Multiple sclerosis. Issues of diagnosis and treatment of multiple sclerosis Get treatment in Korea, Israel, Germany, USA

24 No. 1 (42), 2016

UDC 616.832-004.2-07-08

A.A. Hamidullah

West Kazakhstan State Medical University named after. Marata Ospanova, Aktobe, Kazakhstan

MODERN ASPECTS OF DIAGNOSIS AND TREATMENT OF MULTIPLE SCLEROSIS

This article presents a review of the literature, covering issues of etiology, pathogenesis, clinical picture and treatment of multiple sclerosis at the present stage. The clinical features of the course of multiple sclerosis and approaches to the administration of immunoglobulins are discussed in detail.

Key words: multiple sclerosis, demyelination, interferons, central nervous system, autoimmune process

Multiple sclerosis (MS) is a chronic disease of the central nervous system of an autoimmune nature, which manifests itself with multifocal neurological symptoms and is characterized by the formation of multiple foci of demyelination in the brain and spinal cord. The disease is characterized by an undulating course with periods of exacerbation and complete or partial remission. MS affects mainly young people aged 20 to 40 years, rarely debuts in childhood and in persons over 50 years of age. Currently, there are about 3 million people with MS in the world. Women get sick 1.5-2 times more often than men.

The medical and social significance of MS is determined by the fact that this disease is characterized by the development of persistent disability. During the first 5 years from the onset of MS, 42.6% of patients lose their ability to work, and when the disease lasts up to 10 years - 71.8%. In recent years, there has been a significant increase in the prevalence of MS throughout the world. This is due both to the true increase in the incidence of MS and to the improvement of diagnostic methods with the widespread introduction of modern neuroimaging research methods into neurological practice, which makes it possible to identify the disease in the early stages of development.

Based on many epidemiological studies, differences in the prevalence of the disease depending on geographic latitude have been identified. These differences make it possible to conditionally identify three risk zones for MS - high, medium and low KiI^ke, 1993): the high-risk zone with a prevalence of the disease of 30 or more cases per 100 thousand population includes regions located north of the 30th parallel in all continents, the medium-risk zone includes countries where this indicator ranges from 5 to 29 cases per 100 thousand population, in the low-risk zone there are less than 5 cases per 100 thousand population. The risk of developing MS is associated not only with place of residence, but also with belonging to a certain race or ethnic group: to a greater extent, bo-

illness is common among people Caucasian, rare in Japan, Korea, China: from 2 to 6 cases per 100 thousand population.

In the etiology of MS, according to numerous studies, autoimmune mechanisms caused by the activation of T-lymphocytes play a major role, resulting in damage to the proteins and lipids of the myelin sheath. In addition, there is a polygenic theory of the development of MS, according to which many genes, interacting with each other, form a predisposition to MS, i.e. gene control is responsible for the immune response. At the same time, the HLA system (Human Leucocyte Antigen) plays a role in triggering the immune reaction in response to the introduction of any antigen. This system represents a collection of gene alleles that determine the differences in the immune responses of each person.

Currently one of possible reasons MS deals with viral infections. It was not possible to identify the connection of the disease with any specific virus, but the dominant role is given to herpes viruses. It is also assumed that the cause may be rabies viruses, measles, and sexually transmitted retrovirus.

In the pathogenesis of MS, a two-phase model is considered in the form of the development of an inflammatory response in the central nervous system and neurodegeneration. Inflammation involves the activation of immune system cells, their penetration of the blood-brain barrier and the destruction of myelin fibers. Neurodegenerative processes that develop beyond the exacerbation stage of MS are accompanied by damage and death not only of axons, but also of the neurons themselves. Inflammatory and degenerative processes in the central nervous system differ in clinical manifestations, course of the disease, biochemical, neuroimaging parameters, morphological changes, and response to therapy. Manifestations of an active inflammatory process are clinical exacerbations of MS, the formation of new lesions with the accumulation of contrast agent in them during an MRI examination, positive dynamics of the neurological picture during

A.A. Hamidullah, e-mail: [email protected]

LITERATURE REVIEW | 25

corticosteroid therapy. Degenerative damage is a major factor in the progressive neurological deficits in MS. Also confirming the presence of a neurodegenerative process is the death of axons, apoptosis of oligodendrocytes, neurons, as well as increasing atrophy of the brain and spinal cord.

For the development of autoimmune damage, an infectious agent must enter the body of a person with a genetic predisposition. In this case, activation of auto-aggressive T-lymphocytes in the peripheral blood occurs. When the immune status changes, the body loses the ability to “distinguish” its own antigens from foreign ones, and the immune system begins to “attack” the antigens of its own tissues. In the case of MS, the myelin of the central nervous system becomes such a target. Activated autoaggressive T-lymphocytes, with the help of adhesion molecules, attach to the vascular endothelium of the blood-brain barrier, destroy it and penetrate the central nervous system. There they are reactivated by myelin autoantigens, secreting proinflammatory cytokines. A significant role in the development of the autoimmune process in MS is assigned to pro-inflammatory cytokines produced by T-1 lymphocytes, such as tumor necrosis factor, interferon-gamma, interleukin-2. Cytokines produced by T-2 lymphocytes have regulatory properties and suppress inflammation. These include interleukins - 4,5,10. A number of studies have noted a connection between increased level expression of pro-inflammatory cytokines and disease activity. During remission, on the contrary, the level of expression of some anti-inflammatory cytokines increases. An increase in the level of inflammatory markers during the period of clinical remission can serve as a criterion for an approaching exacerbation. Timely detection of high titers of pro-inflammatory cytokines allows prescribing preventive therapy.

The pathogenesis of MS involves the processes of not only cellular, but also humoral immunity, mediated by B lymphocytes that produce antibodies to the proteins and lipids of the myelin sheath with activation of the complement system. Activation of complement triggers a cascade of reactions leading to the destruction of myelin.

According to the course of MS, the following variants are distinguished: relapsing-remitting, secondary progressive, primary progressive and primary progressive with exacerbations. Relapsing-remitting MS is observed in 85% of cases, in which periods of exacerbations end in complete or partial remission. In 50% of patients with relapsing-remitting MS, a few years after the clinical debut, a gradual progression of neurological disorders is observed with the transition to secondary progressive MS. Primary progressive MS occurs in 10-15% of cases. At the same time, the steady increase in neurological deficits

Cyta is observed from the onset of the disease; remissions are not observed in this form. Primary progressive MS with exacerbations is rare, occurring in 3-5%, and is characterized by a progressive deepening of neurological deficits, against which exacerbations occur.

A separate clinically isolated syndrome is distinguished, which is the first episode of the development of neurological symptoms. Patients with clinically isolated syndrome have a high risk of transition to clinically definite MS in the near future. Studies of the natural history of the disease have shown that over the next 1-3 years, 50-60% of patients with clinically isolated syndrome have a second attack and develop clinically definite MS.

MS is characterized by various clinical manifestations. In the world, it is generally accepted to assess the clinical status of patients using the Functional Systems Damage Scale (FSS) and the J. Kurtzke Expanded Disability Scale (EDSS). The FSS scale involves assessing the severity of symptoms of damage to various brain conduction systems in points from 0 to 6, and the EDSS scale evaluates the overall degree of disability in points from 0 to 10.

The most characteristic clinical manifestations of MS are motor disorders in the form of central paralysis, cerebellar symptoms, and pelvic dysfunction. central type, visual disorders. Spastic paresis, which develops as a result of demyelination of the corticospinal tracts, is observed in 90% of patients and leads to severe disability. Movement disorders can develop as para-, tri- and tetraparesis with a predominant lesion of the lower extremities.

Damage to the cerebellum occurs in % of cases. Ataxia is a common symptom, and the gait of a patient with MS is referred to as spastic-atactic. Cerebellar symptoms are manifested by gait disturbance, dysmetria, dysdiadochokinesis, and intentional tremor of the limbs. Intentional trembling of the vocal and speech muscles makes the patient’s speech intermittently “chanted.” Intention tremor in combination with nystagmus and scanned speech is part of the well-known Charcot triad, and the Marburg pentad additionally includes blanching of the temporal halves of the optic nerves, loss of abdominal reflexes.

Visual impairment in MS can be very diverse. Most often, retrobulbar neuritis occurs (accompanies the onset of the disease in one third of cases). Decreased vision in retrobulbar neuritis is associated with demyelination of optic nerve fibers. In this case, no changes are detected in the fundus. A few weeks after the onset of the disease, the severity

NEUROSURGERY AND NEUROLOGY OF KAZAKHSTAN

vision can be completely restored (in 77% of cases). During this period, the phenomenon of “clinical splitting” in the optical sphere can be detected, i.e. in the fundus, blanching of the temporal half or the entire optic nerve disk is formed, and visual functions are preserved.

Oculomotor disorders are observed in 17-46% of cases. Transient double vision develops in the early stages of the disease in every 10 patients, and in the further course of the disease - in every 3rd. Classic oculomotor disorders in MS are nystagmus and internuclear ophthalmoplegia. Nystagmus, being a manifestation of intentional trembling of the oculomotor muscles, impairs vision due to difficulty in fixation. Internuclear ophthalmoplegia is associated with damage to the medial longitudinal fasciculus in the brainstem.

Sensitivity disorders are observed already in the early stages of the disease in approximately half of the patients. Spontaneous paresthesias are one of the earliest symptoms of MS, often occurring in the fingertips and then spreading proximally. Deep sensitivity is especially often impaired (the posterior columns of the spinal cord are affected in 85-95% of cases at different stages of the disease). As a result of demyelination of deep sensory conductors, Lhermitte's symptom occurs - the sensation of an electric current passing through the spine when the head is tilted.

Violation of pelvic functions of the central type in the form of urinary retention and constipation are also characteristic of MS and develop in 75% of patients. Neuropsychological disorders are manifested by euphoria with decreased criticism, attention and memory disorders, and depression. Constant fatigue syndrome occurs in 75-92% of cases. According to a number of authors, cognitive impairment was observed in more than 65% of MS patients.

The clinical picture of MS includes clinical dissociation syndrome, described by D.A. Markov and A.L. Leonovich. This is a discrepancy between the objective symptoms of damage to the pathways and the subjective sensations of the patient. For example, a decrease in muscle strength in the patient’s legs to 2–3 points is combined with the fact that the patient can walk more than 2 km freely, without assistance. In a patient with increased tendon reflexes and the presence of pathological reflexes, muscle hypotonia is determined, which is caused by simultaneous damage to the cerebellum.

To make a diagnosis of MS, a thorough collection and analysis of the disease history is necessary. Determining the time of the first attack and the first signs of MS, a thorough neurological examination to identify symptoms of damage to the central nervous system are the main stages of diagnosis. Paraclinical data only

further confirm the diagnosis. Characteristic changes in the cerebrospinal fluid are the detection of oligoclonal antibodies to myelin proteins and an increase in the concentration of immunoglobulin G. To diagnose MS, neuroimaging methods are used - MRI of the brain and spinal cord in T2 mode. In this case, foci of demyelination are defined as hyperintense. With reliable MS, such lesions are found in 95% of cases, which are mainly located periventricularly, in the corpus callosum, in the brain stem, cerebellum, spinal cord, mainly in the cervical region.

Treatment of MS remains one of the most serious problems in practical neurology. The strategic goal of MS treatment is to slow down the development of disability. The main goals of therapy are treatment and prevention of exacerbations, weakening the progression of the disease. The drug of choice for relieving exacerbations of MS is glucocorticosteroids. The use of methylprednisolone is most preferable, since its effectiveness and safety have been proven in numerous studies. Methylprednizolon affects immune system in various ways: slows down the activation and proliferation of T-lymphocytes, reduces the formation of antibodies, reduces the permeability of the BBB. To stop an exacerbation, pulse therapy is carried out - 1000 mg of methylprednisolone for 5 days. In patients with severe relapses of MS that do not respond to corticosteroid therapy, plasmapheresis may result in significant improvement. It may also be combined with hormonal or other immunosuppressive therapy.

The main therapeutic agents currently used to treat MS outside of exacerbations are immunomodulators (interferon-beta drugs, glatiramer acetate) and immunosuppressants (mitoxantrone and natalizumab). Until recently, interferon-beta and glatiramer acetate remained the first choice drugs. Their therapeutic effect on MS activity in relapsing-remitting MS and secondary progressive MS with exacerbations has been demonstrated in several multicenter, randomized, double-blind clinical trials guided by magnetic resonance imaging brain monitoring. These drugs reduce the frequency and severity of exacerbations, delay the progression of disability and the emergence of new lesions according to MRI of the brain.

