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Cause The key to understanding SS is to appreciate the concept of “Autoimmune Endotheliopathy.” “Endotheliopathy” means that the endothelial cells (EC) are sick (see Figures 6-8). “Autoimmune” means that the endothelial cells are sick because the person’s own immune system is mistakenly waging an attack on those cells---thereby injuring them. In SS the endothelial cells that are being attacked are the endothelial cells that line the inner walls of the microvasculature (the tiniest arteries and capillaries). This is happening almost exclusively in the microvasculature of the brain, retina, and inner ear. The microvasculature elsewhere in the body (in the lungs, heart, kidney, etc.) is unaffected---though, in an apparently harmless way, the microvasculature in the muscle and skin may sometimes be affected. The endothelial cells that line the large and medium sized arteries are not apparently affected. Figure 6 depicts a magnified version of the cross-section of a tiny artery or capillary. The yellow ovals represent the endothelial cells that line the inner wall of the blood vessel. (For simplicity, only the endothelial cells that are at the edge of the cross-cut blood vessel are shown. The endothelial cells that line the rest of the inner wall of the blood vessel are not shown.) Note that the endothelial cells fit snugly together. There are “tight junctions” between them. Figure 7 depicts early, moderately severe “autoimmune endotheliopathy.” The endothelial cells have been injured and have become swollen. Since they are swollen, they take up more space. This endothelial cell swelling narrows the channel (the opening, the lumen, the passageway) of the blood vessel. This narrowing makes it harder for blood to flow through the vessel. The less blood that flows through the vessel, the less oxygen and nutrients are delivered to the tissues (brain, retina, and inner ear) that are served by those blood vessels. Figure 8 depicts extremely severe “autoimmune endotheliopathy.” The endothelial cells have become markedly swollen, and they have swollen the channel completely shut. No blood can flow through a channel that has been swollen shut. As a result, the tissues (brain, retina, inner ear) normally served by these blood vessels no longer receive adequate oxygenation and nutrients. Consequently, those tissues suffer from lack of oxygen and nutrients. They suffer from “ischemic injury.” (“Ischemia” means lack of oxygen.) Cause (PDF #2) Page 1 If the ischemia is only mild-moderate (due to narrowing as depicted in Figure 7, for example) and of relatively short duration, the tissues (brain cells, for example) become sick, but do not become permanently injured. If the ischemia is severe (as in Figure 8) and/or prolonged, the ischemically injured cells (in the brain, retina, or inner ear) may become so sick that they are irreversibly damaged. The purpose and the urgency of medical treatment is to suppress the immune system’s attack on the endothelial cells as quickly and completely as is safely possible----so that the endothelial cells do not become increasingly swollen and so that the brain, retina, and inner ear do not become irreversibly damaged. Treatment can suppress the mistaken autoimmune attack, normalize the health of the sick endothelial cells, reverse the swelling, open up the channel, improve blood flow to the sick tissues (brain cells, retinal cells, cochlea cells), and help these ischemically injured tissues to recover---assuming it is not too late. The above understanding of “autoimmune endotheliopathy” makes it much easier to understand the ophthalmologic findings, MRI findings, audiological findings and the variety of symptoms of SS. But, before we proceed, let’s address two fundamental questions: • Why does the immune system make this Susac’s Syndrome mistake in the first place? • Can this mistake be corrected? These questions are addressed in the section below. The Immune System, Autoimmune Mistakes, and the Concept of Immunologic Self-Correction The Immune System By the “immune system” we mean that part of our body that is responsible for protecting us from infection. Specifically, we primarily mean the white blood cells (their actions and the actions of the products they produce) that circulate within our blood stream and that also reside in our lymph nodes and other tissues. These white blood cells (WBC) include T lymphocytes, B lymphocytes, macrophages and polymorphonuclear WBC, and the products they produce include cytokines, chemokines, and antibodies. Autoimmune Mistakes We want our immune system to go into action and use its products to attack invading organisms, like bacteria and viruses. But, we do not want our immune system to attack parts of our own body, as if the immune system thinks (erroneously) that it sees bacteria or virus in those parts, or otherwise thinks these parts are foreign or dangerous and need to be attacked. When the immune system does attack a part or parts of our own body, we call that an “autoimmune” attack. Rheumatoid arthritis is probably the autoimmune disease that is best known to people. In rheumatoid arthritis, the person’s immune system is mistakenly attacking that person’s joints, as if their immune system Cause (PDF #2) Page 2 has decided, quite erroneously, that there is infection in the joint that must be attacked. Their immune system is well-meaning, but is making an unfortunate mistake, and chronically so. In Susac’s Syndrome the immune system is making the unfortunate mistake of attacking the endothelial cells that line the inner walls of the microvasculature that feeds the retina, inner ear, and certain parts of the brain. Why does the immune system make such a mistake? As is the case with rheumatoid arthritis, the mistake is usually a spontaneous one---meaning that it is not triggered by anything specific or determinable. It just happens, out of the blue, for no apparent reason. Most autoimmune diseases (rheumatoid arthritis, lupus, dermatomyositis, Susac’s Syndrome, etc.) occur spontaneously. These spontaneous mistakes probably happen, however, because of an underlying “programming error” in the person’s “immune computer.” Our immune systems are, indeed, much like computers. They are “programmed “ to know when to go into an attack mode, and when to leave things alone. This “programming” is done by our “immune response genes.” Some people have immune response genes that, unfortunately, mal-programed their immune computers, such that their immune system is prone to make autoimmune mistakes, like rheumatoid arthritis (a common autoimmune mistake) or Susac’s Syndrome (a rare autoimmune mistake). Immunologic Self-Correction Fortunately, our immune systems are often able to correct their mistakes---though it is apparently harder to self-correct some mistakes than others, and children appear to have better capacity for self-correction than do adults. For example, the immune systems of children usually are eventually able to correct the juvenile rheumatoid arthritis mistake, the juvenile dermatomyositis mistake, and even the lupus mistake; but, the immune system of adults usually has little success in correcting the rheumatoid arthritis mistake. Fortunately, the immune systems of adults and children seem to be able to self-correct the Susac’s Syndrome mistake, often within 1-3 years---though not always. Limitations of Current Treatments Unfortunately, we do not currently have treatments that can specifically and directly correct the immune mistake that an immune system is making. If we did, we would have a “cure” for that particular autoimmune disease. However, we do have treatments (immunosuppressive/anti-inflammatory treatments) that either suppress the extent to which the immune system is making the mistake (by suppressing part or all of the immune system), or at least “throw water” on the fires that the immune system is mistakenly setting. Until we have true “cures” for these autoimmune diseases, the main approach is to use immunosuppressive/anti-inflammatory medications to control the “autoimmune fires” (slow down the firesetting and throw water on the already set fires) until the person’s immune system is able to self-correct. If it is going to take the individual’s immune system 2 years to self-correct, that individual will need immunosuppressive treatment throughout those 2 years. Usually, self-correction occurs gradually, such that doses of immunosuppressive drugs can gradually be reduced after initial control has been achieved. But, the gradual reduction of immunosuppression needs to be done at a pace that is about equal to the pace of Cause (PDF #2) Page 3 self-correction. If immunosuppressive treatment is reduced at a pace faster than the pace of self correction, a flare-up of disease is likely to occur. Sometimes a person’s self-correction is interrupted by a return of loss of control (i.e. a relapse). In such an instance, the immunosuppressive doses that were working well, may no longer be sufficient and may need to be increased, at least temporarily. Cause (PDF #2) Page 4