Disseminated sclerosis

Disseminated sclerosis – chronic progressing disease of nervous system, appearing in young and middle age (15-40 years). The peculiarity of this disease is simultaneous injury of several different section of nervous system, what can result in emerge of different neurological symptoms. Morphologic basis of this disease is appearance of so-called palms of disseminated sclerosis – seat of myelin destruction ( amyelination) of white matter. Size of these palms, as a usual, varies from several millimeters to several centimeters, but in case of progressive disease appearance of symptyhic palms is possible.

Disseminated sclerosis is rather widespread disease – in the world there are about 2 millions sick with disseminated sclerosis. Disseminated sclerosis usually appears at the age of about thirty years, but can be met at younger age. Primary progressive form usually can be met at the age of about fifty years.

The cause of disseminated sclerosis appearance is not determined for sure. At the present day the most widespread thought is that disseminated sclerosis can be caused by accidental combination of unfavorable external and internal factors. Adverse environmental conditions include frequent viral and bacterial infection, the impact of toxic substances and radiation (including solar); food peculiarities; geoecological residence, especially it has large effect on the children’s organisms, traumas, frequent stressful situations. Genetic predisposition to multiple sclerosis, is probably linked with the combination, in given individual, of several genes, which conditions disorders in immunoregulation system.

Researches of recent years confirm the mandatory part of immune system – primary or secondary – in the pathogenesis of MS. Autoimmune theory of MS genesis occurred to be the most widely-spread. However, up to now, it is not possible to consider MS as entirely original autoimmune diseases. Nevertheless, given the central role of immunological disorders, the treatment of this disease is primarily based on the correction of immune disorders.

Healthy people’s hematoencephalic barrier is impervious for blood cells, including immune cells. The permeability of barrier, of MS patients, increases, occurs the migration of activated T-lymphocytes to the brain parenchyma, the raising of proinflammatory cytokines level, B-lymphocytes are activated, they start to synthesize anti-myelin antibodies, and thus a focus of phlogistic demyelination is formed.

The result of immunopathological reaction is a focus of inveterate phlogistic demyelination – MS plaque. The focuses are located in any part of white matter of brain or spinal cord. Given that the autoimmune responses in MS are directed exclusively against myelin proteins, it is clear that the myelin cover of nervous system carriers of white matter in brain and spinal cord is damaged, more often in periventricular space of hemispheres, brain stem, tentorium, chiasm of the visual nerves, sometimes in the hypothalamus and subcortexes area.

In cases of long-lasting MS and apparent myelin destruction it may occur secondary degeneration of axolemmas of nerve filaments, in the future – of the nerve cells and oligodendrocytes. This leads to atrophy of the principal and spinal cord, enlargement of cerebral cavities.

Currently, there is no doubt about the presence of remyelination process synchronous with the demyelination process in MS cases. First of all this is happening on the edges of active plaque. The process of remyelination is very slow and it becomes more slower, as increasing duration of disease.

The degree of loss of nerve fibers in the early stages of MS – 10-20%, but it can grow to 80% in the long course of disease. Acute development of symptoms in the early inflammatory demyelination is associated with hydrops and a violation of descending current. These changes are reversible in nature, which may results in remission. Later destruction of myelin becomes the basic meaning in shaping of the clinical symptoms. Irreversible clinical symptoms develop, probably, due to the secondary degeneration of axial cylinders and neurons.

Clinical implications of MS are connected with focal lesion of several different departments of brains and spinal cord. Generally accepted is considered the evaluation of clinical status of patients, using the scale of damage of the functional systems (FSS) and expanded disability scale assessment of Kurtzke (EDSS). FSS scale provides assessment balls from 0 to 6 degree of manifestation of defeat symptoms of different brain systems paths, and EDSS scale assesses the overall degree of disability in the balls from 0 to 10.

Central and peripheral paralysis of the cranial nerves can be detected with the MS patients, the most common – of oculomotor nerves, trigeminal, facial, hypoglossal nerve. The focuses in supranuclear areas of corticonuclear tract may lead to the development of pseudobulbar syndrome, and focuses in the brain stem – to the emergence of bulbar symptoms. 50-70% of patients with multiple sclerosis have the vertical and horizontal nystagmus.

Frequent symptoms of MS are disabilities of pelvic organs: urgency, accelerations, retention of urine and stool, at later stages – incontience. It is possible incomplete urinary bladder emptying, which is often the cause of urological infections. Some patients may experience problems with sexual function, which may coincide with the dysfunction of pelvic organs or can be an independent symptom.

70% of patients have symptoms of the violation of visual functions: reducing of the visual acuity of one or both eyes, changes in fields of vision, appearance of scotomas, objects turbidity, loss of vision brightness, color distortion, a violation of contrast.

Neuropsychological changes during MS include reduction of intelligence, behavioral disorder, upper cortical functions changing. Neurosis-like symptoms are distinguished, insane violations and unique organic dementia. Insane violations are often manifested through depression or euphoria, emotions control violation. More often patients with multiple sclerosis predominantly suffers from depression, and it may be associated not only with organic brain lesion, but also be determined by the reaction to information about diagnosis, problems at home and at work. When MS euphoria is often combined with decreased intelligence, underestimate of severity of his condition, behavior disinhibition. Approximately 80% of patients with multiple sclerosis in early stages of the disease have signs of emotional instability with multiple sharp change of mood in a short period of time.

