<span style="color: #808080; font-family: 'Times New Roman',Times,serif; font-size: 13pt;">2.1 Cause of Blood-Brain Barrier Damage
<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> The blood-brain barrier (BBB) consists of tight junctions in the blood vessel walls of the brain. The main purpose of the BBB is to keep harmful chemicals and molecules out of the CNS. When the barrier is damaged, toxins and immune cells (leukocytes) can enter the brain that normally would not have access, and this can disrupt normal homeostasis and cellular functioning. Presently, the cause of blood-brain barrier (BBB) damage in MS patients is not fully understood. Minagar et al (2003) has hypothesized that mechanisms for the breakdown of the BBB in patients with MS may involve direct effects of cytokines and chemokines on BBB endothelial regulation. Exposure of the BBB to proinflammatory cytokines can interrupt the BBB endothelium by disassembling cell-cell junctions and enhancing leukocyte endothelial adhesion and migration** [10] **<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">. This would allow the infiltration of lymphocytes across the BBB and into the CNS, promoting further inflammation and demyelination of oligodendrocytes. Morgan et al (2007) performed an experimental autoimmune encephalomyelitis model of MS on rodents to examine the role of BBB tight junction malfunction in individuals with MS, and also found that the tight junction protein occludin seemed to undergo dephosphorylation in the BBB. Both of these studies illustrate that there is more than one mechanism by which the BBB can become damaged, highlighting our limited knowledge of this intricate process.

<span style="color: #808080; font-family: 'Times New Roman',Times,serif; font-size: 13pt;">2.2 Infiltration of Leukocytes
<span style="font-family: 'Times New Roman',Times,serif; font-size: 80%; height: 217px; width: 326px;"> <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> Following damage to the blood brain barrier, leukocytes are able to infiltrate the brain. When immune cells that are not usually present in the CNS enter the brain, they can mount an immune response to various tissues that they do not recognize, even though they are healthy, non-invasive tissues. McCandless et al (2008) has demonstrated that disruption of the chemokine CXCL12 polarity promotes the entry of autoreactive leukocytes, while the normal polarizing expression of CXCL12 prevents leukocyte transmigration into the CNS. This shows that one molecule has the ability to regulate the permeability of the BBB to leukocytes, although it is likely not the only factor involved. <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;"> A more conservative view of the infiltration of leukocytes across the BBB states that once the BBB is damaged, T lymphocytes proliferate and express adhesion molecules and inflammatory cytokines, increasing the amount of damage to the BBB and its permeability. Once the leukocytes cross the BBB, myelin reactive T-lymphocytes accumulate in previously formed lesions and initiate the production of cytokines, chemokines, and inflammatory demyelination accompanied by phagocytosis of myelin by macrophage molecules. Most viewpoints agree that the infiltration of leukocytes into the CNS causes further inflammation of lesions, thus leading to demyelination and scarring of neural tissue. The total effect of the infiltration process is a reduced frequency or efficiency of action potentials, which in turn has a direct effect on signalling pathways in the CNS.

=<span style="font-family: 'Times New Roman',Times,serif;">3. Demyelination Process =

<span style="color: #808080; font-family: 'Times New Roman',Times,serif; font-size: 13pt;">3.1 The Role of Leukocytes
<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;"> <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;">After the BBB has been damaged, B-cells (a type of leukocyte) and other antibodies migrate into the CNS and form myelin-reactive attacking complexes. It is not known whether immune cells directly attack axons, but B-cells and other lymphocytes do play a vital role in the degradation of axons and the destruction of oligodendrocytes ** [14] **<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;">. Cytokines also trigger the activation of microglia, astrocytes, and macrophages, which intensifies the inflammatory process and contributes to the formation of scarring. As a result of the autoimmune response and vascular inflammation, oligodendrocytes are subject to damage in lesioned areas, ultimately leading to demyelination and neuronal injury ** [14] **<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;">.

