Multiple sclerosis is an autoimmune disorder, which affects the central nervous system. It was first described as a separate disease in 1868 by Jean-Martin Charcot (Compston and Coles, 2008). The average prevalence of the disease globally is 30 people from 100000 (Milo and Kahana, 2010). However, the incidence of multiple sclerosis varies greatly depending geography. While in the African countries it happens comparatively rarely, its frequency is increasing consistently in Asia and America. In Europe, multiple sclerosis happens with the highest rate in the world. There are four clinical forms of multiple sclerosis (Compston and Coles, 2008). Relapsing-remitting MS is characterized by the temporary relapses of the disease, which after treatment usually ends and patient returns to normal state. Progressive-relapsing MS happens when the patient even during clinical improvement can not achieve complete remission and, therefore, the disease progresses constantly. The secondary progressive form can be seen when after relapsing-remitting form patient's condition deteriorates and the disease begins to progress rapidly. Primary-progressive form is the most unfavorable form of the disease, which is characterized by rapid increase in symptoms and deterioration of the patient's status from the beginning of the disease, with the inability to achieve stable remission.
Clinical manifestations of the MS can be very different and are caused by the ability of the pathological process development in different parts of the brain and spinal cord. The disease often begins slowly and monosymptomatic, although acute onset with multiple lesions also occurs. The most common initial symptoms of MS at any age is a sense of paresthesias in the form of tingling, the stiffness of a hand or foot that increases for 3-4 days, lasts 1-2 weeks and then gradually disappear. The disease often begins with movement disorders - weakness in the legs. Sometimes in young people aged under 20 years at the onset of MS develops retrobulbar neuritis, which is characterized by a rapid vision impairment of one or both eyes, pain behind the eye that increases with movement of eyes, violation of the color perception, the appearance of the central cattle. Results of ophthalmoscopy show signs of the papillitis (35%). The phase of recovery begins after a few weeks and ends in 3-6 months. Bilateral retrobulbar neuritis occurs in 30% of cases of MS, and more often in men. Less frequently at the onset of MS is observed lesions of oculomotor nerves, which manifest in strabismus and diplopia. In early stages, the disease may cause disorders of pelvic organs (problems with urination process). There are cases of the acute vestibular syndrome at the onset of MS. Often the disease begins with cerebellar disorders - ataxia, incoordination. Among neuropsychological disorders, the most important are cognitive disorders, behavior problems, a decrease in memory, depression, feeling of anxiety. Depression connects with demyelination in both temporal lobes. One of the characteristic symptoms is euphoria that is often associated with cognitive disorders. For MS typical is a syndrome of constant fatigue, which manifests with the need for frequent rest, drowsiness, inability to perform repetitive actions. These signs are serious problems for many patients because they can not perform the usual job for them even during remission stage.
The cause of multiple sclerosis, despite the big amount of long-term studies through the century, is not exactly known. There are two main groups of reasons (according to the theory of multifactorial etiology of MS). The first group includes hereditary and genetic factors and second consists of the factors of the environment. Possible involvement of hereditary factors in the etiopathogenesis of MS was suspected by various scientists such as Eyhorst and Davenport. In general, immunogenetic studies use family and population methods of analysis, methods of evaluation fo the allelic gene set, encoding the protein structure and the research of genetic factors involvement in the development of experimental models of demyelination (Bando et al., 2015). Particular attention was paid to genes that are connected with the functioning of the immune system. Among them were identified major potential genes responsible for susceptibility to MS. All of these genes cause immune reactions uniqueness of each person and play a crucial role in launching the immune process, universal in its mechanism (Tintore et al., 2015). Infectious possibility and the role of infectious factors in the etiology of MS has attracted and continues to attract the attention of the majority of scientists who have devoted themselves to the problem of MS. On the role of infection in the development of MS indicates the presence of inflammatory changes in the foci of demyelination and liquor and increase in antibody titer to various infectious agents in serum and cerebrospinal fluid of patients with MS. In MS patients showed elevated titers of antibodies to the measles virus, rubella, smallpox, Epstein-Bar virus that causes infectious mononucleosis, mumps, parainfluenza, cytomegalovirus (Tintore et al., 2015). In recent years, no one doubts the fact that infections can provoke exacerbation of MS, acting as a starting trigger factors. The results of research on the impact of geography on the prevalence of MS was the highlight performance trends of increased prevalence of MS with the distance from the equator (called "gradient" of latitude). Toxins also can provoke an onset of multiple sclerosis. They lead to changes in biochemical and antigenic properties of myelin, inhibit remyelination and have a damaging effect on suppressor cells, therefore, activating immunomodulation. In the literature, there is a lot of data about high rates of prevalence of MS and regions with the unfavorable ecological situation if the metallurgical, oil refineries and chemical plants. Emotional stress as a factor in the development of MS is described by Jean-Martin Charcot. Even the beginning of the first documented case in the history of MS in Prince Augustus de Este was noticed after emotional stress in the family (1948). Further clinical description of MS repeatedly pointed at communication of MS with acute and chronic stressful situations. In 1970s in the USA, the alimentary theory of MS reached its peak. Later, interest in it has fallen sharply. However, the adverse role of animal proteins and fats in the diet of meat increase the blood-brain barrier, enhancing aggregation deterioration of microcirculation, activation of inflammatory cytokines confirmed by many studies.
