Multiple sclerosis (MS) is a chronic autoimmune disease in which the myelin sheath of the nerve is affected in the brain and spinal cord fibers. Although colloquially “sclerosis” is often referred to as memory impairment in old age, the name “multiple sclerosis” has no relation to senile “sclerosis”, or to absent-mindedness. “Sclerosis” in this case means “scar” and “diffuse,” and “multiple” is characterized as a distinctive feature of the disease at postmortem examination that is the presence scattered throughout the central nervous system without a specific localization of foci of sclerosis. It foresees the replacement of normal neural tissues for the connective ones (Brill, 15). Jean-Martin Charcot first described multiple sclerosis in 1868 (Brill, 17). The disease mostly occurs in young and middle age (15 – 40 years) (Brill, 24). A feature of the disease is the simultaneous failure of several different parts of the nervous system that leads to a variety of patients with neurological symptoms. The disease is characterized by formations of areas of inflammation, and myelin destruction that affects the white matter of the brain and spinal cord. Dimensions of plaques usually vary from a few millimeters to a few centimeters, but as the disease progresses, there is a formation of large confluent plaques (Brill, 20). The purpose of the paper is to analyze the factors, mechanisms, diagnostics, and treatment of multiple sclerosis.
The cause of multiple sclerosis is not exactly clear. At present, the most common belief is that multiple sclerosis may result from the interaction of a number of unfavorable external and internal factors. Adverse environmental factors include viral (e.g. HHV-6A) and/or bacterial infection; influence of radiation and toxic substances (including solar radiation); nutrition habits; geographical location and ecological conditions ( its impact is especially large on children); trauma; frequent stressful situations (Brill, 78). Genetic predisposition to multiple sclerosis is possible due to a combination of several genes in individual that determine violations in immune system.
Multiple sclerosis is not considered as hereditary disease. However, it is shown that certain genetic changes increase the risk of developing the disease. The risk of MS is higher in patient relatives compared with the general population, especially in case of siblings, parents, and children. Family sclerosis occurs in 2-10% of all cases, depending on the population (Debouverie, Pittion-Vouyovitch, Louis and Guillemin, 918). In monozygotic twins, the degree of concordance is only approximately 35% (Debouverie, Pittion-Vouyovitch, Louis and Guillemin, 919). Siblings have the degree of only 5% and half-siblings have considerably less risk (Debouverie, Pittion-Vouyovitch, Louis and Guillemin, 920). Some ethnic groups have more inclinations and higher risk of multiple sclerosis.
There have been some differences in the frequency of combined gene expression system HLA-class I and II, depending on the ethnic affiliation of patients (Brill, 75). For example, in the United States an increased connection of MS patients with the presence of antigens B7, DR2 was established, while in Russia with antigens A3, B7, A1 and A9 (Brill, 78). In European nations, where multiple sclerosis is mostly developed among individuals with haplotype DR2 (DW2) DRB1 * 1501 – DQA1 * 0102 – DQB1 * 0602, HLA-class II system is defined (Brill, 78).
At the same time, there are reports about the absence of patients with multiple sclerosis loci detected in healthy people, the so-called protective loci. The presence and a different combination of various genetic markers may predetermine not only the possibility of the disease, but also affect the features of the pathogenesis of immune regulation in patients with multiple sclerosis clinical type of the disease. For example, the presence of TNF and DR3-a 9 markers associated with unfavorable course of multiple sclerosis, TNF-a 7 associates with a milder clinical manifestation of the disease (Lucchinetti, Brück and Lassmann, 370).
There are infectious and non-communicable risk factors for multiple sclerosis. Geographic latitude is the first factor. MS is more common in people who live farther from the equator, although there are many exceptions. Areas with less sunlight presuppose high risk of developing MS. It explains the reduction of endogenous and exogenous intake of vitamin D (Ascherio and Munger, 510). Secondly, stress may influence MS (Ascherio and Munger, 511). Heavy stress can also be a risk factor for multiple sclerosis, although it is not reliably proved yet. Moreover, smoking belongs to possible causes associated with lifestyle and it is independent risk factor for MS.
Vaccination against Hepatitis B is not fully understood in the development of multiple sclerosis (Ascherio and Munger, 508). Some studies proved the link between vaccination against hepatitis B and the incidence of multiple sclerosis. However, the World Health Organization (WHO) issued a statement saying that the analysis of the available data does not support the hypothesis that vaccination against Hepatitis B increases the risk of multiple sclerosis (Ascherio and Munger, 508). In addition, most studies show no association between MS and vaccines (Ascherio and Munger, 513). Furthermore, patients with MS exhibit low levels of uric acid (Ascherio and Munger, 510). It led to the creation of hypothesis that uric acid protects against MS.
MS presupposes compulsory participation of the immune system in the pathogenesis of multiple sclerosis. Abnormalities in the immune system are the features associated with the set of genes that control the immune response. In patients of different nationalities and ethnic groups with multiple sclerosis, a genetic peculiarity may cause the specific features of the disease, the clinical forms of the treatment type, as well as the duration and outcome of the disease.