The first interferon-beta introduced into clinical practice was betaferon. The effectiveness of betaferon has been shown in pilot studies: it reduces the frequency of exacerbations in relapsing-remitting MS by 34%, the number of hospitalizations by 43%,

LITERATURE REVIEW | 27

leads to a decrease in the formation of new active lesions in the brain and spinal cord, slows down the progression of the disease. The drugs "Rebif" and "Avonex" are beta-1a interferons. Rebif can be used in 2 dosages - 22 mcg and 44 mcg. In a comparative analysis of the use of 2 dosages conducted in the PRISMS study (Prevention of Relapses and disability by Interferon beta-la Subcutaneously in Multilpe Sclerosis - interferon beta-la administered subcutaneously to prevent exacerbations and progression of PC) it was shown that the use of more dose leads to a slowdown in the formation of new foci of demyelination and, accordingly, less progression of the disease by 33% compared to placebo. However, in the ETOMS study (Early Treatment Of Multiple Sclerosis), a lower dosage of 22 mcg is recommended at the onset of the disease. And this is the dose that is approved for use in children over 14 years of age. The results of studies on Avonex (CHAMPS - Controlled High-risk subjects Avonex Multiple sclerosis Prevention Study - a study of the effectiveness of Avonex in preventing MS in individuals at high risk of developing it) showed that its use after a clinically isolated syndrome prolongs the period before the development of significant MS by 43%. The advantage of Avonex is that it has an accumulation effect and is used once a week. With this frequency of use, Avonex remains effective in reducing the frequency of exacerbations by 32%, reduces the risk of developing cognitive impairment by 47% and does not cause adverse events.

Glatiramer acetate acts on the very initial link in the pathogenesis of MS, forming a strong connection with the major histiocompatibility complex class II, displacing other autoantigens from the trimolecular complex and being, as it were, a false target for activated autoaggressive T-lymphocytes. The interaction of glatiramer acetate with T lymphocytes leads to the proliferation of Copaxone-specific T lymphocytes capable of penetrating the BBB. Studies involving MS patients with constant administration of the drug have shown a shift in the T-cell response towards the synthesis of anti-inflammatory cytokines - interleukins - 4, 10, tumor necrosis factor - beta, etc., which provide a protective effect. A study conducted in the USA showed that the drug not only helps to reduce exacerbations, but also slows down the increase in disability.

Currently, along with first-generation drugs, new second-generation drugs have appeared. For the treatment of relapsing-remitting MS, Fingolimod, the first drug for oral administration, was approved as a second-line drug. Fingolimod is a synthetic modulator of sphingosine-1-phosphate receptors on the surface of lymphocytes. It reduces the yield of activated T lymphocytes

from the lymph nodes and their penetration into the central nervous system, thereby reducing the severity of inflammation and the degree of damage to nervous tissue. The effectiveness and safety of the drug was proven in a placebo-controlled phase III study of fingolimod (FREEDOMS), where there was a significant reduction in the frequency of exacerbations compared to placebo by 60% (at a dose of 1.25 mg), tolerability was also close to that of placebo.

Also second generation drugs include the synthetic antitumor drug Mitoxantrone. This is a cytotoxic drug that interrupts DNA synthesis, thereby stopping the proliferation of leukocytes. This drug is mainly used in the treatment of secondary progressive MS, progressive MS with exacerbations and “aggressive” MS resistant to treatment with first-generation drugs.

In the treatment of MS, especially in aggressive cases, the use of natalizumab, which belongs to the group of recombinant monoclonal antibodies to adhesion molecules that block the penetration of lymphocytes through the blood-brain barrier into the central nervous system, is effective. nervous system. Natalizumab is indicated for patients with active disease despite interferon treatment and for patients with rapidly progressive severe MS. Despite the proven effectiveness of natalizumab in large clinical trials, its use is associated with the risk of severe opportunistic infections and the development of progressive multifocal leukodystrophy.

In recent years, the use of intravenous immunoglobulins has demonstrated its effectiveness in the treatment of MS. Intravenous immunoglobulins are drugs that consist of antibodies filtered from the donor blood of several thousand people. The main mechanisms of their action include: effects on autoantibodies, suppression of the complement binding reaction, activation of Fc receptors and blockade of macrophages, suppression of the synthesis of inflammatory cytokines and adhesion molecules, activation of T-cell function. A number of large randomized studies have been conducted that have shown a significant effect of intravenous immunoglobulin on reducing disease activity: in 1998, Fazekas et al (148 patients with relapsing-remitting MS); J. Haas, O. Homes in 2007 (173 pregnant women with relapsing-remitting MS); D. Pohlau et al. in 2007 (231 patients with progressive MS). Based on European guidelines, intravenous immunoglobulins are currently considered as second-line therapy for relapsing-remitting MS with exacerbations. Indications for this type of treatment are intolerance to first-line drugs (recommendation level B) and pregnancy.

Among the new approaches to the treatment of autoimmune diseases of the nervous system, special interest

NEUROSURGERY AND NEUROLOGY OF KAZAKHSTAN

res represents transplantation of hematopoietic stem cells using high-dose immunosuppressive therapy. Stem cell transplantation was first used to treat MS in 1995. Since that year, this method has been used in a number of centers in Europe, Russia, Israel, China, the USA, Canada, Australia and Latin America. To date, more than 700 similar procedures have been performed on patients with various forms of MS. The safety and effectiveness of the method have been studied in international multicenter studies. Stem cell transplantation consists of several stages: 1) collection of hematopoietic stem cells from the patient's bone marrow; 2) carrying out massive immunosuppressive therapy to suppress auto-aggressive T-lymphocytes; 3) introduction of hematopoietic stem cells. The results of international clinical studies show that stem cell transplantation in combination with immunosuppression can completely stop the progression of the disease in the majority of MS patients. Of 183 MS patients included in the European Bone Marrow Transplantation Group registry from 1995 to 2004, 63% showed sustained improvement and stabilization of the course of the disease after transplantation. Most patients experienced a decrease in the degree of disability on the EDSS scale by 1 to 4 points and a significant decrease in the frequency of exacerbations. Wherein

progression-free survival was 6080%.

In Kazakhstan, the first experimental studies in the treatment of MS were devoted to the use of fetal hepatocytes. When assessing the long-term results of fetal neurotransplantation in patients with MS for 36 months, 93.3% showed a positive clinical effect in the form of regression of the degree of disability on the EDSS scale by 21.9%, as well as positive dynamics on MRI in the form of a decrease in the number and the size of the foci of demyelination with regression of perifocal edema around them, there was a significant decrease in the marker of damage to nervous tissue in the cerebrospinal fluid (the difference between the control and main groups was 78.5%).

Thus, today MS remains a socially significant disease that leads to severe disability in patients. Existing treatment methods make it possible, with varying degrees of effectiveness, to reduce the risk of exacerbations, slow down the progression of the disease, and delay disability. The treatment of MS requires further detailed study. It is necessary to conduct large-scale randomized studies of drugs under development, and to verify and confirm the results of experimental clinical studies.

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TUY1NDEME

A.A. Hamidullah

Marat Ospanov atyndash Batys K,azak,stan Memlekettk medicine university Aktvbe k., K,azakstan

SHASHYRANDA SKLEROZDYTS DIAGNOSTICS ME EM1NSCH

ZAMANAUI ASPECT1LER1

Wasps makalada k, azirgi uakytta shashyranda sclerozdyts etiology, pathogenesis clinic-sy zhene emdeu meseleane katysty edebi sholu malimetteri ¥sonilFan. Shashyranda sclerosis aFymynyn klinikalyk, erekshelikteri zhene immu-

noglobulinderdi tafayindau zheynde suraktary tere^rek karastyrylFan.

Nepzp seder: Shashyranda sclerosis, demyelination, interferondar, ortalyk, zhyYesi nerve, autoimmune process.

A.A. Khamidulla

West Kazakhstan Marat Ospanov State Medical University, Aktobe, Kazakhstan

MODERN ASPECTS OF DIAGNOSIS AND TREATMENT OF MULTIPLE SCLEROSIS

The review of the literary data devoted to etiology, pathogenesis, clinical signs and treatment of multiple sclerosis at the present stage are presented in this article. Current clinical features of the multiple

sclerosis, the approaches to the appointment of immunoglobulins are detailed considered.

Key words: Multiple sclerosis, demiyelinization, interferons, central nervous system, autoimmune process.

“T.E.Schmidt, N.N.Yakhno MULTIPLE SCLEROSIS GUIDE FOR DOCTORS 5th edition Moscow “MEDpress-inform” UDC 616.832-004.2 BBK 56.12 Sh73 All rights reserved. No part of this book may be..."

T.E.Schmidt, N.N.Yakhno

ABSORBED

GUIDE FOR DOCTORS

5th edition

"MEDpress-inform"

UDC 616.832-004.2

All rights reserved. No part of this book may be reproduced in any form or by any means without the written permission of the copyright holders.

Carefully study the manufacturer's accompanying instructions for the use of medicines.

The book is intended for medical professionals.

Schmidt T.E.

Multiple sclerosis: a guide for doctors / T.E. Schmidt, N.N. Yakhno. – Ш73 5th ed. – M.: MEDpress-inform, 2016. – 272 p. : ill.

ISBN 978-5-00030-337-5 In the book, the authors tried to highlight the state of the problem of multiple sclerosis at the present stage. Additions and changes have been made to almost all sections, but the most significant changes have been made to the chapters that address the pathogenesis of multiple sclerosis. Emotional, affective and cognitive disorders are presented in more detail. The section devoted to the clinical picture of acute disseminated encephalomyelitis has been significantly expanded. A variety of new approaches to treatment are considered, some of which are already being introduced into everyday practice. This publication includes a chapter devoted to multiple sclerosis in children and its differential diagnosis.

The book is intended for practicing neurologists.

UDC 616.832-004.2 BBK 56.12 © Schmidt T.E., Yakhno N.N., 2010, 2016 ISBN 978-5-00030-337-5 © Design, original layout, illustrations.

Publishing house "MEDpress-inform", 2010, 2016 CONTENTS List of abbreviations

Preface to the 4th edition

Introduction

PART I Chapter 1. Epidemiology, clinical forms, pathomorphology, etiology and pathogenesis of multiple sclerosis

1.1. Epidemiology

1.2. Clinical forms

1.3. Pathomorphology

1.4. Etiology

1.5. Pathogenesis

Chapter 2. Clinical picture of multiple sclerosis

2.1. Retrobulbar neuritis

2.2. Oculomotor and pupillary disorders

2.3. Sensory disorders and pain syndromes.................................. 50

2.4. Movement disorders

2.5. Swallowing disorders

2.6. Dizziness

2.7. Pelvic disorders

2.8. Sexual dysfunction

2.9. Neuropsychiatric disorders

2.10. Fatigue

2.11. Paroxysmal disorders

2.12. Autonomic disorders

2.13. Disturbances in sleep, level of consciousness and wakefulness................................. 80 Chapter 3. Diagnosis of multiple sclerosis and research methods

3.1. Neuroimaging methods of examination

3.2. Evoked potentials of the brain and spinal cord.................................... 97

3.3. Laboratory diagnostics

3.4. Diagnostic criteria

Chapter 4. Clinical options and prognosis of the course of multiple sclerosis

Chapter 5. Differential diagnosis of multiple sclerosis.

5.1. Acute disseminated encephalomyelitis

5.2. Retrobulbar neuritis

5.3. Inflammatory and granulomatous diseases

5.4. Vasculitis

5.5. Hereditary and metabolic diseases of the central nervous system............ 132

5.6. Subacute combined degeneration of the spinal cord (funicular myelosis) and other deficiency conditions... 139

5.7. Central nervous system tumors

5.8. Arnold–Chiari malformation

5.9. Vertebrogenic cervical myelopathy

5.10. Psychogenic disorders

Chapter 6. Age-related features of the clinical picture and course of multiple sclerosis

6.1. Late onset of multiple sclerosis

6.2. Multiple sclerosis in children

PART II Chapter 7. Treatment of exacerbations of multiple sclerosis

7.1. Hormone therapy

7.2. Plasmapheresis

7.3. Immunoglobulin G

Chapter 8. Immunomodulatory therapy for multiple sclerosis.

