[Results of a phase 1 clinical study of anti-CD20 monoclonal antibody (BCD-132): pharmacokinetics, pharmacodynamics and safety]. / Rezul'taty I fazy klinicheskogo issledovaniia monoklonal'nogo antitela protiv CD20 (BCD-132): farmakokinetika, farmakodinamika i bezopasnost'.

AIM: To study the pharmacokinetics, pharmacodynamics, and immunogenicity of two intravenous dosing regimens of the new anti-B-cells drug BCD-132 (JSC BIOCAD, Russia) at ascending doses in patients with remitting multiple sclerosis. MATERIAL AND METHODS: Twenty-four patients with multiple sclerosis were sequentially randomized in the multicenter open-label uncontrolled multicohort phase I study (3+3 design) and assigned to 4 cohorts (8 groups). Patients in each cohort received an intravenous infusion of BCD-132 at a predefined dose ranging from 100 to 1000 mg based on the planned algorithm of dose escalation if no dose-limiting toxicities occurred. RESULTS: The assessment of the number of cells positive for the main B-cell antigens over time demonstrated a direct effect of BCD-132 on B lymphocytes when used at a wide range of doses (100 to 1000 mg) in patients with remitting multiple sclerosis. No significant variation of the number of T-cells was observed, which clearly proves strict specificity of BCD-132 exclusively to B lymphocytes. CONCLUSION: BCD-132 has an expected pharmacodynamic effect of long-term depletion of CD19+ and CD20+ B lymphocytes and an acceptable safety profile when used to treat patients with remitting multiple sclerosis at all tested doses.

[Cortical atrophy in multiple sclerosis]. / Atrofiia kory golovnogo mozga pri rasseiannom skleroze.

Objective. To identify clear patterns of the cerebral cortex atrophy in multiple sclerosis that may provide valuable information for the development of additional paraclinical methods of stages and variants of MS objectification and verification and used for assessing treatment efficacy. Material and methods. The results of morphometric data analysis of 117 patients with different variants of MS and 25 healthy volunteers are presented. The original algorithm for postprocessing MRI images was used. Age, disease duration, type of disease, FS and EDSS scores, morphometric results were the source parameters for the statistical analysis. Results. The correlation analysis showed that the total cortex volume was in inverse correlation with EDSS score, pyramidal and cerebellar dysfunction, but not with disease duration. An analysis of regional changes in 43 bilateral regions of interest (ROI) demonstrated similar results in 7 ROIs in the left (dominant) hemisphere and in 4 ROIs in the right hemisphere. ANOVA revealed atrophic changes in 20 ROIs bilaterally. Deficit of certain functional systems was accompanied by the atrophy of various functional cortex regions. ANOVA of the regional cortical atrophy in groups with varying disease severity showed the presence of significant changes in patients with moderate to severe disability. Duration and type of MS were not predictive for development of atrophy, with the exception of the precuneus bilaterally, the right paracentral lobule and right posterior cingulate gyrus. Conclusion. Regional cortical atrophy is detected in the earliest stages of the disease and increases as the disease progresses. Inconsistency of data across studies can be explained by the lack of generally accepted morphometric standards and pathogenetic heterogeneity of MS. Regional cortical atrophy may be considered as a sensitive neuroradiological biomarker for MS.

[Diagnosis of isolated angiitis of the central nervous system].

We have analyzed clinical presentations, neuroimaging data, blood and cerebrospinal fluid diagnostic tests in isolated angiitis of the central nervous system on the basis of data of recent publications and 22 our own cases. Due to the insufficient diagnostic value of invasive methods including biopsy of leptomeningeal and intracerebral vessels, we considered practical approaches to the diagnosis of cerebral vasculitis and ways of its optimization. We suggested the stratification of clinical, neuroimaging and laboratory criteria for the evaluation of their sensitivity and specificity and for the development of diagnostic algorithms.

[Treatment of relapses of multiple sclerosis (a review)].

The most common clinical type of multiple sclerosis (MS), affecting up to 85% of patients living with this disease, is relapsing remitting(RRMS). Relapses are associated with significant functional impairment and decreased quality of life. Residual symptoms after MS relapses may persist and lead to sustained disability. Adequate management of MS relapses may help to shorten and lessen the symptoms and disability associated with their course. Systemic corticosteroids and adrenocorticotropic hormone (ACTH) have broad regulatory approval and remain the most established and validated treatment options for MS relapses. Recently, the direct anti-inflammatory effects and immunomodulatory activity of ACTH have been shown. Algorithms of using these medications for MS relapse treatment, data on plasmapheresis and perspectives of other therapeutic methods are reviewed.

[Intrathecal immunoglobulin production in the diagnosis and differential diagnosis of multiple sclerosis].

The evaluation of diagnostic significance of different immunological tests for intrathecal immunoglobulin production is summarized on the historical basis of investigation of patients with inflammatory, demyelinating and other neurological disorders. The assessment of cerebrospinal fluid lost its previous significance in the 2010 revision of diagnostic criteria for multiple sclerosis. Nowadays, it is used only for the diagnosis of primary progressive multiple sclerosis. Nevertheless, the requirements of the analysis of the cerebrospinal fluid are increasing due to subtle, subclinical and atypical cases of multiple sclerosis as well as undetermined demyelinating disorders. Intrathecal humoral immune response may be pathogenic in multiple sclerosis as suggest immunological data and effectiveness of anti-B cells treatment. Based on these tests, it is useful, to differentiate subgroups of patients and to evaluate different effects of treatment in perspective.