There is one most widespread autoimmune theory of the multiple sclerosis origin (Demetriou, 104). However, there is still no answer to the question whether such immunological reactions primary or secondary ones (Brill, 78). If the brain tissue inflammation and demyelination are a consequence of the immunological response to brain antigens, one can speak of a primary autoimmune disease similar to rheumatism, rheumatoid arthritis, and others (Brill, 64). In case where the sensitization of immune cells to brain antigens occurs due to the inflammation and destruction of myelin, it indicates secondary autoimmune component in the pathogenesis of multiple sclerosis. Under such circumstances, brain antigens penetrate through the damaged blood-brain barrier and there occurs subsequent development of the complex immunopathological reactions.
Given the key role of immunological disorders, the treatment of this disease depends on mitigating the consequences and correction of immune causes and disorders. The random combination of endogenous and exogenous risk factors, which are individual and adverse, leads to the formation of multiple sclerosis. Endogenous factors are primarily attributed to the complex gene loci HLA- class II, and possibly the genes encoding TNF-a, causing the failure of genetic immunoregulation (Brill, 105). It should be emphasized that no factor taken in isolation may be important in the origin of multiple sclerosis, only certain combination of them. In the body, as a result of genetically caused failure of the regulatory systems of immunity, the activation of the immune system of non-specific precipitating factors can occur, such as viral infection, trauma or stressful situation. Thus, antigen-stimulated macrophages and activated T-helper cells are fixed on the blood-brain barrier (BBB), endothelium (Demetriou, 106). Cytokines secreted by fixed cells on the BBB surface express antigens of major histocompatibility complex class I and II (for antigen presentation), as well as cell adhesion molecules (Demetriou, 106). The blood-brain barrier (BBB) in healthy people is impervious to blood elements (erythrocytes and all types of immune cells). In patients with multiple sclerosis, BBB permeability increases, T lymphocytes become activated and then they move to the brain. Consequently, it increases the levels of certain families of cytokines that are proinflammatory-g-interferon, TNF-a, IL-1 and others (Demetriou, 108). The B-cells activate and begin to synthesize antibodies that act against myelin, thus forming inflammatory demyelination. Inflammation compensation is achieved through the production of cytokines, such as IL-4, IL-10, IL-6, TRF (Demetriou, 109).
In multiple sclerosis, morphological changes may be recorded not only directly in foci of demyelination but in normal myelin and in normal cell at the molecular level. Depending on the degree of ripeness and time, several types of plaques can be identified in the same patient: acute (active new foci of demyelination), old (chronic inactive lesions), and old chronic foci with some activation characteristics, usually at the periphery of plaques, which can be regarded as a continuation of the plaque growth.
The areas of inflammation can be found everywhere in brain and spinal cord white matter. Myelin proteins are the target for autoimmune response in multiple sclerosis. As a result, in the white matter of the brain and spinal cord myelin sheath, wires of the nervous system are affected most often in the periventricular area of the cerebral hemispheres, brainstem, cerebellum, visual nerves chiasm, etc. Long MS duration can lead to the brain and spinal cord atrophy, and cerebral ventricular expansion. Remyelination in multiple sclerosis along with demyelination process is obvious. It primarily occurs at some areas of the active plaques, while remyelination process is slow and slows down even more as disease prolongs. The loss of nerve fibers can reach from 10% to 20% at early stages of disease, but can increase to 80% after prolonged course of the disease (Brill, 26). Acute symptoms in the early multiple sclerosis processes (inflammatory demyelination) associated with edema and impaired impulse conduction through the fiber. Consequently, such changes may result in remission.
The classic clinical criteria for diagnosis of multiple sclerosis are clinically reliable ones. They include the presence of objective evidence of damage to the nervous system. Moreover, clinical symptoms should have a transitory nature and meet one of the following requirements: there must be two or more episodes of worsening separated by a period of not less than 1 month and not less than 24 hours or there should be slow and gradual progression of the process for at least 6 months. Additionally, based on neurological examination or medical history, the signs of at least two separately arranged MS foci should be present. Neurological symptoms should show the primary thinning of the conductors’ white matter. The disease begins between the ages of 10 and 50 years inclusive. Available neurological disorders may be more adequately explained by other pathological processes (such conclusion can only be done by the doctor qualified in Clinical Neurology).
The most reliable way to diagnose MS is Magnetic resonance imaging (MRI), which is a diagnostic method based on the nature of the protein-lipid membrane structure of the myelin, where water is located in a certain order between the layers of the myelin sheath (Milo and Miller, 105). Such order is broken in demyelination, when the water is released. MRI is constantly being improved and different variants of mathematical calculation of the amount of volume, with a total area of foci are introduced. One of the latest achievements is the use of paramagnetic contrast, amplifying the signal from the zone of inflammation. Such method allows differentiating the degree of maturity of the outbreaks meaning that active fresh outbreaks demonstrate accumulation of contrast, and the increase in the size of the old hearth is accompanied by accumulation of contrast on the periphery of the foci. The use of contrast enhanced MRI allows objectifying the activity of the pathological process, especially when using this method in the dynamics of the same patient. In multiple sclerosis, a variety of multiple sizes and shapes of lesions in different parts of the brain and spinal cord material are revealed. There are different diagnostic criteria of MRI data (Milo and Miller, 105).