<span style="color: #808080; font-family: 'Times New Roman',Times,serif; font-size: 13pt; line-height: 25px;">**3.2 Neuronal and Axonal Damage**
<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;"> <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">Demyelination plaques vary with the type and severity of MS. If demyelination occurs, not only will the neuron have slower impulses, but it may also degenerate. Axonal damage can be due to a number of factors during the disease process, including inflammation, which affects energy metabolism and damages mitochondrial DNA. The effect of inflammation includes increased aggregation of leukocytes surrounding the lesion, leading to demyelination and a reduction in the efficacy of action potentials. After demyelination has occurred, the neuron will usually degenerate and contribute to scar tissue in the brain. At this point in the disease process, the damage is irreversible** [1] **<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;">.

<span style="color: #808080; font-family: 'Times New Roman',Times,serif; font-size: 13pt;">3.3 Remyelination
<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;"> Remyelination is the process of reinsulating damaged or demyelinated axons. Remyelination helps reinsulate nerve fibers, speed up action potential conduction, and protect against secondary degeneration <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">. Remyelination normally takes place in patients with MS, but it is usually incomplete or insufficient, which prevents full recovery and allows relapse into the demyelination process of the disease. There are many important mechanisms thought to be involved in axonal repair, notably axon and glial cell interactions. This explains the role of oligodendrocytes and their precursors in repairing demyelinated and damaged axons, and that not all glial cells are damaged in MS. Another interesting finding by Coman et al (2006) showed that sodium channel (Na v <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">) clustering around lesion borders is the initial event in the remyelination process ** [17] **<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;"><span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">. Coman et al (2006) also hypothesized that a malfunction in Na v <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">channels may be a causal factor in the failure of remyelination in patients with MS ** [17]  **<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;">. Understanding the initial steps in the remyelination process is crucial for the future of MS therapies. The process of remyelination is eventually redundant, as recurring lesions in the brain begin to overwhelm the ability of glial cells to remyelinate axons of the CNS.

=<span style="font-family: 'Times New Roman',Times,serif; font-size: 14pt;">4. Conclusion =

<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;">Multiple Sclerosis is an inflammatory, autoimmune disease that affects the ability of neurons to conduct action potentials. Although the pathophysiology of MS is not fully understood, considerable advances have been made in understanding the factors that contribute to lesions, the breakdown of the blood-brain barrier, and the transmigration of leukocytes into the CNS. Further research needs to be done on the immunological actions of leukocytes on the CNS, especially the precise mechanism of the demyelination and remyelination process. This discovery will allow more efficient treatment mechanisms and a potential cure for Multiple Sclerosis.

=<span style="font-family: 'Times New Roman',Times,serif; font-size: 14pt; line-height: 32px;">**5. See Also** =

<span style="color: #808080; font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;"> <span style="color: #808080; font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;">**For more information on Multiple Sclerosis, please see:**

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 * 1) <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">Multiple Sclerosis, Pubmed Health. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001747/
 * 2) <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">Multiple Sclerosis Society of Canada. http://mssociety.ca/en/
 * 3) <span style="font-family: 'Times New Roman',Times,serif; font-size: 16px; line-height: 21px;">A video detailing future research possibilities based on knowledge of the pathophysiology of Multiple Sclerosis, adapted from http://www.5min.com/Video/Future-Treatments-for-Multiple-Sclerosis-252526791:

=<span style="font-family: 'Times New Roman',Times,serif; font-size: 14pt;">6. References = <span style="font-family: 'Times New Roman',Times,serif; font-size: 14pt; line-height: 21px;">

<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;"> 19. Wingerchuk, D., Lucchinetti, C., Noseworthy, J. Multiple Sclerosis: Current Pathophysiological Concepts. //Lab Invest//, 2001; **81**:263-28

<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;"> 20. Alexander, Edmond. (n.d). Edmond Alexander Medical Illustrator. In Shannon Associates Illustrations. Retrieved April 1, 2012, from http://www.shannonassociates.com/artists.php?artist=edmondalexander#url=artists/alexander/fs/Multiple_Sclerosis_Blood_Brain_Barrier_1082911.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt; line-height: 21px;"> 21. Franklin, R., French-Constant, C. Remyelination in the CNS: from Biology to Therapy. //Nat Rev Neurosci//; 2008 **9**:839-855.