[Possibilities of magnetic resonance morphometry and laboratory biomarkers in studying the progression of multiple sclerosis]. / Vozmozhnosti magnitno-rezonansnoi morfometrii i laboratornykh biomarkerov v izuchenii progressirovaniya rasseyannogo skleroza.

OBJECTIVE: To show that magnetic resonance morphometry and laboratory biomarkers are promising methods for early detection of progressive forms of multiple sclerosis (MS). MATERIAL AND METHODS: Eighty-one patients with MS were examined, magnetic resonance morphometry was performed in all of them, 60 patients were analyzed for neurofilament light chains (sNFL), phosphorylated neurofilament heavy chains (spNFH) and glial fibrillary protein (sGFAP) in serum by enzyme-linked immunosorbent assay. RESULTS: Brain volumes were negatively correlated with disease duration, EDSS score, 25-foot walk test score and 9-ring test and positively correlated with the Symbol-Numeric Test and the Montreal Cognitive Assessment. Patients with progressive types of MS (PMS) had smaller volumes of brain gray matter, cerebellar white matter, occipital lobes, caudate nucleus, hippocampus, pallidum, thalamus, and contiguous nucleus. A CSF volume greater than 15.06% could suggest progression (CI 54.79-91%) with a sensitivity of 77.78% and specificity of 70.18%. When patients were on DMT, they had larger thalamic volumes (median 1.09% [1.6; 1.16] vs 1.04% [0.95; 1.14]; p=0.02) and smaller CSF volumes (13.86±2.87% vs. 15.55±3.49%; p=0.03). The levels of sNFL and spNFH were not increased in PMS and during exacerbations, and the low obtained values of sNFL suggest poor sensitivity of the method. There were trends (p=0.374) towards higher sGFAP in patients with PRS (median 3.2 ng/mL [1.85; 4.6] compared to remitting MS (2.05 ng/mL [1.29; 4.52]). CONCLUSION: The results demonstrate the differences in brain volumes in patients with different types of MS and emphasize the importance of long-term follow-up to better assess disease progression.

[Difficulties of cerebral toxoplasmosis diagnosis in a patient with multiple sclerosis and HIV]. / Trudnosti diagnostiki tserebral'nogo toksoplazmoza u patsientki s rasseyannym sklerozom i VICh-infektsiei.

Toxoplasmosis is a widespread parasitic disease. It is caused by an intracellular parasite Toxoplasma gondii. It can affect various tissues and organs, forming cysts and continuing to replicate within them. In people with intact immune system, tissue cysts remain in latent state throughout their whole life. However, in cases of cellular immunodeficiency the infection can be reactivated, which leads to secondary generalization of the process. People with HIV most commonly present with cerebral toxoplasmosis. Non-specific neuroimaging signs, as well as absence of pathognomonic symptoms and specific laboratory data lead to difficulties of cerebral toxoplasmosis diagnosis, particularly in the cases with a history of multiple sclerosis that has similar clinical symptoms and brain MRI data suggesting of tumefactive multiple sclerosis image. A clinical case of cerebral toxoplasmosis in a female patient with multiple sclerosis and HIV infection is described.

[Transverse myelitis syndrom as a result of neuromyelitis optica spectrum disorders, systemic lupus erythematosus and myasthenia gravis combination]. / Sindrom perechnogo mielita v rezul'tate sochetaniya zabolevaniya spektra neirooptikomielita, sistemnoi krasnoi volchanki i miastenii gravis.