Another method is the analysis of evoked potentials. Evoked potentials (EP) is a method of characterizing the degree of some pathways preservation (Milo and Miller, 105). Given the central role of immunological reactions in the pathogenesis of multiple sclerosis, it is especially important to monitor the activity and development of the pathological process in this disease, which requires a regular study of patients immunological blood test (immunological monitoring). Based on many years of research immunity data in patients with multiple sclerosis, firstly, clinical immunological changes are important; secondly, immunopathological process should be dynamic. The course of the disease varies, and the reaction of the immune system during the disease changes as there is depletion of a number of compensatory and simultaneously developing several new protective reactions. Consequently, the immune system of a patient with multiple sclerosis operates at a different level compared to the one of the same person before the disease. As a result, immunological monitoring is important as it is necessary to compare the performance of immunity to previous figures of the same patient, but not to healthy control group.
Patient needs an individual approach to the treatment of multiple sclerosis. It means that the doctor in his diagnosis should be as close to understanding at what stage the disease currently is (active, inactive, or stabilization during the transition from one stage to another) as possible. It will require an MRI examination of the patient over time, as well as immunological blood tests (Wang, 165). Immunological parameters together with MRI and clinical data allow judging the activity of the pathological process in a patient at a given time. It makes it possible to resolve the issue of the appointment, duration of application, the possibility of cancellation of the active immunosuppressive agents, such as steroids, cytostatic medicine, and others. These are the methods of diagnosis and control of the treatment performed.
Additional methods of diagnosis and monitoring of treatment are electrophysiological methods, namely the electromyography and studies of visual, auditory, and somatosensory evoked potentials. Electrophysiological techniques allow people judge about the level and extent of damage to the pathways of the nervous system. In addition, the changes detected by the given methods increase the accuracy of diagnosis of multiple sclerosis. With the problems in the visual pathway, it is advisable to undergo constant monitoring by an ophthalmologist. Upon necessity, a neuropsychologist’s survey is required for administering psychotherapy patients and often their families.
Thus, for the successful treatment of a patient with multiple sclerosis there is a need for constant contact of the patient with a number of specialists: a neurologist, immunologist, electrophysiology, neuropsychology, neuro-ophthalmologist, and urologist. The main treatment goals are to prevent the worsening of the disease; affect the foci of autoimmune inflammation; stimulate the development or enhancement of compensatory-adaptive mechanisms. More objectives include prevention or postponing the development of new exacerbations, or reducing their severity, which may result in subsequent neurological deficit in a patient affecting the symptoms that make it difficult to perform different activities, and maintain patients’ lifestyle (symptomatic treatment). Lastly, it is necessary to select activities that allow the patient to adapt to the existing effects of the disease to facilitate his/her life. Regardless of the fact that the given area is more social than medical, the patient often goes to the doctor in an attempt to fight the disease. Consequently, the doctor determines the time for implementation of certain recommendations, based on the capabilities of the patient and disease prognosis.
In the treatment of exacerbations and progressive course of multiple sclerosis doctors use corticosteroids and its analogs. These drugs reduce the duration and severity of the inflammatory process and have immunosuppressive effect. The mechanisms of immunosuppressive action are used to reduce the content of activated immune cells, influence on cell-mediated immunity, reducing the formation of autoantibodies. Anti-inflammatory effect is primarily due to a decrease in vascular permeability and the BBB due to inhibition of prostaglandin synthesis (Healy and Liguori, 170). Due to the decrease in the permeability of the endothelium of the capillaries, the microcirculation improves the exudation of white blood cells and other cells as the inflammation decreases. Moreover, it helps stabilize the membranes of the myelin sheath and microvascular cells. It such case, it is recommended to use drugs that reduce the permeability of the BBB and strengthen the vascular wall (angioprotectors), antiplatelet agents, antioxidants, inhibitors of proteolytic enzymes, as well as drugs that enhance the metabolism of brain tissue (in particular, vitamins, amino acids, nootropics) (Healy and Liguori, 170). Other medicine may have the antioxidant effect, which is associated with the suppression of lipid peroxidation.
Multiple sclerosis is a disease, in which the immune system destroys the protective sheath covering the nerves (myelin sheath). This process prevents the processes between the brain and the rest of the body from occurring. Ultimately, damaging of nerves is an irreversible process. The treatment of multiple sclerosis has not yet been developed, however, it is already possible to prevent aggravation of the disease, and change or facilitate symptoms. The precise causes of multiple sclerosis are unknown. It is believed that it is an autoimmune disease in which the immune system destroys its own tissues. In multiple sclerosis, the myelin is destroyed (a special layer that covers and protects the nerve fibers of the brain and spinal cord). Since the causative agent of the disease is not identified, the treatment of multiple sclerosis should be directed primarily at relieving active immunological process that results in a demyelination. The factors leading to MS are age, race, lifestyle, genetic factors, and others.