First line drugs

8.1. Interferons beta

8.2. Glatiramer acetate (Copaxone)

8.3. Comparison of the effectiveness of interferon beta and glatiramer acetate

8.4. The influence of antibodies on the effectiveness of interferons beta and glatiramer acetate and switching to another drug.................................... 183

8.5. Dimethyl fumarate (tecfidera)

8.6. Teriflunomide (Abagio)

8.7. To whom, when and how should immunomodulatory therapy be prescribed and discontinued?

Chapter 9. Other immunomodulatory drugs and stem cell transplantation

9.1. Fingolimod (Gilenia)

9.2. Mitoxantrone (novantrone, oncotron)

9.3. Natalizumab (Antegren, Tysabri)

9.4. Immunoglobulin G

9.5. Stem cell transplant.

Chapter 10. Treatment of multiple sclerosis in the progression stage

Chapter 11. Symptomatic therapy of multiple sclerosis.

11.1. Retrobulbar neuritis

11.2. Nystagmus

11.4. Tremor

11.5. Spasticity

11.6. Pelvic disorders

11.7. Sexual dysfunction

11.8. Neuropsychiatric disorders

11.9. Fatigue

11.10. Paroxysmal disorders

11.11. Rehabilitation of patients with multiple sclerosis

Chapter 13. Possible ways to improve the effectiveness of treatment for multiple sclerosis

13.1. Combination therapy

13.2. New approaches to the treatment of multiple sclerosis.................................. 246 Chapter 14. Ethical and deontological problems of multiple sclerosis

Applications. The most commonly used rating scales.............. 260 Assessment of functional systems according to Kurtzke

Expanded Disability Status Scale according to Kurtzke (EDSS scale)

Assessment of neurological status using the SCRIPPS scale

Arm Function Assessment (Arm Index)

Fatigue Severity Scale (FSS) 267 MSNQ (Multiple Sclerosis Neuropsychological Questionnaire)

INTRODUCTION Multiple sclerosis (MS) is a fairly widespread dysimmune-neurodegenerative disease of the central nervous system, which mainly affects individuals young and almost inevitably leads at a certain stage of its development to disability.

This disease is chronic, in most cases progressive, unpredictable in course and currently incurable. In recent years, there has been an increase in the incidence of MS. This is due to both the improvement of diagnostic methods and the absolute increase in the number of cases.

The latter is associated with the growing urbanization of the population and the impact of various unfavorable environmental factors in industrialized areas.

The age range of this disease is also expanding:

The typical age at which MS begins is now considered to be between 10 and 59 years of age. The exclusion of a large number of able-bodied people from active life due to disability, high costs for diagnosis, treatment, rehabilitation and social assistance make the problem of MS socially and economically significant.

Between 1981 and 1992, at least 75–85% of MS patients were forced to stop working in the US, UK and Australia. MS-related costs in the UK each year amount to £1.2 billion, of which £150 million comes from direct medical care and £300 million from social care. In the USA, the average cost per patient per year is $39,500. These data are provided without taking into account expensive immunomodulatory therapy. It is estimated that around £400 million a year is required to treat patients with betaferon alone in the UK. The “cost” of MS is directly proportional to the degree of disability of patients.

Thus, in European countries, 18,000 euros per year are spent on a slightly disabled patient; for moderate disability – 36,500 euros, and for severe disability – 62,000 euros. At the same time, the costs of immunomodulatory therapy account for only 21%, and the remaining costs are associated with early retirement, reduction of working hours, psychological adaptation courses after informing the patient of the diagnosis, nursing care and other indirect costs. Unfortunately, we were unable to find similar data for Russia and the CIS countries.

The history of the study of MS goes back more than 100 years, and although significant progress has been made in recent years in understanding the disease and its treatment, many unresolved questions remain. To date, the understanding of the very essence of MS has changed as a disease that “affects the myelin sheaths of the conductors of the brain and spinal cord,” in which periods of exacerbations are replaced by periods of complete or almost complete clinical well-being. It is now known that already in the early stages of the disease there is damage to the axons themselves (and diffuse, and not only in the foci of demyelination), and therefore MS is currently considered not only as an autoimmune demyelinating disease, but also as a neurodegenerative one. However, the relationship between inflammation and neurodegeneration remains largely unclear. It has been reliably shown that even in the phase of complete clinical remission, the activity of the disease remains, which is confirmed by the appearance of new foci of demyelination (according to magnetic resonance imaging), damage to the axons of the central conducting systems and ongoing disorders in the immune system. Thus, MS is not a “remitting” disease in the full sense of the word.

Until recently, the timing of establishing the correct diagnosis of MS in the development of neurological symptoms was not particularly important, since the doctor could not influence the development of the disease to any extent.

Treatment of patients consisted only of stopping exacerbations and providing symptomatic therapy. In recent years, the situation has changed radically due to the advent of so-called preventive, or immunomodulatory, therapy. These drugs, although not able to cure the patient, significantly change the course of MS in many patients, preventing the development of exacerbations and slowing down the development of disability. The activity of research devoted to the morphology, etiology and pathogenesis of MS, and, as a consequence, the development of new therapeutic approaches to its treatment, gives reason to believe that in the not too distant future it will be possible to find methods for secondary clinical prevention and pathogenetic radical treatment of MS.

3.1. Neuroimaging methods of examination 87 The most common method of neuroimaging in MS is MRI in T2 mode.

Foci of demyelination, defined as hyperintense in T2 mode, are found in 95% of cases of definite MS. If MRI reveals the presence of lesions in patients with “probable MS” (in the case of a clinically isolated syndrome), then in 65% of cases they are predictors of the development of definite MS within 5 years. The size of lesions typical for MS is usually 3 mm or more. These foci can be ob- Fig. 4. MRI of the cerebellum.

appear periventricularly, in the callus - On MRI in T2-mode, the stoma is visible (with the characteristic shape of areas of increased signal spreading from it into the white matter - in the cerebellar hemispheres.

artery - “Dawson's fingers”), in the brain stem, cerebellum (Fig. 4), spinal cord (Fig. 5) and in the optic nerves. The detection of hyperintense foci in several zones of the central nervous system in T2 mode reflects the “dispersion of the process in space” (see Fig. 6, 7). Most a b Fig. 5. MRI of the spinal cord.

Sagittal tomograms in T2 mode reveal multiple confluent areas of increased signal in the substance of the spinal cord at the cervical, thoracic and upper lumbar levels (arrows). The diameter of the spinal cord is reduced (atrophy).

3.1. Neuroimaging methods of examination 89

–  –  –

7.1. Hormonal therapy When analyzing exacerbations of MS, 3 parameters are assessed: their frequency, duration, and severity clinical symptoms and instrumental characteristics. Methylprednisolone is the most widely used drug for relieving exacerbations of MS. It has a diverse effect on the immune system: it slows down the activation and proliferation of T-lymphocytes, participates in their apoptosis in both peripheral blood and brain parenchyma, reduces the formation of antibodies, but its most important effect in MS is a decrease in the permeability of the BBB. It is achieved by affecting adhesion molecules and reducing the level of matrix metalloproteases. As is known, disruption of the BBB due to inflammatory changes in the central nervous system is one of the first stages in the formation of new foci of demyelination. Relative stabilization of the BBB persists for several weeks after treatment with corticosteroids.

In recent years, the use of methylprednisolone has become the “gold standard” for the treatment of exacerbations of MS. Methylprednisolone is a synthetic glucocorticoid that is structurally different from cortisol. This difference increases the glucocorticoid effect, reduces the mineralocorticoid effect and increases the duration of action of the drug. During pulse therapy, most of the methylprednisolone remains in the serum in a free state. Only in this unbound form can the drug penetrate the BBB and into the cell, interacting with specific intracellular glucocorticoid receptors. Most exacerbations coincide in time with the formation of new active lesions on MRI in the brain and spinal cord, which indicates a new wave of inflammation. The use of high doses of corticosteroids accelerates their disappearance. Currently, according to the standards for the treatment of MS adopted by the EFNS (European Federation of Neurological Societies), the method of relieving exacerbations of MS is corticosteroid intravenous pulse therapy: 1–2 g of methylprednisolone is administered with 500 ml for 3–7 days saline sodium chloride solution for 1–2 hours without subsequent administration of oral prednisolone. However, since the effect of corticosteroids and hormonal therapy is short-lived, after cessation of hormonal therapy, a new outbreak of disease activity may be observed, accompanied by changes in MRI. This may be related to the rate of hormone withdrawal, so some authors still recommend subsequent oral prednisone with different dosing regimens.

For example, 4 days - 200 mg, 4 days - 100 mg, 2 days - 50 mg and then, reducing the dose every day by 10 mg or 2 days - 80 mg, 2 days - 60 mg, 2 days - 40 mg followed by a daily dose reduction of 5–10 mg.

This treatment is usually well tolerated. Prednisolone is always prescribed at once, for use in the first half of the day. Another scheme for intravenous administration of methylprednisolone has been proposed - 1000 mg of methylprednisolone is administered for 3 days, and then over the next 20 days the dose of the drug is gradually reduced to 40 mg on the last day of infusions. It is believed that this regimen of methylprednisolone administration provides a better clinical effect and increases the time to the next exacerbation more than the standard treatment regimen described above. A small number of studies have shown equal effectiveness when intravenous and oral corticosteroids are used at equally high doses.

At the same time, oral administration of high doses of corticosteroids causes complications from the gastrointestinal tract no more often than their intravenous administration. This suggests that gastrointestinal complications are not due to the direct effect of corticosteroids on the gastric mucosa, but rather to secondary systemic mechanisms that are independent of the route of administration. Since oral administration is simpler and cheaper, it can be recommended in cases where intravenous administration is for some reason difficult.

If after 2 weeks. after the end of intravenous administration of the hormone there is no desired improvement, repeated pulse therapy at a higher dose is possible: 5 injections of 2 g of methylprednisolone. If there is no effect, plasmapheresis should be performed. In the case where symptoms continue to increase during pulse therapy, plasmapheresis should be started immediately after the end of pulse therapy.

Exacerbations of MS in children are also stopped by the administration of corticosteroid pulse therapy - methylprednisolone at a dose of 20 mg/kg.

There is no specific time frame for starting pulse therapy after the onset of an exacerbation. There is evidence that its greatest effectiveness can be achieved by prescribing corticosteroids as early as possible after the onset of an exacerbation. However, in practice this is not always possible, but even in cases of delayed use of hormones, their effectiveness in the vast majority of patients is undoubted.

Contraindications for corticosteroid therapy are a significant increase in blood pressure, diabetes with high blood glucose levels, pulmonary tuberculosis, the presence of any other infectious process, erosive gastritis or gastric ulcer. In this regard, all patients, before prescribing 160 Chapter 7. Treatment of exacerbations of multiple sclerosis, hormonal therapy, need to conduct a blood glucose level test, lung radiography and gastroscopy.

The most common side effects of pulse therapy are insomnia and mild euphoria, anxiety, metallic taste in the mouth during infusion, increased appetite, nausea, headaches, myalgia, and hiccups. Less common are more serious complications of hormonal therapy - the development of psychosis, cardiac arrhythmias, hyperglycemia.

They require quick correction, and such treatment must be carried out in a hospital setting. To prevent the ulcerogenic effect of corticosteroids, H2-histamine receptor blockers - ranitidine, cimetidine, pirenzepine (gastrozepin) - should be prescribed simultaneously with them. To replenish the loss of potassium and calcium, asparkam (1 tablet 3 times a day after meals), panangin (1 tablet 3 times a day after meals) are prescribed, and bananas are recommended for consumption. In addition, it is necessary to limit fluid intake and use potassium-sparing diuretics - spironolactone (veroshpiron). Sometimes, after discontinuation of corticosteroids, the condition worsens, in these cases it is necessary to reintroduce 20-40 mg of prednisolone orally per day and then reduce its dose at a slower pace. Frequent use of pulse therapy can be complicated by osteoporosis, osteonecrosis, fatty liver degeneration, and the appearance of Cushingoid signs.

The use of hormones in the form of pulse therapy gives more fast recovery, and in the case of a monosymptomatic debut of the disease, it increases the time before the formation of reliable MS (as shown for retrobulbar neuritis). Long-term use of small doses of steroids is not indicated, since various side effects are very likely to occur (osteoporosis, aseptic bone necrosis, arterial hypertension, hyperglycemia, cataracts, psychosis) in the absence of the effectiveness of this treatment method. Intravenous administration of hormones allows for higher doses and is better tolerated. Short-term oral use of fairly high doses of prednisolone (1–1.5 mg/kg) gives good short-term results, but leads to greater disease activity over the next 2 years.