Neuromyelitis optica spectrum disorders (NMOSD) - autoimmune condition characterized by an inflammatory lesions mainly of the spinal cord with the development of longitudinally extensive transverse myelitis (LETM) and/or involvement of the optic nerve with the development of usually bilateral optical neuritis (ON). In recent years, there has been increased awareness that NMOSD can be combined with other autoimmune diseases, including myasthenia gravis (MG), systemic lupus erythematosus (SLE) et al. The simultaneous presence of several autoimmune diseases in one patient can adversely affect the course of each of the diseases, causing the so-called mutual burden or «overlap syndrome¼. In this article, we describe our own clinical observation of a 51-year-old woman of European origin who developed acute relapsing TM seropositive for AQP4-IgG, by 23 years after the diagnosis of generalized MG seropositive for antibodies to acetylcholine receptors (AChR-Ab) and the occurrence of SLE, criterially confirmed, several months after the initial TM attack. During the fourth TM attack, partial positive dynamics was achieved only against the background of the combined use of intravenous methylprednisolone (pulse therapy), high-volume plasma exchange, rituximab and cyclophosphamide. The NMOSD is a rare disease leading to severe disability. In patients with MG, when symptoms of damage to the central nervous system appear, an analysis should be performed for AQP4-IgG and possibly for antibodies to myelin glycoprotein of oligodendrocytes (MOG-Ab), as well as markers characteristic of systemic connective tissue diseases (SCTD). In patients with STDD, when symptoms of involvement nervous systemappear, testing for AQP4-IgG (and, if necessary, for MOG-Ab) should be performed to exclude NMOSD, as well as AChR-Ab (and, if necessary, antibodies against muscle specific kinase (MuSK-Ab)) to exclude MG.

[Progress and prospects of metabolic therapy in multiple sclerosis]. / Dostizheniia i perspektivy metabolicheskoi terapii rasseiannogo skleroza.

Side-effects and incomplete response to standard therapy of patients with multiple sclerosis (MS) stimulate the development of an alternative therapy, that influences, in particular, metabolic functions of MS patients. Metabolic therapy (vitamins, antioxidants and others) have been used for a long time in neurologic practice for the treatment of MS on the basis of pathophysiological mechanisms, positive clinical experience, low rate of side-effects and practical availability. Recent objective scientific data explain the necessity of correction of the disturbed metabolic profile (metabolome) in MS, and the first evidence of the efficacy of several metabolic agents, particularly, biotin and vitamin D, was shown. Taking into account the mechanisms of action and clinical experience, the authors consider the prospects of using the combined medicine cytoflavin, that contains succinate, nicotinamide, riboflavin and inosine, in metabolic therapy of MS.

[Modern conception of the pathogenesis of neurodegenerative diseases and therapeutic strategy]. / Sovremennaia kontseptsiia patogeneza neirodegenerativnykh zabolevanii i strategiia terapii.

Here we discuss the pathogenesis of the inflammatory and degenerative nervous system disorders on the example of Parkinson's disease, Alzheimer's disease, multiple sclerosis. Common mechanisms of neurodegeneration in these diseases are reviewed. The role of neurodegeneration as the main process leading to the resistant disability of patients with multiple sclerosis is discussed. The authors consider a contribution of inflammatory process and chronic infection to the manifestation and progressing of a neurodegenerative disease and discuss the use of treatment not usually indicated including interferon, anti-inflammatory drugs, statin, vitamin D, monoclonal antibodies, correction of the intestinal microbiota in Parkinson's disease and Alzheimer's disease.

Enterococcus faecium strain L-3 and glatiramer acetate ameliorate experimental allergic encephalomyelitis in rats by affecting different populations of immune cells.

The effect of probiotic Enterococcus faecium strain L-3 was studied in rats with experimental allergic encephalomyelitis (EAE). Glatiramer acetate (GA) was used as control drug. E. faecium strain L-3 and GA both were able to reduce the severity of EAE in a similar fashion. Both approaches increased the proportion of EAE resistant rats and rats with mild disease, prolonged the inductive phase of EAE and reduced the disease duration. Study of the phenotypes of immune cells in blood revealed the differences in immunoregulatory pathways that mediate the protective action of probiotic or GA treatment of EAE. The presence of pronounced protective and immunomodulating effects of the probiotic E. faecium strain L-3 opens an opportunity of its application for the treatment of multiple sclerosis.

[Multiple sclerosis vaccine: possibilities of the use of dendritic cells immunomodulatory potential].

For the first time we carried out a clinical assessment of the safety, tolerability and clinical efficacy course of repeated administration of experimental modified autologous vaccine interleykin (IL-10) dendritic cells in two patients with secondary-progressive multiple sclerosis patient and one with relapsing-remitting multiple sclerosis. In the course of treatment, we carried out clinical and immunological monitoring. It was found out that intradermal dose of 3 x 106 cells applied to spinal area 6-12. times did not cause any serious side effects. After the treatment with dendritic cells, the following results were observed: 1) a significant positive clinical effect in patients with secondary-progressive multiple sclerosis exacerbations; 2) moderate positive clinical effect in patients with relapsing-remitting multiple sclerosis, in a state of remission; 3) a complete absence of any clinical results in patients with secondary-progressive multiple sclerosis without exacerbations. The immune response was characterized by a significant absolute and relative increase of serum T-regulatory cells. Discovered distinct anti-inflammatory properties of dendritic cell therapy allow us to consider it as a promising area of personalized treatment based on an individual vaccination against multiple sclerosis.