In favor of viral etiology of MS suggest described epidemic outbreaks, the bond of its debut or exacerbation with the acute viral infection, different models of experimental allergic encephalomyelitis caused by the virus and identification of viruses and antiviral antibodies in patients. As proof of the viral theory, scientists report numerous clinical trial data which suggests an increase in antibody titer to measles, rubella, mumps, chicken pox, herpes simplex virus, influenza and parainfluenza. Hypothetically supposed contact with the virus during the prenatal period or in early childhood, followed by a persistent virus and the development of the disease after a long latency period. The emergence of multiple sclerosis is often associated with Epstein-Barr virus, which is likely to provoke or simulates the autoimmune process in multiple sclerosis. Obviously, autoimmune process is being triggered not by one particular virus. It may be a combination or not yet known virus. Genetic predisposition to MS shows itself in the form of family cases that are 2-5%, with the women in these families suffer 5-6 times more often than men. The greatest risk has close relatives, especially siblings. According to statistical studies, while the risk of MS for the population as a whole is less than 0.2%, the families of already affected people have higher the risk of disease for three generations - 20%. Studies of twins have shown that the risk of MS in monozygotic twins is much higher (25-40%) than in heterozygous (3,3-4,7%), in which it is virtually indistinguishable from other siblings (Tintore et al., 2015).
Most important in the pathogenesis of MS are autoimmune mechanisms leading to the destruction of myelin, although to this time it is unknown whether autoimmune reactions are primary or secondary. The basic theory of pathogenesis - infectious and allergic autoimmune theory. The destruction of myelin is caused by chronic inflammation in the brain and spinal cord. External infectious agent (virus) is embodied in the cells oligodendrocytes of the myelin sheath and causes the disintegration of myelin, distorts the synthesis of nucleic acids. New protein compounds acquire properties of antigen, against which are produced the antibodies, preferably against myelin proteins. As a result develops the autoimmune reaction, which leads to the destruction of myelin, to inflammatory and proliferative processes and formation of sclerotic plaques. In blood circulate abnormal immune complexes containing antibodies to myelin basic protein, lipids and other proteins. All kinds of metabolism are disturbed as well as hormonal activity. The intercourse of immunopathological process has a definite phase character: in the early stages, autoallergy is observed, and later - persistent immunodeficiency. The pathogenesis of autoimmune process in the CNS has several essential factors. The state of the blood-brain barrier, which provides passive protection of the brain from the blood immune system and actively selects cells that are possible to penetrate the brain. Increased blood-brain barrier permeability leads to stimulation of autoimmune reactions and is associated with the onset of MS (Cramer et al., 2015). Next factor is the level of antigen presentation and activity in the tissue adhesion to vascular endothelial cells. This factor also regulates the activity of immunopathological reactions in the CNS. Activation of T cells plays an important role in the pathogenesis of the MS. When due to the increased permeability of BBB T-cells reach the brain tissue, they attack brain cells as foreign cells, because normally these cells must not contact. Lack of regulatory systems, which means a failure of mechanisms which are monitoring immune responses. Crucial to the development of immunopathological reactions has a balance of inflammatory and anti-inflammatory cytokines. Cytokines are universal mediators of intercellular interactions. They are produced directly in the CNS and have receptors on cells of the nervous system.Transforming growth factors and TNF are common pro-inflammatory cytokines which take part in the MS. Inflammatory cytokines increase the expression of adhesion molecules and MHC on the cells, activate T- and B- cells, inhibit the activity of suppressor mechanisms and directly destroy myelin. Thus, the main culprits of the chronic demyelinating process are the activation of inflammatory cytokines (mainly interleukins, growth factors, TNF, beta and gamma interferon). Based on the above data we can draw some conclusions. Clinical and immunologic manifestations in the pathological process of MS are connected to each other, and immunopathologic changes can bee is seen before the onset