A slightly different scheme for the use of hormones is also proposed for patients with high disease activity with or without exacerbations (the appearance of 3 new lesions on MRI within 6 months): monthly single intravenous administration of 500 mg of methylprednisolone followed by oral administration of prednisolone for 3 days - according to 40, 20 and 10 mg respectively.

Hormonal pulse therapy not only stops exacerbations of MS, but also slows the progression of both RRMS and SPMS. For the treatment of SPMS, it is possible to carry out it every 2 months - 500 mg for 3 days. Pulse therapy for chronic MS is also indicated because this mode of hormone administration reduces spasticity.

Chapter 14. ETHICAL

AND DEONTOLOGICAL

PROBLEMS OF ABSOLUTELY

Work in this direction should begin from the stage of the first meetings with the patient. The doctor often sees his role only as a specialist in diagnosis and treatment, which is only part of his job. Even before establishing an accurate diagnosis, it is necessary to achieve complete mutual understanding with the patient. It is now believed that a patient should be informed of the possibility of an MS diagnosis unless there is a specific reason to hide it.

In all other cases, it is probably better to tell the patient that his diagnosis is still unclear, and therefore he should be under the supervision of a neurologist, receiving symptomatic therapy if necessary. The possibility of a diagnosis of MS should be reported before further testing is undertaken to confirm it. The patient should receive complete information about the disease and existing treatment methods, including all immunomodulatory drugs. The results of a survey of patients show that 90% of them would like the diagnosis to be communicated to them immediately. Moreover, 97% of patients prefer that the diagnosis be communicated to them by a doctor, and 3% by relatives. However, approximately 30% of patients are not diagnosed until 1–3 years later, and 30% even later. This delay in reporting a diagnosis significantly reduces trust in the doctor. However, it should be remembered that communicating the established diagnosis to the patient means for him the beginning of a new life, in which all its aspects will change - physical, mental, social. The doctor must listen carefully to the patient and allow him to ask a variety of questions.

As a rule, nowadays patients are quite well informed about their illness, and they have more respect for a doctor who can openly discuss with them all issues related to diagnosis and treatment.

Chapter 14. Ethical and deontological problems of multiple sclerosis 255 One of the most difficult tasks is to make a timely diagnosis of MS.

Establishing a correct diagnosis can be very difficult, and other curable diseases must be excluded at an early stage. It is important to remember that at the onset of the disease, its manifestations can only be subjective and can easily be classified as “neurotic” or “hypochondriacal.” This attitude naturally worsens the patient’s contact with the doctor, which makes correct diagnosis even more difficult.

The main question is not whether or not to tell the patient about his diagnosis, but how to talk about it. Many patients, talking about how they learned about their disease, note that they were told the diagnosis too late and without relevant information about the disease. Often they accidentally learn about their diagnosis from a conversation between doctors or by looking at their medical history. How the doctor communicates the diagnosis and how he listens to the patient determines the patient’s subsequent psychological adaptation. Even when MS is suspected, patients experience significant emotional stress. Patients' perceptions of diagnosis are well illustrated in an article published in 1977.

Psychiatrist Alexander Barnfield, who himself has MS. He described his own experience, which is typical for the vast majority of MS patients. His emotional reaction to the long process of establishing an accurate diagnosis was very vivid; he felt the need for answers to many questions. After the diagnosis was made, he first experienced shock and fear, then anger at the injustice of fate, and only later did emotional recovery and “acceptance” of the diagnosis occur.

It is possible to delay reporting the diagnosis only in certain cases: if the patient is under 20 years of age; with severe emotional lability or decreased intelligence; in the absence of support from others; if relatives want to inform the patient of the diagnosis themselves.

Patients prefer that the diagnosis be communicated to them in the absence of other patients, in the presence of a spouse or other family members. The diagnosis must be communicated in the most friendly manner possible, always with encouragement and hope for a benign course of the disease and possible new prospects for treatment. The diagnosis is better accepted by patients if the doctor calls it multiple sclerosis rather than demyelinating disease or inflammation of the spinal cord. It should be explained that although there is no cure for MS yet, in the natural course of the disease the body copes with most attacks on its own. The most difficult time is the first 6–12 months after diagnosis, when the patient “listens” to various “little things” that are not related to the disease, which is important to explain to the patient. Still, communicating a diagnosis is a significant stressor for patients. They fear the physical, emotional and social consequences of the disease, and most need to be prescribed anxiolytics or antidepressants for a certain period.

Sometimes both reporting a diagnosis and hiding it can lead to complications both for the patient and (legally) for the doctor. Assessment of neurological status using the SCRIPPS 265 scale is described

–  –  –

The patient's score on the SCRIPPS scale The score in the special category is subtracted from the sum of all points, all other points on the systems are added up.

266 Applications. Most used rating scales

–  –  –

1 = minimal symptoms in one or both arms that do not interfere with the listed functions;

2 = moderate symptoms in one or both arms, making it difficult to perform the listed functions (although possible);

3 = severe symptoms in one or both arms, making it impossible to perform at least one of the listed functions;

4 = severe symptoms in both hands, making it impossible to perform all of the listed functions, although minimal movements aimed at performing them are possible;

5 = severe symptoms in both arms, even minimal directed movements are impossible;

x = movement difficulties are not due to MS, but to other reasons.

MSNQ (Multiple Sclerosis Neuropsychological Questionnaire - Neuropsychological Questionnaire for Patients with Multiple Sclerosis) 1. For the patient

Date of:

Gender: M/F (circle as appropriate) Instructions Below are questions that address issues you may be facing. Indicate how often such difficulties occur and to what extent they are expressed. The assessment is carried out for a period including the last 3 months.

Place a check in the appropriate cell in the table.

–  –  –

What are you reading about?

6. Do you have difficulty talking about programs you recently watched on television?

7. Do you need to repeatedly explain the essence of the tasks to be completed?

8. Do you have to be reminded about planned tasks?

9. Do you forget about errands that you planned to complete?

10. Do you have difficulty answering questions?

11. Is it difficult for you to do 2 things at the same time?

MSNQ (Multiple Sclerosis Neuropsychological Questionnaire…

12. Do you lose the meaning of what someone is trying to convey to you in verbal form? Ministry of Education and Science of the Perm Territory Department of Education of Perm Federal State Budgetary Educational Institution of Higher Professional Education "Perm State National Research University" Organizing Committee of Regional Subject Olympiads for Schoolchildren Subject Methodological Commission of Perm regional stage of the All-Russian Olympiad for schoolchildren in ..."

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Tasks and answers for the final stage, grades 8-9. Task 1. Arrange the plants in ascending order of flower diameter A. Wolfia rootless B. Rafflesia arnoldii C. Rosehip D. Common lilac...”

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MULTIPLE SCLEROSIS
guide for doctors

Binding

Standard 10 copies.

Format: 140×90/16 (140×210 mm)

In the 2nd edition of the book, the authors tried to highlight the current state of the problem of multiple sclerosis. Additions and changes have been made to almost all sections, but the most significant changes have been made to the chapters that address the pathogenesis of multiple sclerosis. Emotional, affective and cognitive disorders are presented in more detail. The section devoted to the clinical picture of acute disseminated encephalomyelitis has been significantly expanded. A variety of new approaches to treatment are considered, some of which are already being introduced into everyday practice. This publication includes a chapter devoted to multiple sclerosis in children and its differential diagnosis.

The book is intended for practicing neurologists.

NEUROLOGY OF PREMATURE BABIES

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This manual reflects the authors' long-term research in the field of neurology of premature infants, and also summarizes the achievements of various neurological and neonatological schools in this area. The issues of epidemiology, etiology, mechanisms of development and nature of lesions of the nervous system in premature infants are considered, taking into account the specific features of the formation of these lesions at different stages of ontogenesis of the nervous system in a prematurely born infant. Considerable attention is paid to the clinical manifestation of brain lesions in premature infants, modern methods their diagnostics. A prominent place is occupied by the description of the patterns of further development of premature infants depending on the nature and severity of brain damage. Treatment is presented in accordance with modern requirements of evidence-based medicine.

For neonatologists, neurologists, pediatricians, general practitioners, medical students.

SPIRAL AND MULTILAYER COMPUTED TOMOGRAPHY. Volume I
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SPIRAL AND MULTILAYER COMPUTED TOMOGRAPHY. Volume II
Tutorial

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The rapid development of computed tomography (CT) technology, including the introduction of helical scanning, requires novice radiologists to study its methods, and specialists in this field to master new possibilities for its use in various diseases. These challenges can be addressed in this widely acclaimed Guide to Helical and Multislice CT, which provides detailed CT anatomy necessary for proper diagnostic image evaluation and highlights new or improved CT applications such as cardiac CT and CT angiography.

For radiologists involved in CT diagnostics, as well as for residents, interns and medical students interested in the problems of modern CT.
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MUSCLE TENSION
From diagnosis to treatment

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This clinical manual describes techniques for functional diagnosis through palpation and manual treatment of muscle contractures and myofascial pain syndromes from the standpoint of the anatomy and physiology of individual muscles and muscle groups.

The guide is intended for neurologists, orthopedists, sports doctors, physical therapy doctors, physical and manual therapists.