[EFFECT OF PROBIOTIC ENTEROCOCCI AND GLATIRAMER ACETATE ON THE SEVERITY OF EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS IN RATS ].

Currently intestinal microbiota is considered as a potential target for influence in various pathologies which have inflammation, autoimmunity or neurodegeneration in the genesis. Multiple sclerosis (MS) combines all these processes in the pathogenesis. Furthermore, the balance of the components of intestinal microbiota is disrupted during MS and followed by disbiosis. Different probiotics - bacteria with proven beneficial properties are widely used to correct dysbisis. In this paper, was investigated the ability of probiotic strain Enterococcus faecium L-3 to reduce disease severity in multiple sclerosis model - experimental allergic encephalomyelitis (EAE). E. faecium L-3 were used alone or in combination with glatiramer acetate (GA). It is shown that administration of E. faecium L-3 reduces the severity of EAE in rats almost as same as that of GA. However, when the probiotic enterococci administered together with GA the protective effect does not observed. It is assumed that these preparations stimulates different ways of the immune system, because their action stimulate different immune cells populations. The study demonstrates the ability of E. faecium L-3 to influence on the immune system in MS, directly and indirectly (through the correction of dysbiosis). This fact allows us to consider E. faecium L-3 as a potential tool for immunomodulation in autoimmune, inflammatory and neurodegenerative diseases.

[Intravenous immunoglobulins: perspectives in multiple sclerosis (a literature review with own results)]. / Perspektivy primeneniia vnutrivennykh immunoglobulinov pri rasseiannom skleroze.

In this review, we have analyzed a role of intravenous immunoglobulins (IVIGs) in multiple sclerosis (MS) therapy. Main mechanisms of IVIGs are elucidated and the results of the most prominent investigations of IVIGs in MS are reported. Based on these data, we discuss a role of IVIGs as second line therapy in MS. We also present results of our own open observational study of IVIG therapy of 41 patients with relapsing-remitting and secondary progressive with relapses MS, in which a clear decrease of relapse rate (by 2-3 times) and disability (in average by 0.38-0.48 EDSS points) were revealed. We found some differences between complex IVIGs and pure IgG IVIGs clinical efficacy with some prevalence of complex IVIGs that were discussed. High IVIGs safety and tolerability (only slight transitory side effects in up to 14% of patients) were found.

[The Effect of the Disease Duration on the Changes of the Visual Evoked Potentials and Contrast Sensitivity in Multiple Sclerosis].

The most sensitive methods to detect pathological changes in the visual system are the method of recording visual evoked potentials and the psychophysical method of measuring contrast sensitivity. Described in the literature features of functional disorders of the visual system in patients with multiple sclerosis are controversial. The results of the study allowed us to make an assumption about the depen-dence of the nature and severity of changes of the evoked potentials and contrast sensitivity and the duration of disease in patients with multiple sclerosis. In some patients with disease duration from 3 to 10 years there are irregularities in the magno-channels (reduced amplitude component P1), in others-- parvo-channels (amplitude reduction N 1) without increasing the latency, in patients with a disease duration of 10 to 14 years--both channels dysfunction (decreased amplitude components P1 and N1) with an increase of latency. The data indicate heterogeneity of pathophysiological changes upon increase of the degree of demyelination and damage of optic nerve fibers in multiple sclerosis.

[Brain metabolism in multiple sclerosis: effects of neurotrophic therapy].