of clinical manifestation. During the MS, the imbalance between activation and suppressor cytokines, which manifests itself primarily in autoimmune reactions to myelin antigens. The dynamic immunopathological process, that change all parameters of immunity during the MS. At various stages of MS symptoms vary from immunosuppression to immune system activation. Very important in the chronic pathological process in MS is insufficient suppressor mechanisms. Clinical and immunological studies have shown immunological reactions during following stages. In the acute stage, cn be observed growing number of proteolytic enzymes, increased activity of lipid peroxidation processes, inhibited cellular factors immunity, humoral hyperstimulation, there is hyperproduction of autoantibodies, increasing the penetration rate of the blood-brain barrier and cytotoxic antibodies. In remission decreases the intensity of lipid peroxidation, T suppressor are activated, decreases the intensity of the formation of autoantibodies, the normal function of the blood-brain barrier is restored, decreases the level of cytotoxic antibodies against brain cells. In the pathogenesis of MS particular importance have the rheological properties of blood, especially the metabolism of brain tissue. Thus, according to the generally accepted today autoimmune theory of MS, an unfavorable combination of genetic factors, infectious external factors, disability of immunoregulation leads to disruption of BBB, the breakdown of immunological tolerance to proteins in the brain and penetration of autoreactive clones of immune cells into the brain tissue. Pathomorphological during the MS is seen numerous foci of demyelination in the white matter of the brain and spinal cord, followed by the formation of sclerotic plaques (Bando et al., 2015). They are located in different parts of the central nervous system, but mainly in the areas of the optic nerves, periventricular space of hemispheres of the brain, brain stem, cerebellum, lateral and posterior spinal cord. Macroscopically locus of MS look like round formations gray-pink or white сolour and an average diameter of 0.2 cm to 1 cm, with clear contours. They observed as complete disappearance of myelin formation. In the early stages axons remain intact and during activation of remyelination process, the normal structure of the fibers can be restored (Hanafy and Sloane, 2011). With the deepening of the process of myelin destruction and active formation of sclerotic plaques, axial cylinders also get damaged, which points to an irreversible loss of their function. Every patient's plaques can be in various stages of development. In the period of the acute disease in the nervous system can be an ovbserved strengthening of demyelination, violation of the structure of nerve fibers, the formation of new plaques. These processes can occur both in new places and next to the old locus, accompanied by the increasing size of the latter. During remission dominates reverse process strengthening of remyelination, restoration of the structure of nerve fibers, reducing the area of demyelination lesions (Hanafy and Sloane, 2011).
All above-written information shows that despite a long history of medical research of multiple sclerosis, it remains a big problem for global health care system, especially in the developed countries of Europe and North America. However, with the modern breakthroughs in treatment and the appearance of new drugs against the disease suggest that in the future it can be overcome.
References
Bando, Y., Nomura, T., Bochimoto, H., Murakami, K., Tanaka, T., Watanabe, T. and Yoshida, S. (2015). Abnormal morphology of myelin and axon pathology in murine models of multiple sclerosis. Neurochemistry International, 81, pp.16-27.
Compston, A. and Coles, A. (2008). Multiple sclerosis. The Lancet, 372(9648), pp.1502-1517.
Cramer, S., Modvig, S., Simonsen, H., Frederiksen, J. and Larsson, H. (2015). Permeability of the blood–brain barrier predicts conversion from optic neuritis to multiple sclerosis. Brain, 138(9), pp.2571-2583.
Hanafy, K. and Sloane, J. (2011). Regulation of remyelination in multiple sclerosis. FEBS Letters, 585(23), pp.3821-3828.
Milo, R. and Kahana, E. (2010). Multiple sclerosis: Geoepidemiology, genetics and the environment. Autoimmunity Reviews, 9(5), pp.A387-A394.
Tintore, M., Rovira, À., Río, J., Otero-Romero, S., Arrambide, G., Tur, C., Comabella, M., Nos, C., Arévalo, M., Negrotto, L., Galán, I., Vidal-Jordana, A., Castilló, J., Palavra, F., Simon, E., Mitjana, R., Auger, C., Sastre-Garriga, J. and Montalban, X. (2015). Defining high, medium and low impact prognostic factors for developing multiple sclerosis. Brain, 138(7), pp.1863-1874.