T.E.Schmidt, N.N.Yakhno MULTIPLE SCLEROSIS GUIDE FOR DOCTORS 2nd edition Moscow “MEDpress-inform” 2010 UDC 616.832-004.2 BBK 56.12 Sh73 All rights reserved. No part of this book may be reproduced in any form or by any means without the written permission of the copyright holders. The authors and the publisher have made every effort to ensure the accuracy of the indications, adverse reactions, and recommended dosages of medications given in this book. However, this information is subject to change. Carefully study the manufacturer's accompanying instructions for the use of medicines. Sh73 Schmidt T.E. Multiple sclerosis: a guide for doctors / T.E. Schmidt, N.N. Yakhno. - 2nd ed. - M.: MEDpress-inform, 2010. - 272 p. : ill. ISBN 5-98322-632-1 In the 2nd edition of the book, the authors tried to highlight the state of the problem of multiple sclerosis at the present stage. Additions and changes have been made to almost all sections, but the most significant changes have been made to the chapters that address the pathogenesis of multiple sclerosis. Emotional, affective and cognitive disorders are presented in more detail. The section devoted to the clinical picture of acute disseminated encephalomyelitis has been significantly expanded. A variety of new approaches to treatment are considered, some of which are already being introduced into everyday practice. This publication includes a chapter devoted to multiple sclerosis in children and its differential diagnosis. The book is intended for practicing neurologists. UDC 616.832-004.2 BBK 56.12 ISBN 5-98322-632-1 Schmidt T.E., Yakhno N.N., 2010 Design, original layout. Publishing house "MEDpress-inform", 2010 CONTENTS List of abbreviations.................................................... ............................................... 6 Preface to the 2nd publication........................................................ ................ 8 Introduction.................................. ........................................................ ....................... 9 PART I Chapter 1. Epidemiology, clinical forms, pathomorphology, etiology and pathogenesis of multiple sclerosis.......... ........................ 1.1. Epidemiology................................................. ............................... 1.2. Clinical forms......................................................... ........................... 1.3. Pathomorphology........................................................ ........................ 1.4. Etiology................................................. .................................... 1.5. Pathogenesis. ........................................................ .................................... 13 13 15 19 20 24 Chapter 2. Clinical picture of multiple sclerosis ....................... 2.1. Retrobulbar neuritis................................................... ............... 2.2. Oculomotor and pupillary disorders................................................. 2.3. Sensitivity disorders and pain syndromes.................................. 2.4. Movement disorders................................................................... .............. 2.5. Swallowing disorders................................................... .................... 2.6. Dizziness................................................. ........................ 2.7. Pelvic disorders........................................................ .................... 2.8. Sexual dysfunction.................................................................. ........ 2.9. Neuropsychiatric disorders................................................................. 2.10. Fatigue......................................................... ........................... 2.11. Paroxysmal disorders................................................................ 2.12. Vegetative disorders................................................................ ............ 2.13. Disturbances in sleep, level of consciousness and wakefulness................................. 43 44 47 50 54 57 58 58 61 61 75 78 79 80 Chapter 3. Diagnosis of multiple sclerosis and research methods.. ........................................................ ........................................... 85 3.1. Neuroimaging methods of examination.................................... 86 3.2. Evoked potentials of the brain and spinal cord.................................. 97 3.3. Laboratory diagnostics................................................... ............ 99 3.4. Diagnostic criteria......................................................... .......... 101 Chapter 4. Clinical options and prognosis of the course of multiple sclerosis................................. ........................................................ .. 107 Chapter 5. Differential diagnosis of multiple sclerosis........... 112 5.1. Acute disseminated encephalomyelitis (ADEM) ..................................... 112 5.2. Retrobulbar neuritis................................................... ............... 116 4 Contents 5.3. Inflammatory and granulomatous diseases.................................... 119 5.4. Vasculitis......................................................... .................................... 128 5.5. Hereditary and metabolic diseases of the central nervous system. ............. 132 5.6. Subacute combined degeneration of the spinal cord (funicular myelosis) and other deficiency conditions.............. 139 5.7. Tumors of the central nervous system................................................... ................................... 141 5.8. Arnold-Chiari malformation.................................................... ... 142 5.9. Vertebrogenic cervical myelopathy.................................................... 142 5.10. Psychogenic disorders................................................................ ......... 143 Chapter 6. Age-related features of the clinical picture and course of multiple sclerosis.................................. ................................ 146 6.1. Late onset of multiple sclerosis.................................................... 146 6.2. Multiple sclerosis in children.................................................. .......... 147 PART II Chapter 7. Treatment of exacerbations of multiple sclerosis................................... 159 7.1 . Hormonal therapy................................................... ................... 159 7.2. Plasmapheresis......................................................... ......................................... 162 7.3. Immunoglobulin G ................................................... ........................ 163 Chapter 8. Immunomodulatory therapy for multiple sclerosis. First line drugs............................................................. ........................... 165 8.1. Interferons beta................................................... ........................... 165 8.2. Glatiramer acetate (Copaxone) .................................................. ........ 173 8.3. Comparison of the effectiveness of first-line drugs.................. 179 8.4. The influence of antibodies on the effectiveness of preventive therapy and switching to another drug.................................................... ....................... 182 8.5. To whom, when and how should immunomodulatory therapy be prescribed and discontinued? ........................................................ ..... 188 Chapter 9. Other immunomodulatory drugs and stem cell transplantation.................................................... ........................................................ .. 199 9.1. Mitoxantrone (Novantron, Oncotron) ............................................... 199 9.2. Natalizumab (Antegren, Tysabri) .................................................... .... 200 9.3. Immunoglobulin G ................................................... ........................ 202 9.4. Stem cell transplant................................................................... ......... 203 Chapter 10. Treatment of multiple sclerosis in the progression stage.................................................... ........................................... 207 Chapter 11. Symptomatic treatment of multiple sclerosis .......... 213 11.1. Retrobulbar neuritis................................................... ............. 213 11.2. Nystagmus......................................................... ........................................ 214 11.3. Pain................................................. ............................................... 214 11.4. Tremor................................................. ........................................... 215 11.5. Spasticity......................................................... ........................... 216 Contents 5 11.6. Pelvic disorders........................................................ ..................... 219 11.7. Sexual dysfunction.................................................................. ...... 221 11.8. Neuropsychiatric disorders................................................... 222 11.9 . Fatigue......................................................... ........................... 225 11.10. Paroxysmal disorders............................................................. 230 11.11. Rehabilitation of patients with multiple sclerosis.................................... 230 11.12. Recommended long-term management regimens for patients with MS..... 231 Chapter 12. Multiple sclerosis and pregnancy................................... ..... 234 Chapter 13. Possible ways to improve the effectiveness of treatment for multiple sclerosis.................................... ........................................................ 238 13.1. Combination therapy......................................................... .......... 238 13.2. New approaches to the treatment of multiple sclerosis.................................. 241 Chapter 14. Ethical and deontological problems of multiple sclerosis.......................... ........................................................ ....................................... 250 Applications. The most commonly used rating scales......................... 256 Assessment of functional systems according to Kurtzke.................................... .......... 256 Expanded Disability Status Scale according to Kurtzke (EDSS - Expanded Disability Status Scale) ........................... ..................................... 259 Assessment of neurological status using the SCRIPPS scale .......... ............ 261 Assessment of hand function (Arm Index) .............................. ........................... 262 Fatigue Severity Scale (FSS) . .......... 263 MSNQ (Multiple Sclerosis Neuropsychological Questionnaire - Neuropsychological Questionnaire for Patients with Multiple Sclerosis) ....................... ........................................................ ..................... 264 LIST OF ABBREVIATIONS AG ACTH APK AT IVIG VP VPRS GABA GHC GCG GEB IL CIS CT ​​MAG MAO ME MMP MNTF MOG MRI NAT NT-3 OAT MBP ODC OM OREM PLP PML pRS PPRS PPRSO - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - PET RBN RRS RS SKV TVP TKR TM - - - - - - - - antigen adrenocorticotropic hormone antigen-presenting cells antibodies intravenously administered immunoglobulin evoked potentials secondary progressive multiple sclerosis gamma-aminobutyric acid hyperhomocysteinemia major histocompatibility complex blood-brain barrier interleukins clinically isolated syndrome computed tomography myelin-associated glycoprotein monoamine oxidase international units matrix metalloproteases brain neurotrophic factor myelin oligodendrocyte glycoprotein magnetic resonance imaging neutralizing antibodies neurotrophin-3 oligoclonal antibodies myelin basic protein oligodendrocytes opticomyelitis acute multiple encephalomyelitis proteolipid protein progressive multifocal leukoencephalopathy pediatric multiple sclerosis primary progressive multiple sclerosis primary progressive multiple sclerosis with exacerbations positron emission tomography retrobulbar neuritis relapsing-remitting disseminated sclerosis multiple sclerosis systemic lupus erythematosus trigeminal evoked potentials T-cell receptor transfer magnetization (magnetization transfer) PREFACE to the 2nd edition The study of multiple sclerosis - an organic disease of the central nervous system - today is perhaps one of the most dynamically developing areas of clinical neurology and related neurosciences . In recent years, data have been obtained that have made it possible to explain the mechanisms of axonal and neuronal degeneration in multiple sclerosis, and the hypothesis of the dual role of inflammation in this disease has been substantiated. Multiple sclerosis in children and rarer forms of demyelinating diseases: acute disseminated encephalomyelitis, Devic's opticomyelitis, are attracting increasing attention. Pharmacotherapy for multiple sclerosis is developing and improving at a very rapid pace, based on a deeper understanding of the mechanisms of its development. Attempts are being made to influence various parts of the pathogenesis of multiple sclerosis. In the 2nd edition of our book, designed, as before, primarily for practicing physicians, we tried to highlight the state of the problem of multiple sclerosis at the present stage. We have made additions and changes to almost all sections, but the most significant changes have been made to the chapters that address the pathogenesis of multiple sclerosis, in particular, the relationship between inflammation and degeneration, disruption of humoral immune mechanisms and remyelination mechanisms. Emotional, affective and cognitive impairments in multiple sclerosis are presented in more detail. The section devoted to the clinical picture of acute disseminated encephalomyelitis has been significantly expanded. A variety of new approaches to treatment are considered, some of which are already being introduced into everyday practice. The results of the most significant international studies of recent years are presented. In this publication we also included a chapter devoted to multiple sclerosis in children and its differential diagnosis. The number of illustrations has been increased - the authors express gratitude to the staff of the Department of Neuroradiology of the Research Institute of Neurosurgery of the Russian Academy of Medical Sciences. N. N. Burdenko - Academician of the Russian Academy of Medical Sciences, Doctor of Medical Sciences V.N. Kornienko, Doctor of Medical Sciences, Prof. I.N. Pronin, Ph.D. S.V. Serkov - and the head of the department of radiology diagnostics of the clinic of nervous diseases of the Moscow Medical Academy named after. I. M. Sechenova Ph.D. E. V. Shashkova for providing magnetic resonance tomograms, as well as Doctor of Medical Sciences. G. G. Toropina for illustrating changes in evoked potentials in multiple sclerosis. INTRODUCTION Multiple sclerosis (MS) is a fairly widespread dysimmune-neurodegenerative disease of the central nervous system, which mainly