We studied 15 patients with relapsing-remitting multiple sclerosis (MS) in the state of remission (disease duration 1-5 years, EDSS scores 2.5-5.5) treated with сerebrolysin (Cere) to investigate the rate of brain metabolism changes. All patients continued to receive their disease modified treatment therapy (copaxon or interferons). Patients of the main group (n=10) received i.v. 20 ml of Cere (diluted in 200 ml NaCl 0.9%) for 10 days and vitamins B (pentovit) in tablets. Patients in the control group (n=5) were treated only with pentovit in tablets. All the patients underwent magnetic resonance spectroscopy (MRS) (Siemens Symphony 1.5T) prior to the beginning of treatment and 1-3 days after the end of therapy. Five patients of the main group who had best results according to the data obtained from the 2nd MRS underwent a third MRS investigation after 3 months. After 10 days of Cere treatment, the level of N-acetylaspartate in MS lesions had increased from 2.12 to 2.39 (p<0.001) and the level of lactate had decreased by 4 times (from 0.21 to 0.05; p<0.001). In perifocal lesion areas, the level of lactate had significantly decreased from 0.22 to 0.1 (p<0.05). We have also found the trend towards NAA increase in morphologically intact brain tissues. The positive metabolic changes after Cere therapy remained in some patients for 3 months. In the control group, there was the increase of creatine level in intact brain tissues from 1.16 to 1.30 (p<0.05) without significant changes in other areas. All the patients in the main group reported subjective improvement and one patient had the improvement in EDSS scores by 1.0 point.

[Effect of therapeutic apheresis on the lymphocyte sensitivity to corticosteroids in patients with secondary progressive multiple sclerosis].

Therapeutic apheresis combined with pulse therapy with small doses of corticosteroids was used in 7 patients with secondary progressing multiple sclerosis (MS) during 4 years. Before perfusions, we investigated the lymphocyte sensitivity to methylprednisolone in vitro in the reaction of leukocyte migration with myelin basic protein in each patient. The introduction of test doses of corticosteroids in each patient's blood sample before perfusion procedures showed the different rate of leukocyte migration with the myelin basic protein. On this basis, we selected an individual optimal methylprednisolone dose that was infused intravenously just after each perfusion procedure. The number of patients sensitive to low doses of methylprednisolone increased after therapeutic apheresis. These findings allow to consider the reaction of leukocyte migration with the presence of myelin basic protein as a new method of individual selection of corticosteroid doses for increase of treatment efficacy of secondary progressing multiple sclerosis.

[Diagnosis and differential diagnosis of demyelinating optic neuropathy in multiple sclerosis].

The previous research has shown the very common subclinical damage of the optic nerve in multiple sclerosis patients with the absence of obvious clinical symptoms of optic neuropathy (ON). Other causes of ON (pathology of connective tissue, infections, tumors or ischemic diseases) are rather uncommon. We carried out a detailed neuroophthalmologic examination of 137 (274 eyes) patients with relapsing-remitting multiple sclerosis (MS) including 58 patients (74 eyes) with a previous history of ON. Acute clinical symptoms of ON were recorded in 42% of MS patients. Moreover, in 31% of ON patients, ON was the first and only symptom of MS. In other 56% of MS patients, a subclinical damage of the optic analyzer was recorded. The examination of the central vision fields with the help of standard static automated perimetry ("Humphrey"-24/2) showed the reduction of the light sensitivity threshold in 90% of MS cases and in 100% ON cases. The contrast sensitivity was considerably reduced in the whole frequency band, including high frequency, in MS patients with the previous history of ON and with MS lasting for over 5 years. The use of the Sloan low-contrast test revealed the sharp reduction in the identification of signs with the contrast level of 2,5% and 1,25% in all ON cases and in 70% MS cases without ON. In 82% of MS cases, the pattern visual evoked potentials (PVEP) revealed the increase in P100 latent period from 10 to 50 msec above the upper norm limit. A distortion of the shape of PVEP P100 complex of W-type and amplitude reduction were recorded in over 90% MS cases with the previous history of ON. The use of optical coherence tomography (OCT) revealed that the average thickness of the retinal nerve fiber layer (RNFL) in MS was decreased compared to the control group (87 (76; 97) and 105 (99; 115) microns, respectively). Patients with the previous history of ON had the lowest RNFL thickness of 73 (65; 84) microns. Diffusion tensor imaging showed that the index of fractional anisotropy (FA DTI) was considerably reduced in the optical nerve area and tract. Its average value was equal to 570,0 (510; 615) versus 651,9 (610; 710) microns in the control group.

[Transplantation of mesenchymal stem cells in multiple sclerosis].