The course of disease is chronic. Variants of MS disease course are various: the initial stages of the disease often marked with relapsing-remitting disease course, which sometimes can go a second time progressing. Rarely observed primary progressive type of disease or stable multiple sclerosis.

Following clinical forms of disease are distinguished: cerebral, spinal, cerebellar, stem, optical. This classification is based on the prevalence of the defeat of one of departments of the nervous system. Type of illness, duration of remission, exacerbations, response to treatment, the selective occurrence of patches of MS in the brain is extremely individual.

The diagnosis of MS is based on the anamnesis, neurological examination and results of additional methods of examination. Successful is to identify the main criteria of diagnosis of MS: «symptoms dissemination in the place and time». This term means undulation chronic disease involving in pathological process of several leading systems. For today the most informative in the diagnosis of MS are considered Magnetic Resonance Imaging (MRI) of head and spinal cord and the presences of oligoclonal immunoglobulins in patients’ spinal fluid.

Given the central role of immunological reactions in the pathogenesis of multiple sclerosis, essential for activity and development monitoring of the pathological process in this disease is becoming a regular study of patients immunological blood test (immunological monitoring). On the basis of long studies of MS patients immunity, we can state that, at first, immunological changes run ahead clinical changes, and secondly, immunopathological process is dynamic, during disease progress the immune system response to illness varies, it occurs the exhaustion of some compensatory and simultaneously it is developing several new protective reactions. As a result, the immune system of multiple sclerosis patients operated on another level than the same person before disease, and moreover, than healthy one. This is why the immunologic monitoring is so important: it is necessary to compare indicators of immunity with previous figures of the same patient, but not healthy persons of control group.

Treatment of patients with multiple sclerosis includes the following main tasks:

to cut short the exacerbate of disease;
impacting on autoimmune inflammatory focuses, stimulate the development or strengthening of compensatory- adaptive mechanism;
to prevent or postpone in time the development of new exacerbations, or reduce their evidence, and therefore, the following patient’s neurological deficit;
to influence the symptoms, which are complicating the opportunity to work, to maintain normal lifestyle (symptomatic treatment);
to choose activities, that allow the patient to adapt to the consequences of disease, in order to mostly facilitate his life.
Pathogenetic treatment should be aimed primarily at active immune inflammatory process stopping, resulting in demyelination. When treating of exacerbations and progressive course of MS it is usually used corticosteroids, adrenocorticotropic hormone and its analogs. These are: prednisolone, methylprednisolone, metypredmedrol, methylprednisolone succinate Na, dexamethasone, cortisol. These drugs reduce the duration and evidence of inflammatory process, have immunosuppressive effect.

Up to now six drugs are registered for pathogenetic treatment of MS in the world, which change the course of the disease (the so-called Group PITRS). Three of them belong to β-interferon: Avoneks (Biohen), Rebif (Merk – Serono) and Betaferon (Bayer Sharing Pharma). In addition, for MS treatment it is used a synthetic polymer of four amino acids – glatiramer acetate – Kopakson (TEVA), cytostatic mitoxantrone and medication of monoclonal antibodies to molecules intehrins – natalizumab – Tisabri (Biohen).

All drugs in controlled clinical studies have shown effectiveness in reducing the frequency of exacerbations when remittent multiple sclerosis, in addition for betaferon and mitoksantrone there is the possibility of slow increase of disability when secondary-progressive MS. But none of the drugs provides significant effect on patients with primary progressive type of disease.

Regenerative medicine gave patients with multiple sclerosis hope of recovery. It is based on two real facts. At first, demyelination is necessarily accompanied by remyelination, , which means reversibility pathological process. Second, neural stem cells can turn into oligodendrocytes – cells that produce myelin.

All over the world several attempts to treat MS by using stem cells were made. Here, as in other areas of regenerative medicine, there are several methodological approaches. One of them is the use of embryonic or adult stem cells for oligodendrocytes in the lab with their further transplantation into the affected area of the brain, using stereotaxic technology. However, not all areas of the brain are available for such manipulation. Moreover, in the case of allogenic cells usage, the immune conflict is joined inevitably, which can dramatically accelerate the progress of disease.

At the Institute of Cell Therapy it is used cotransplantation of large doses of hematopoietic and mesenchymal cells in combination with subcutaneous introduction of neural stem cells for the treatment of MS. But in this case, despite the immunosuppressive effect of mesenchymal stem cells and tolerance-induced effect of hematopoietic stem cells, the need for immunosuppressive drugs (takrolimus) taking still remains.

Clinical example. The patient B., 33 year old, came for treatment with the diagnosis of MS at the stage of frank motor disorders. The patient could not move herself, her hands brought her with his hands to the clinic. Large doses of hematopoietic and mesenchymal cells were transplanted in combination with subcutaneous introduction of neural stem cells, designated tacrolimus (Prohraf) in small doses (3 mg a day). After 3 months, patient’s motor function was recovered, and she could return to work (teacher of junior school), getting to school by bicycle. However, after 6 months, disease had anticipated against the increasing of antibodies titer to basic protein myelin. Repeat grafting was done and the dose of tacrolimus increased to 6 mg per day. At these days the patient moves independently, works, being under the supervision of a doctor.