affects young people and almost inevitably leads to disability at a certain stage of its development. This disease is chronic, in most cases progressive, unpredictable in course and currently incurable. In recent years, there has been an increase in the incidence of MS. This is due to both the improvement of diagnostic methods and the absolute increase in the number of cases. The latter is associated with the growing urbanization of the population and the impact of various unfavorable environmental factors in industrialized areas. The age range of this disease is also expanding: the typical age at which MS debuts is now considered to be between 10 and 59 years of age. The exclusion of a large number of able-bodied people from active life due to disability, high costs for diagnosis, treatment, rehabilitation and social assistance make the problem of MS socially and economically significant. In the period from 1981 to 1992 in the USA, Great Britain and Australia, at least 75-85% of MS patients were forced to stop working. MS-related costs in the UK each year amount to £1.2 billion, of which £150 million is in direct health care and £300 million in social care. In the USA, the average cost per patient per year is $39,500. These data are provided without taking into account expensive immunomodulatory therapy. It is estimated that around £400 million a year is required to treat patients with betaferon alone in the UK. The “cost” of MS is directly proportional to the degree of disability of patients. Thus, in European countries, 18,000 euros per year are spent on a slightly disabled patient; for moderate disability - 36,500 euros, and for severe disability - 62,000 euros. At the same time, the costs of immunomodulatory therapy account for only 21%, and the remaining costs are associated with early retirement, reduction of working hours, psychological adaptation courses after informing the patient of the diagnosis, nursing care and other indirect costs. Unfortunately, we were unable to find similar data for Russia and the CIS countries. The history of the study of MS goes back more than 100 years, and although significant progress has been made in recent years in understanding the disease and its treatment, many unresolved questions remain. To date, the understanding of the very essence of MS has changed as a disease that “affects the myelin sheaths of the conductors of the brain and spinal cord,” in which periods of exacerbations are replaced by periods of complete or almost complete clinical well-being. It is now known that already in the early stages of the disease there is damage to the axons (and diffuse, and not only in the foci of demyelination), and therefore MS is currently considered not only as an autoimmune demyelinating disease, but also as neurodegenerative. However, the relationship between inflammation and neurodegeneration remains largely unclear. It has been reliably shown that even in the phase of complete clinical remission, the activity of the disease remains, which is confirmed by the appearance of new foci of demyelination (according to magnetic resonance imaging), damage to the axons of the central conducting systems and ongoing disorders in the immune system. Thus, MS is not a “remitting” disease in the full sense of the word. Until recently, the timing of establishing the correct diagnosis of MS in the development of neurological symptoms was not particularly important, since the doctor could not influence the development of the disease to any extent. Treatment of patients consisted only of stopping exacerbations and providing symptomatic therapy. In recent years, the situation has changed radically due to the advent of so-called preventive, or immunomodulatory, therapy. These drugs, although not able to cure the patient, significantly change the course of MS in many patients, preventing the development of exacerbations and slowing down the development of disability. The activity of research devoted to the morphology, etiology and pathogenesis of MS, and, as a consequence, the development of new therapeutic approaches to its treatment, gives reason to believe that in the not too distant future it will be possible to find methods for secondary clinical prevention and pathogenetic radical treatment of MS. Part I Chapter 1. EPIDEMIOLOGY, CLINICAL FORMS, PATHOMORPHOLOGY, ETIOLOGY AND PATHOGENESIS OF MULTIPLE SCLEROSIS 1.1. Epidemiology Multiple sclerosis is the most common, after traumatic brain injury, organic disease of the central nervous system among young people. MS prevalence rates in the world in Lately tend to increase. This is due to the standard use of modern neuroimaging research methods, which make it possible to diagnose MS with great accuracy, as well as to the increase in life expectancy of patients due to improved treatment, rehabilitation and social assistance . In addition, there is a noticeable increase in the occurrence of new cases, i.e. There is a real increase in the incidence of MS. According to some data, over the past 70 years it has increased 5 times, and if previously areas with a high prevalence of MS were considered to be areas with a number of patients of 30 or more per 100 thousand population, today this figure is 50 or more per 100 thousand. Epidemiological MS research is significantly complicated by the fact that the time of the first manifestations of the disease is often significantly distant from the time of its diagnosis. This makes it difficult to interpret data obtained over a certain period of time. In addition, different epidemiological studies use different diagnostic criteria. What is undoubted, however, is the fact that all specialists involved in the epidemiology of MS note a significant increase in the number of such patients. The prevalence of MS is highly dependent on geographic zones: it is lowest in the equator and increases with distance from it to the north and south. Thus, in Northern Europe, Italy, the USA, Australia and New Zealand it is high and amounts to more than 50 per 100 thousand population; in Southern Europe, the Mediterranean, North Africa - on average 10-49 per 100 thousand, and in other African countries, Mexico, Caribbean countries 14 Chapter 1. Epidemiology, clinical forms, pathomorphology, etiology and pathogenesis... basin low - less than 10 per 100 thousand. According to 2007 data, in the countries of the European Community there are 400-450 thousand patients with MS, i.e. 1 person in a thousand suffers from this disease. MS is least common in Africa among black Africans (only isolated cases have been reported). MS is also rare in Asia, where it is represented by a special form with predominant damage to the optic nerves and spinal cord - transverse myelitis. Because the disease was thought to occur most frequently in people with white skin, renowned MS researcher J. F. Kurtzke characterized MS as a “disease of the white race.” Recently, however, MS has been increasingly described among people of other races, although African Americans with MS have some clinical features and respond less well to immunomodulatory therapy than whites. These features are most likely genetically determined. Currently, according to various estimates, there are about 3 million people with MS in the world. Of these, about 450 thousand are in Europe, over 350 thousand in the USA. Thus, the prevalence of MS in general is probably 1:1000 of the population. Based on this indicator, there may be about 150 thousand people with MS in Russia. The prevalence of this disease is especially high in the northern, northwestern and western regions of Russia, where it varies from 30 to 70 cases per 100 thousand population. Moreover, about 5 thousand new cases of the disease are registered every year. Women suffer from MS one and a half to two times more often than men. The predominance of women is especially high in the group of familial cases and among young patients. Since MS, as previously thought, is very rarely the direct cause of death in patients, mortality rates for this disease have not been well studied. However, according to the Dutch registry of MS patients, more than half of them (56.4%) die directly from MS (with the localization of massive foci of demyelination in the brain stem, leading to swallowing and breathing disorders) and complications associated with MS (urinary tract infections and , as a consequence of this, renal failure, pneumonia and sepsis in the case of bedsores in immobilized patients). However, according to the World Health Organization, the mortality rate of people with MS in Western Europe has decreased by 30% over the past 30 years, while in Northern and Eastern Europe it has remained the same. This difference is probably explained by the different level of medical and social care for patients. An analysis of life expectancy in MS shows that in 1/3 of cases the duration of the disease from the time of its onset to death exceeds 30 years, and in general, MS patients live 10 years less than their peers. Life expectancy is shortened the most in patients with MS onset after age 50. But in general, the disease has little effect on this 1.2. Clinical forms 15 indicator: in patients with MS it is 78±0.31 years, and in the population - 81±0.91 years. The causes of death in MS depend on the period of the disease: in its early stages, the main cause of death is suicide (the suicide risk in MS is 37% higher than that in the population), in the later stages of MS - its complications mentioned above, cardiovascular and concomitant diseases. 1.2. Clinical forms Currently, the traditional identification of clinical forms of MS (optic, cerebrospinal, cerebellar, etc.) based on the leading manifestations of the disease is not accepted, since data from neuroimaging and electrophysiological research methods indicate damage to various parts of the central nervous system in any of these forms . Clinical forms of MS are distinguished based on the type of disease: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and primary progressive MS with exacerbations (PPMS) (see. rice. 1). The main indicators of the course of the disease are the presence and frequency of clinically detectable exacerbations and the rate of increase in neurological deficit. An exacerbation is considered to be the appearance of new neurological symptoms that are detected during a clinical examination and persist for at least 24 hours. Exacerbations should be distinguished from “pseudo-exacerbations.” “Pseudo-exacerbation” is the appearance of a new clinical symptom or aggravation of an existing one, which can develop against the background of a concomitant disease or, for example, with an increase in body temperature and passes with the normalization of the general condition. This determines the importance of a detailed clinical analysis of the dynamics of the patient’s condition when considering the effectiveness of ongoing immunomodulatory therapy and a possible transition to another drug. RMS is characterized by episodic exacerbations with complete or incomplete clinical recovery and a phase of stabilization of the patient’s clinical condition between exacerbations. In 75-85% of cases, the disease initially develops this way. Clinical remissions do not mean attenuation of the pathological process, which continues even in the absence of clinical manifestations. This is convincingly evidenced by data from neuroimaging research methods, which reveal an increase in the size of existing or the appearance of new lesions and the accumulation of contrast in some of them. As a rule, over time, remissions become less complete and shorter, and in most patients the disease enters the stage of secondary progression. SPMS is characterized by a gradual increase in neurological disorders in patients who previously had RRMS. SPMS can occur 16 Chapter 1. Epidemiology, clinical forms, pathomorphology, etiology and pathogenesis... Relapsing-remitting multiple sclerosis A - isolated exacerbations with complete clinical remissions B - exacerbations with incomplete clinical remissions, but there is no increase in symptoms between them Secondary progressive multiple sclerosis A - exacerbations persist, and between them the symptoms continue to increase B - there are no exacerbations, only temporary stabilization of the condition is possible Primary progressive multiple sclerosis A - symptoms have been steadily increasing since the onset of the disease B - periods of stabilization of the condition or even slight improvement are possible Primary progressive multiple sclerosis with exacerbations After the first attack, exacerbations are repeated, but the symptoms progress steadily from the very beginning Fig. 1. Variants of the course of multiple sclerosis. 8.4. The influence of antibodies on the effectiveness of preventive therapy and switching to another drug 187 Reliable MS Assignment of BMI No effect (over 1 year): - more than 1 exacerbation with CS therapy - increase in EDSS There is an effect (over 1 year): - absence of exacerbations or reduction in their frequency - no progression - positive dynamics on MRI C IF-beta Continued BMI Switch to another BMI IF in a higher dose There is an effect Copaxone There is an effect No effect Continue Copaxone There is an effect With Copaxone IF-beta No effect Continue IF in a higher dose There is an effect Continue No effect Continue No effect No effect Escalation of therapy (immunosuppressants), monoclonal antibodies Fig. 19. Algorithm for the use of immunomodulatory therapy and drug change in patients with definite relapsing-remitting multiple sclerosis. and completion of breastfeeding. Termination of pregnancy is not required. There are isolated observations that describe continued treatment with interferons beta and Copaxone during pregnancy. In all such cases, healthy children were born, and monitoring them until the age of 3 did not reveal any deviations from the norm. However, during pregnancy and breastfeeding, treatment with such drugs should not be continued. After completing the period of breastfeeding, it is advisable to start or resume preventive therapy as soon as possible in order to avoid a possible and very likely exacerbation. Some patients interrupt treatment without receiving the expected reduction or disappearance of symptoms of the disease. That is why it is necessary to explain to the patient that the main effect of preventive therapy is Tatyana Evgenievna Schmidt, Nikolai Nikolaevich Yakhno MULTIPLE SCLEROSIS Guide for doctors Editor-in-chief: V.Yu. Kulbakin Responsible editor: E.G. Chernyshova Proofreader: N.Yu. Sokolova Computer typing and layout : I.A.Kobzev, A.Yu.Kishkanov License ID No. 04317 dated 04/20/01. Signed for printing on 04/07/10. Format 60x90/16. Offset paper. Offset printing. Conditional oven l. 17.00 Headset Times. Circulation 2000 copies. Order No. O-414 Publishing house "MEDpress-inform". 119992, Moscow, Komsomolsky Prospekt, 42, building 3 E-mail: offi [email protected] www.med-press.ru Printed by OJSC PIK “Idel-Press” in full accordance with the quality of the materials provided. 420066, Kazan, st. Dekabristov, 2