To assess safety and tolerability of treatment with autologic multipotent mesenchymal stem cells (MSC) in multiple sclerosis (MS), we have obtained autologic red bone marrow-derived MSC from 8 patients. Proliferation, immunophenotype and caryotype of MSC, their sterility, the absence of hemopoetic cells, chromosomal aberrations and signs of aging were controlled during the cell growth. The inverse injection of MSC in patient's blood was conducted in accordance to the elaborated protocol in a short intravenous infusion in dose 2.0 x 10(6)/kg of body mass once in 30 days. The duration of treatment was from 4 to 8 months. The efficacy of treatment was assessed after 4, 8 and 12 months. All patients tolerated repeated intravenous infusions of autologic MSC well with no significant side-effects as in the early as well in the remote periods of treatment. The distinct positive effect was seen in some cases 2 months after the beginning of treatment. The improvement of 0.5 point on EDSS was seen in 5/8 patients after 4 months. After 12 months, the improvement of 0.5-1 point on EDSS was seen in 6/8, stabilization in 1/8, progression in 1/8. These results revealed the safety of the elaborated protocol of treatment and the moderate clinical efficacy of treatment in non-curable patients or those with poor response to treatment that suggested continuing the study and enrollment of new patients.

[Possibilities of treatment of multiple sclerosis exacerbations without corticosteroids: a role of metabolic and antioxidant therapy].

A multicenter randomized post-registration control-comparative trial included 94 patients with relapsing-remitting and secondary-progressive multiple sclerosis (MS) in the acute phase. Patients were stratified into 2 groups: patients of group 1 (n=53) received cytoflavin and basic treatment (trental and group B vitamins) and patients of group 2 (n=41) received only basic treatment. Based on the results of the 5-day treatment, each of these groups was stratified into 2 subgroups: patients of subgroup 1A (n=22) who demonstrated a positive effect continued to receive cytoflavin and basic treatment; subgroup 1B (n=31) received corticosteroids (metipred) as an add-on in the pulse- treatment regime; group 2A (n=14) continued to receive basic treatment due to the positive effect; group 2B (n=27) received corticosteroids as an add-on in the pulse-treatment regime. The treatment including cytoflavin, trental, group B vitamins and corticosteroids, was well-tolerated. The positive effect was due to the decrease in the need for corticosteroids: 41.5% of patients treated with cytoflavin and only 34% of patients receiving basic treatment did not need corticosteroids. The significant reduction of neurologic symptoms assessed with the EDSS was seen in patients treated with cytoflavin compared to the group which did not receive this drug. The clinical effect was observed in all patients. There was a decrease in lipid peroxidation levels and in the content of antibodies to basic myelin protein and the improvement of cognitive function.

[New morphological data on multiple sclerosis].

The brain from 6 patients who died of multiple sclerosis was studied with MR tomography (MRT), macroscopy, light (CD 3, CD 20, LCA antigens) and electron microscopy (EM). Typical foci of demyelinization (plaques) were found in all cases. Alterations of brain arteries were found particularly in arteries of narrow lumen--with disturbance or even absence of elastin and muscle layer. Up to 30% of the vessels were surrounded by microcavities. Perivascular infiltrates consisting primarily of T lymphocytes were observed around the vessels (up to 70% of all vessels). This indicates the importance of vascular changes in the disease pathogenesis. Four variants of demyelinization (plaques) are distinguished depending on the degree of destruction of myelin, axons and glia. Two types of cells were found in the plaques with most pronounced changes: astrocytes and newly formed oligodendrocytes. Classification of plaques is suggested.

Clinical and quality of life responses to high-dose chemotherapy plus autologous stem cell transplantation in patients with multiple sclerosis: two case reports.

During the last several years high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) has been established as a therapeutic option for multiple sclerosis (MS) patients. We report on the long-term effects of HDCT + ASCT in two female patients affected by secondary progressive and relapsing-remitting types of MS, respectively. As a result, disease stabilization was achieved in the first case and disease improvement in the second one. Both patients were off immunosuppressive or immunomodulating therapy throughout the post-transplant period. Notably, HDCT + ASCT resulted in an excellent quality of life (QoL) response in both cases. Our findings demonstrate that HDCT + ASCT could be considered as an effective treatment for MS patients. Moreover, QoL measurement seems to be an effective approach to assessment of treatment outcomes at long-term follow-up of patients with MS.