For quotation: Zavalishin I.A., Peresedova A.V., Stoyda N.I., Alekseeva N.S., Gulevskaya T.S., Guryanova O.E., Arzumanyan N.Sh., Eliseeva D.D., Trifonova O .V., Bryukhov V.V. Issues of diagnosis and treatment of multiple sclerosis // RMJ. 2011. No. 7. P. 468

Despite multi-directional long-term research, the study of various aspects of multiple sclerosis (MS) remains an urgent problem, the medical and social significance of which is due to the high frequency of occurrence, the incidence of the disease among young people of working age, the possibility of rapid development of persistent disability with insufficient effectiveness in some cases of existing therapeutic agents.
At the present stage, the presence of unified criteria for diagnosing MS contributes to the early prescription of specific pathogenetic treatment aimed at both relieving the symptoms of exacerbation and modulating the course of the disease, which became possible thanks to significant progress in understanding the mechanisms of development of the pathological process in MS, as well as biotechnological methods for creating new medicines.
Currently, the generally accepted diagnostic criteria for MS are those proposed by W. McDonald et al. in 2001 and updated in 2005 (Table 1).
According to the criteria presented in Table 1, 3 out of 4 of the following signs are considered positive on MRI:
. 1 lesion accumulating contrast agent in the brain or spinal cord or 9 T2 hyperintense lesions in the brain and/or spinal cord in the absence of contrast-enhancing lesions;
. 1 or more infratentorial lesions in the brain or spinal cord;
. 1 or more juxtacortical lesions;
. 3 or more periventricular lesions.
Evidence of dissemination over time on MRI is considered to be:
. presence of a lesion accumulating contrast agent after at least 3 months. after the onset of the first clinical deterioration, located in a location different from the first exacerbation,
or
. in the case of a new T2 lesion on a scan taken at any time, relative to a scan done at least 30 days after the first clinical deterioration.
Positive changes in the cerebrospinal fluid (CSF) include oligoclonal IgG chains in the CSF (if absent in serum) or an increased IgG index. A positive change in visual evoked potentials is an increase in the latency of the waves while maintaining their shape.
Excluding alternative diagnoses is especially necessary in early clinical manifestations of the disease, when there is no typical relapsing course. Various combinations of neurological symptoms and MRI findings can be observed in patients with clinically isolated syndrome (CIS), which is currently defined as a monophasic symptomatology caused by a presumed inflammatory demyelinating disease. In this case, monophasicity implies the first development of a separate clinical episode with a relatively rapid onset. It is possible to simultaneously detect multiple clinical/paraclinical manifestations, but dissemination over time should not be obvious. In this regard, the modern classification of CIS distinguishes the following options: type 1 - clinically monofocal; at least 1 asymptomatic MRI lesion; type 2 - clinically multifocal; at least 1 asymptomatic MRI lesion; type 3 - clinically monofocal; MRI may be without pathology; no asymptomatic MRI lesions; type 4 - clinically multifocal; MRI may be without pathology; no asymptomatic MRI lesions; type 5 - no clinical manifestations suggestive of demyelinating disease, but there are suggestive MRI findings.
As can be seen from the criteria given by W. McDonald et al. (2005), to make a diagnosis of MS in patients with CIS, confirmation of the dissemination of the pathological process in space and time is necessary. Subsequently, J.K. Swanton et al. (2006) proposed new MRI criteria for MS, according to which dissemination in space is confirmed by identifying one or more subclinical lesions in T2 mode, localized in at least two of the four areas characteristic of MS according to W. McDonald criteria (juxtacortical, periventricular, infratentorial areas, as well as the spinal cord). At the same time, to verify dissemination over time, it is necessary to identify a new lesion in T2 mode on later images, regardless of the time of the earlier MRI. Compared with the criteria of W. McDonald et al., these MRI criteria are also highly specific for clinically significant MS, are more sensitive and do not require the identification of lesions that accumulate contrast agent; on the other hand, to confirm dissemination over time, at least two MRI studies are necessary, and compliance with the minimum interval between the onset of clinical symptoms and MRI is not necessary.
In the criteria of W. McDonald et al. time interval of 3 months. was chosen to rule out acute disseminated encephalomyelitis (ADEM), a usually monophasic disease that may, however, show the appearance of new lesions on later MRI during the recovery period with a mixed pattern of enhancing and nonenhancing lesions. However, ADEM is rare in adults and there are a number of clinical and MRI features that can be used in the differential diagnosis of ADEM and MS. In this regard, the results of the study presented by A. Rovira et al. (2009), served as the basis for the concept that the simultaneous presence of both contrast-enhancing and non-contrast-accumulating lesions in the brain substance on a single MRI performed during the first 3 months. after the onset of CIS, suggests different stages of their evolution and therefore confirms dissemination over time. According to the authors, the data should be taken into account when further modifying MRI diagnostic criteria for MS in order to optimize the study in terms of “ease, simplicity and cost.”
However, given the significant difficulties in making a diagnosis of MS in atypical cases, the Scientific Center of the Russian Academy of Medical Sciences conducted a clinical and morphological study of the pseudotumorous course of MS and acute focal demyelination. 43 patients were observed; Of these, in 32 patients the diagnosis was clarified based on histological examination of surgical material obtained during stereotactic biopsy or surgery. Groups were identified with a pseudotumoral monofocal process, with a combination of a pseudotumorous focus of subclinical multifocal demyelination, with the development of a pseudotumorous course with exacerbation of reliable MS. Eleven patients were diagnosed as a result of a comprehensive study and follow-up.
The following clinical features of the pseudotumorous course of the demyelinating process have been identified: the age of onset of the disease is typical for multiple sclerosis, the same frequency of occurrence has been revealed in men and women, and a predominantly hemispheric localization of the pseudotumorous focus with a subacute course of the disease is characteristic.
A morphological study of biopsy and surgical material revealed changes in brain tissue characteristic of an acute focal demyelinating process, the main signs of which are the destruction of myelin fibers of the white matter with the removal of their breakdown products by lipophages, proliferation and hypertrophy of astrocytes producing glial fibers, inflammatory perivascular infiltrates consisting from lymphocytes, monocytes and a few plasma cells, hyperemia of small vessels and capillaries, swelling of brain tissue. It has been established that the decay of axons in the focus of demyelination occurs already at the very early stages of the development of demyelinating disease.
The data obtained made it possible to clarify the algorithm for examining patients with the pseudotumor type of the pathological process and certain approaches to the tactics of managing these patients. Thus, if controversial CT and MRI data are detected at the onset of pseudotumor demyelinating disease, a comprehensive additional examination of the patient is recommended, including high-field MRI of the brain, cervical, thoracic spine, and registration of evoked brain potentials to exclude “dissemination of the pathological process in space.” In the case of the development of a pseudotumor variant of the disease within the framework of CIS with multifocal brain damage or with reliable MS, it is advisable to carry out pulse therapy with methylprednisolone, and in the absence of a response to this treatment, a biopsy is indicated. Despite the fact that stereotactic surgery to obtain a biopsy has an important diagnostic value in identifying a pseudotumor lesion, expanding the possibilities of examining these patients makes it possible to avoid it in some cases.
Another atypical symptom of MS, as previously thought, is hearing impairment. During the analysis of cochlear disorders in MS, 70 patients were examined, of which 35 had complaints of hearing loss; the control group consisted of 18 people.
The noted clinical features of auditory disorders in MS were a wide range of complaints, which varied from irritation phenomena, such as congestion, tinnitus, hyperacusis, to loss phenomena, up to acute one-sided deafness. A diverse range of auditory complaints was noteworthy: the appearance of hearing disorders on one side or the other, a combination of hearing loss with dizziness, tinnitus, as well as the appearance of hearing disorders at the onset or during exacerbation of the disease. Sometimes patients indicated any hearing impairments only during pointed questioning.
A comprehensive audiological examination made it possible to exclude the conductive form of hearing loss in the majority of the examined patients with MS. Thus, according to the results of audiometry, both tone threshold and in the extended frequency range (high frequency), in patients with MS with cochlear complaints on the side of the worse hearing ear and on the opposite side, as well as in the group of patients without such complaints, compared with the control The group revealed an increase in the threshold for sound perception at all frequencies, but a more pronounced increase in air conduction thresholds was noted for high frequencies, which is typical for sensorineural hearing loss. In addition, with tympanometry, which evaluates the acoustic impedance of the middle ear, results were obtained indicating the absence of pathology of the middle ear and the normal functioning of the auditory tube.
Finally, with acoustic reflexometry, which is a valuable diagnostic test for the topical diagnosis of hearing disorders (in particular, it makes it possible to distinguish between cochlear and retrocochlear disorders) in MS, a significant increase in the absolute and relative thresholds of the acoustic reflex was recorded, as well as its frequent loss, which is characteristic of retrocochlear lesion. It is important to note that acoustic reflexometry in both patients with complaints of hearing impairment and in patients with MS with dizziness revealed signs of unilateral or bilateral damage to the auditory nerve and auditory centers of the medulla oblongata and pons, which is more typical for patients with cochlear disorders. The data obtained confirm, on the one hand, the sensitivity of acoustic reflexometry in detecting pathology of the auditory nerve in MS, and on the other, the high frequency of involvement in the pathological process not only of central structures, but also of retrocochlear neural lesions, even in patients without hearing impairments; At the same time, they emphasize the role of such combined lesions in the development of cochlear disorders in MS.
In connection with the presented data, from a practical point of view, it is important to consider the following aspect of auditory disorders in MS: when turning to otolaryngologists for patients with complaints of hearing loss, sensorineural hearing loss of unknown origin is detected when carrying out differential diagnosis, it is necessary to take into account the possibility of the demyelinating nature of the process, since timely diagnosis of MS and identifying signs of its activity are of fundamental importance for adequate therapy.
In recent years, due to the fairly large selection of drugs that modulate the course of MS and the need for their individual prescription, approaches to the pathogenetic therapy of MS have undergone certain changes.
A number of therapeutic algorithms are offered. Escalation (increasing) and induction approaches are discussed: the escalation scheme involves starting treatment with safer drugs and moving on to more aggressive ones if they are ineffective; the induction approach involves an initially more aggressive effect on the immune system, however, the use of this type of therapy may be limited by the possibility of developing a whole spectrum side effects.
The Multiple Sclerosis Treatment Consensus Group (MSTCG) proposed an integrated scheme based on the separation of basic and escalation therapy. According to this algorithm, appropriate treatment of an exacerbation is initially necessary, followed by the earliest possible administration of first-line immunomodulators. If disease activity is not effectively controlled, escalation to greater levels is necessary. intensive care. Recommended first-line agents include glatiramer acetate and interferon-β (IFN-β) and, in certain circumstances, natalizumab. If treatment is ineffective or poorly tolerated, transfers from one of these classes to another or to natalizumab are possible. According to the MSTCG recommendations, dynamic monitoring of patients is necessary, including both clinical assessment and a number of laboratory and instrumental examinations.
As already mentioned, first-line drugs that modulate the course of MS include IFN-b and glatiramer acetate. Currently, the following IFN-b drugs are registered in Russia: IFN-b1a for subcutaneous administration (Rebif, Genfaxon); IFN-b1a for intramuscular administration (Avonex, Synnovex); IFN-b1b (betaferon, extavia, ronbetal), which differ from each other in the source of production, chemical structure, as well as in the method and frequency of administration.
The therapeutic effects of IFN-β are thought to be related to effects on antigen presentation and inhibition of inflammatory cell proliferation and activation; inhibition of the production of pro-inflammatory cytokines and a change in the cytokine profile towards an anti-inflammatory phenotype, as well as a decrease in the flow of leukocytes into the central nervous system through the blood-brain barrier due to the effect on adhesion molecules, chemokines and matrix metalloproteinases. As a result of the above, neuronal damage is reduced. In addition, IFN-b induces the synthesis of nerve growth factor by astrocytes, and also enhances the secretion of this neurotrophin by endothelial cells during their interaction with T-lymphocytes (i.e. at the level of the blood-brain barrier), which also determines its immunomodulatory effect and, possibly, causes direct effect on neuronal cells.
The mechanisms of action of glatiramer acetate include competitive binding with myelin basic protein to the class II molecule of the major histocompatibility complex involved in the presentation of antigens, as well as activation of the Th2 phenotype of CD4+ T cells that cross the blood-brain barrier and secrete anti-inflammatory cytokines (interleukin-4, interleukin- 10, interleukin-13, transforming growth factor - b), which leads to suppression of the autoimmune response to multiple myelin antigens. In addition, glatiramer acetate-specific T cells have been shown to express brain-derived neurotrophic factor and transforming growth factor b. Results obtained in a model of experimental allergic encephalomyelitis suggest that glatiramer acetate promotes neurogenesis.
Double-blind, placebo-controlled trials have been conducted for betaferon, Rebif, Avonex and glatiramer acetate in relapsing-remitting MS, demonstrating their positive effect on the activity of the pathological process, both according to clinical and neuroimaging data. In addition, Rebif and Avonex in relapsing-remitting MS have been shown to slow the progression of neurological deficits on the EDSS scale. When studying the effectiveness of glatiramer acetate and betaferon, a slowdown in the increase in neurological disorders was also noted, but these changes in these studies were not statistically significant.
In secondary progressive MS, double-blind, placebo-controlled studies of the effectiveness of Rebif and Betaferon were conducted, demonstrating a decrease in the number of exacerbations and a decrease in the severity of immuno-inflammatory reactions according to MRI results. Also, when prescribing betaferon, a slowdown in the rate of increase in patient disability (on the EDSS scale) is shown, regardless of the initial degree of neurological impairment and the presence of exacerbations before or during the study. When treated with Rebif, a lower percentage of patients with progression of symptoms in the presence of exacerbations over the past 2 years was noted (as opposed to patients without exacerbations).
It is important to note that when summarizing the results of long-term immunomodulatory therapy for MS with betaferon, Rebif, Avonex, and glatiramer acetate, data were obtained indicating its effectiveness and safety.
Despite the conflicting data on the role of neutralizing antibodies in IFN-b therapy, a decrease in the clinical effectiveness of treatment under their influence cannot be ruled out: a clear negative effect of these antibodies on clinical (frequency of exacerbations) and neuroimaging indicators of MS activity, as well as on the progression of disability, has been shown. In this regard, EFNS guidelines have now been developed for the assessment of antibodies to IFN-b and the clinical application of the measurement of neutralizing antibodies. In particular, neutralizing antibody tests should be performed at 12 and 24 months. from the start of therapy; measurement of neutralizing antibodies should be stopped if they are absent during this period, but studies should be resumed if disease activity increases; if neutralizing antibodies are detected, the test should be repeated after 3-6 months; IFN-b therapy should be discontinued in patients with high titers of neutralizing antibodies that are detected during repeated changes at 3-6 month intervals.
At the same time, during glatiramer acetate therapy, most patients also develop binding antibodies to the drug, which is observed already in the first 3-4 months. after the start of treatment. However, these antibodies do not affect the effectiveness of therapy.
It is important to note that the frequency of occurrence of these antibodies differs when treated with different IFN-b drugs; in addition, IFN-b are characterized by different immunogenicity (titer of neutralizing antibodies produced). According to various researchers, when using Avonex, the lowest frequency of occurrence of neutralizing antibodies and the lowest immunogenicity are observed compared to other IFN-b drugs.
It is also necessary to emphasize that in recent years the Rebif formula has been modified, which has led to a decrease in immunogenicity and fewer side effects.
Due to the large selection of first-line drugs that modulate the course of MS, it is quite relevant to compare their clinical effectiveness. In the course of a comparative analysis of immunomodulatory therapy for multiple sclerosis carried out at the Scientific Center of the Russian Academy of Medical Sciences over 3 years of treatment of 400 patients with MS, IFN-b1b (betaferon), IFN-b1a for subcutaneous administration (Rebif) at a dose of 22 μg or glatiramer acetate showed the same high effectiveness of the studied drugs against reducing the number of exacerbations in both relapsing-remitting and secondary progressive MS. Prevention of the increase in the severity of neurological disorders in relapsing-remitting MS was demonstrated in all three therapeutic groups, and in secondary progressive MS - when prescribing Rebif-22 mcg and glatiramer acetate. During therapy with glatiramer acetate, a lower incidence of side effects was noted throughout 3 years of therapy compared with the subgroups treated with IFN-b [Zavalishin I.A. et al., 2007].
The findings are consistent with the results of recently completed multicenter studies. Thus, when comparing the effectiveness of Rebif and glatiramer acetate in relapsing-remitting MS (REGARD) after 96 weeks. therapy, no differences were identified in the primary assessed indicator - the time before the onset of the first exacerbation. Secondary criteria (number and change in volume of active lesions in T2 mode according to MRI, changes in the volume of lesions accumulating contrast agent) also did not differ between the two treatment groups. The small number of exacerbations during the study, in contrast to what was expected, led the authors to suggest that low disease activity in the study population limited the ability to detect clinical superiority of a particular drug. In another study (BEYOND), when analyzing the primary criterion - the risk of exacerbations over 2 years of therapy, no differences were found when prescribing betaferon and glatiramer acetate.
When discussing issues of therapy that modulates the course of MS, it should be noted that much attention is paid to the early administration of such treatment. Thus, a number of studies have shown the therapeutic effectiveness of betaferon, Rebif, Avonex and glatiramer acetate in CIS.
Important from a practical point of view is the possibility of prescribing these drugs in childhood, in connection with which it must be emphasized that Rebif is approved for use from 12 years of age, Avonex - from 16 years of age.
In 2009, another IFN-b1b, Extavia, was registered and approved for use in Russia, while the active substance of Extavia and Betaferon comes from the same manufacturer, thus, the drugs are absolutely identical in composition and quality [Schmidt T.E., Yakhno N N., 2010].
Also in 2009, the domestic IFN-b was registered - ronbetal, the active substance of which is human recombinant IFN-1b. The drug is indicated to reduce the frequency and severity of exacerbations in patients with relapsing-remitting MS, to slow the rate of disease progression in patients with secondary progressive MS.
The results obtained in the course of a multicenter prospective randomized comparative clinical trial including patients with relapsing-remitting and secondary progressive (with exacerbations) MS showed comparability of data on the safety and tolerability of the original IFN-b1b drug betaferon and its bioanalogue ronbetal, and also allowed us to make preliminary conclusion about their comparable effectiveness [Baidina E.V. et al., 2010]. So, in 7.5 months. When taking the drugs, the observed adverse events, including laboratory abnormalities, in the group receiving ronbetal were consistent with those for the original drug. The statistically significant difference in the incidence of influenza-like syndrome between the groups treated with ronbetal and betaferon, revealed in this study (a significantly lower incidence was detected in the group receiving ronbetal), requires clarification in further studies. The obtained data on the reduction in the risk of exacerbations during the use of ronbetal were consistent with the results of multicenter clinical studies on the use of IFN-β. During the study, no statistically significant increase in EDSS scores was noted; there were no differences in the average EDSS values ​​between the groups either at the beginning of the study or over time. The dynamics of the number and volume of demyelination foci observed in this study according to MRI data during therapy with IFN-β drugs was similar to the data of international multicenter studies.
Also in 2010, the following IFN-β1a were registered in Russia: Genfaxon (for subcutaneous use), as well as Synnovex (for intramuscular administration).
In Russia in 2010, a number of drugs with different mechanisms of action and routes of administration were registered for patients with relapsing-remitting MS: Tysabri (natalizumab), Movectro® (cladribine), Gilenya (fingolimod).
Thus, natalizumab is a monoclonal antibody and is a selective inhibitor of adhesion molecules. Natalizumab binds to the ά4 subunit of human integrin, large quantities expressed on the surface of all leukocytes, with the exception of neutrophils. In particular, the drug specifically binds to ά4β1-integrin, while blocking the interaction with the corresponding receptor, vascular cell adhesion molecule (VCAM-1). In this regard, antibodies to adhesion molecules inhibit one of the main stages of MS pathogenesis - interaction with endothelial cells and migration of lymphocytes across the blood-brain barrier. A further mechanism of action of natalizumab may be due to the suppression of inflammatory reactions in affected tissues by suppressing the interaction of ά4-expressing leukocytes with their ligands. Thus, natalizumab can suppress inflammatory activity in affected tissues and further attract immune cells to the site of inflammation.
The high efficacy of natalizumab therapy in relapsing-remitting MS was demonstrated in the following randomized, placebo-controlled phase III studies. Thus, when using natalizumab as monotherapy, compared with the placebo group, a significant reduction in the average annual frequency of exacerbations, the formation of new or enlarging lesions on T2 MRI and the average number of lesions accumulating contrast agent was shown, as well as a decrease in disease progression. The combination of natalizumab and Avonex has also been demonstrated to be significantly more effective than Avonex monotherapy.
Currently, the drug natalizumab is indicated for monotherapy of relapsing-remitting multiple sclerosis in the following groups of patients: patients with an active course of the disease, despite treatment with IFN-β; patients with rapidly progressive severe relapsing-remitting MS. Contraindications to its use are: hypersensitivity to natalizumab or any of the excipients; progressive multifocal leukoencephalopathy (PML); increased risk of infection with opportunistic microorganisms, including immunodeficiency states; simultaneous use of IFN-β or glatiramer acetate; malignant neoplasms, with the exception of basal cell skin cancer; children's and adolescence. Natalizumab should not be used during pregnancy unless absolutely necessary; if the patient becomes pregnant while taking it, therapy should be discontinued; Patients receiving the drug should stop breastfeeding. The use of natalizumab in patients over 65 years of age is not recommended due to the lack of safety data for this category of patients [Instructions for medical use of the drug tysabri].
The drug is used as an intravenous infusion once every 4 weeks.
However, when using natalizumab, it is necessary to remember the possibility of developing various side effects. In particular, its use may increase the risk of developing such a dangerous adverse event as progressive multifocal leukoencephalopathy (PML), and the danger increases with the duration of therapy, especially when treated with the drug for more than 2 years. When prescribing this drug, careful monitoring of patients is necessary, including monitoring of side effects: infections, including PML and infections with opportunistic microorganisms; development of hypersensitivity to drug administration; side effects on liver function, etc. In this regard, special monitoring programs are being developed for individuals receiving natalizumab; the drug is prescribed only after appropriate information to the patient, and the doctor and patient must individually consider the balance of benefit and risk when treating with the drug.
The next two new drugs for the treatment of relapsing-remitting MS, Gilenya (fingolimod) and Movectro®Ò (cladribine), are intended for oral administration.
Fingolimod is a sphingosine-1-phosphate receptor modulator. Once phosphorylated, fingolimod acts as a functional antagonist of sphingosine-1 phosphate type 1 receptors, causing them to shift from the outer to the inner membrane of lymphocytes, which makes T and B lymphocytes unresponsive to signals that stimulate their exit from secondary lymphoid tissue. The resulting redistribution of lymphocytes into the lymph nodes and the prevention of their migration from the lymph nodes reduces the flow of autoaggressive lymphocytes into the central nervous system. Due to its lipophilicity, fingolimod penetrates the blood-brain barrier and undergoes phosphorylation in the central nervous system. Fingolimod has also been shown to have neuroprotective effects and promote remyelination in the CNS by interacting with sphingosine-1 phosphate receptors on neurons.
In two studies conducted, fingolimod was used in two daily doses: 1.25 or 0.5 mg. One study showed an advantage of fingolimod at both doses compared with intramuscular IFN-b1a in terms of efficacy parameters such as exacerbation rates and MRI data (fewer new or enlarging T2 hyperintense lesions; lesions accumulating contrast agent in T1 mode; percentage decrease in brain volume from the initial level). Two fatal infections were reported in the fingolimod 1.25 mg group: disseminated primary Varicellazoster virus infection and herpes simplex virus encephalitis. Other adverse events in patients receiving fingolimod included nonfatal herpes infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver enzymes.
In another study, patients received fingolimod at one of the indicated doses or placebo. The drug in both doses significantly reduced the risk of increasing disability; MRI indicators of disease activity (appearance of new or enlargement of old lesions in T2 mode, lesions accumulating contrast agent, brain atrophy). Reasons for drug discontinuation and fingolimod-related adverse events included bradycardia and atrioventricular block at the start of treatment, macular edema, elevated liver enzymes, and mild hypertension.
It should be noted that the registered dose of Gilenya (fingolimod hydrochloride) is 0.5 mg orally once a day; The indication for its use is relapsing-remitting MS, to reduce the frequency of clinical exacerbations of the disease and reduce the risk of progression of disability. The drug is contraindicated in case of hypersensitivity to fingolimod or any of its other components, pregnancy and during breastfeeding. The effectiveness and safety of Gilenya in children and adolescents under 18 years of age have not been established. There are also a number of conditions for which this drug is prescribed with caution. In this regard, it is necessary to carefully examine the patient before prescribing the drug, monitor the first dose, as well as dynamic monitoring while taking the drug and monitoring for adverse events.
The mechanism of action of cladribine is due to the fact that the intracellular accumulation of its active metabolite, 2-chlorodeoxyadenosine triphosphate, leads to disruption of cellular metabolism, inhibition of DNA synthesis and repair and, accordingly, apoptosis. Cladribine primarily acts on lymphocytes. Accumulation of cladribine nucleotides causes a rapid and long-lasting decrease in the number of CD4+ and CD8+ cells, and also has a rapid but more transient effect on CD19+ B cells with relative sparing of other immune cells. Cladribine also reduces the level of proinflammatory cytokines and chemokines in serum and cerebrospinal fluid, the expression of adhesion molecules, and the migration of mononuclear cells.
In a placebo-controlled study in patients with relapsing-remitting MS who received oral cladribine at a dose of 3.5 mg or 5.25 mg per 1 kg of body weight, compared with the placebo group, there was a significant reduction in the frequency of exacerbations, a higher proportion of patients without exacerbations, more low risk sustainable for 3 months. progression of disability, as well as a significant decrease in the number of lesions in the brain, according to MRI. Adverse events that were more frequently reported in the cladribine-treated groups included lymphocytopenia and herpes zoster infection.
The registered drug Movectro® in tablets containing the active substance cladribine (10.00 mg in 1 tablet) is indicated for use in the treatment of relapsing (remitting) MS. Contraindications for use are: hypersensitivity to cladribine and other components of the drug; acute infectious disease or exacerbation of a chronic disease; decreased immunity due to disease or due to the use of immunosuppressants, including cyclosporine, methotrexate, mitoxantrone, natalizumab, or long-term use of glucocorticosteroids; vaccination during the 3 months preceding treatment. attenuated vaccine (live or weakened vaccines); pregnancy, lactation period; age under 18 years (insufficient clinical data). Due to the fact that Movectro®Ò contains sorbitol, its use is not recommended in patients with fructose intolerance. There are also a number of conditions for which this drug is prescribed with caution.
Movectro® therapy is carried out in courses; each course consists of one or two tablets for the first 4 or 5 days of a 4 week period. (the dose is calculated based on the required courses of treatment and the patient’s body weight). Typically, treatment with the drug begins with 2 treatment courses. Depending on the severity of the disease, 4 courses of treatment may be recommended at once. These 2 or 4 courses are called “Initial Therapy”. The interval between courses of treatment with Movectro® as part of the “Initial Therapy” is 4 weeks. Initial therapy, including 4 consecutive courses, is recommended for patients with severe disease activity. Additional courses begin after 48 and 52 weeks. after completion of initial therapy. These 2 courses are called “Repeat therapy”. Both before starting therapy and during therapy with Movectro®, it is necessary to perform certain examinations in order to monitor the patient’s condition.
In secondary progressive and relapsing-remitting MS, with rapid progression of the disease and the ineffectiveness of first-line drugs that modify the course of MS, the cytostatic drug mitoxantrone is widely used to reduce the frequency and severity of exacerbations and slow the rate of disease progression. However, when using mitoxantrone, like other cytostatic drugs, it is necessary to take into account the possibility of side effects, in particular myelosuppression and cardiotoxicity, which requires careful selection of patients and monitoring of relevant indicators. According to the publication Multiple Sclerosis Therapy Consensus Group, it is also recommended to reduce the maximum cumulative dose to 100 mg per 1 m2 of body surface (in some cases it is possible to achieve a total dose of 140 mg per 1 m2 of body surface); Conducting echocardiography before each administration of mitoxantrone. Continuation of the course of the drug is possible only if the patient is sensitive to the treatment and signs of disease activity persist. When prescribing the drug to young women, it is necessary to take into account the possibility of developing prolonged or permanent amenorrhea. In addition, the drug can also affect fertility in men.
Thus, in recent years, there has been a significant expansion of the range of drugs for the treatment of MS, which is due not only to the emergence of a number of generics of long-known drugs IFN-b and a biosimilar of IFN-b1b, but also to the registration of drugs with other mechanisms of action. On the one hand, this increases the possibilities of modern therapy that modulates the course of MS, on the other hand, it requires an individual approach to the selection of treatment with a careful analysis of indications/contraindications and conditions requiring caution, possible side effects, and careful monitoring of the condition of patients during treatment in order to assess both the effectiveness and safety of the prescribed therapy.

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