[Current possibilities of the comprehensive diagnostic assessment in the differential diagnosis of inflammation and tumors of the spine cord].

The article discusses the differential diagnosis of transverse myelitis. An algorithm for the assessment of patients was given. The authors present two clinical examples demonstrating the role of the integrated neuroradiological approach in the differential diagnosis of difficult cases.

[Symptomatic epilepsy in inflammatory demyelinating diseases].

Based on the own observations, we have summarized the features of symptomatic epilepsy in multiple sclerosis and conducted a clinical analysis of the most diagnostically difficult cases of inflammatory and demyelinating diseases in which epilepsy was the major clinical syndrome. The cases of post-infectious acute disseminated encephalomyelitis, idiopathic cerebral angiitis, Rasmussen's encephalitis are reviewed. Peculiarities of MRI structural brain lesions in these patients are discussed. The use of additional laboratory studies, including a study of cerebrospinal fluid, is considered.

[Brain atrophy and neurological impairment in patients with multiple sclerosis].

An aim of the study was to investigate a relationship between global and local brain atrophy with neurological impairment (motor dysfunction) in multiple sclerosis (MS) patients with different levels of disease severity. Fifty five patients with definite MS (Mc Donald's criteria), aged 18-60 years, disease duration 1-30 years, and 25 healthy age-matched controls have been studied. Neurological assessment (Kurtzke and EDSS scales) was performed in the all patients. The patients were divided into 3 groups: EDSS<3.5 mild disability, EDSS 3.5-6.0 moderate disability, EDSS>6.0 severe disability. In MS patients, the global brain atrophy was accompanied by the local atrophy of subcortical structures (thalamus, basal ganglia) and cerebellum. The processes of cerebral grey matter total and local atrophy were not similar. The progression of MS, neurological impairment is accompanied by the cerebellum and lentiform nuclei atrophy. There was the decrease of brain parenchyma volume, nucleus caudate and cerebellar local atrophy in patients with moderate disability. The severe disability was correlated with the thalamic atrophy and marked basal ganglia and cerebellar atrophy. Thus, we can suppose that the thalamic atrophy is important for the development of severe motor dysfunctions in MS patients.

[Neuromyelitis optica: problems of heterogeneity and systematization].

Prospective-retrospective data on 10 cases of neuromyelitis optica (NO) have been analyzed. Demographic and clinical features of patients with primary NO as well as NO comorbid with other organospecific disorders are discussed. Magnetic-resonance imaging data of the brain and spinal cord are summarized and discussed in the context of its heterogeneity. Positron emission tomography with the functional imaging of the brain performed in 3 patients revealed changes in glucose metabolism in the brain regions corresponding to deficits in motor and sensory functional systems. The issues of additional laboratory analyses, including those of cerebrospinal fluid, are reviewed.

[Clinical and radiological (PET, MRI) correlations depending on disease progression in patients with multiple sclerosis].

The aim of the study was to investigate the structural-functional changes in the cerebral gray matter (cortical and subcortical areas) of patients with multiple sclerosis (MS) depending on the disease severity. One hundred and seven patients (107) with definite diagnosis of MS (Mc Donald's criteria), aged 16-60 years, illness duration 1-30 years, and 21 healthy age-matched controls have been studied. Neurological assessment including Kurtzke and EDSS scales (range 0-8) was performed in all the patients. The patients and controls underwent MRI with a 1,5 imager and PET using 18F-flurodeoxyglucose (FDG). A type of the disease course was determined as remitting in 63 patients, primarily-progressive in 8, remitting progressive in 6 and secondary-progressive in 30. To analyze pathogenesis of the disease progression, the patients were divided into 3 clinical groups: (1) remitting (RRMS, n=63); (2) progressive (PRMS) with EDSS < or =6 (n=34); 3) PRMS with EDSS >6 (n=11). Along with the progression of MS from RRMS to PRMS and increasing of EDSS, the rCMRglu reduction of the cerebral gray matter developed from the supplementary motor cortex of a dominant hemisphere to the marked global reduction of cerebral metabolic rate in the PRMS group (EDSS >6). In the PRMS group with EDSS56, there was functional reorganization of cortical and subcortical areas compensatorily developing with the disease progression. In the PRMS group with EDSS >6, the data obtained did not support the evidence for the regional compensatory increase of rCMRglu in the same brain areas. Decompensation of the functional cortical reorganization in the PRMS group with EDSS >6 correlated with diffuse brain atrophy as well as with atrophy of the gray matter of the regional basal ganglia, first of all of the thalamus.

[Magnetic-resonance tomography in differential diagnosis of brain lesions in demyelinating and systemic autoimmune diseases].

An aim of the study was to establish MRT signs that may be useful for differential diagnosis of multiple sclerosis (MS). Three groups of patients have been examined: 300 patients with MS, 35 with demyelinating diseases (acute disseminated encephalomyelitis, neuromyelitis optica--Devic's syndrome); 90 patients with systemic autoimmune diseases (systemic lupus erythematosus, primary antiphospholipid syndrome, sclerodermatitis, Sjugren's syndrome, autoimmune thyroiditis, vasculitis and vasculopathy). Classification of MRT syndromes in MS and their frequency are presented: syndrome of chronic inflammatory demyelination (79%), syndrome of acute inflammatory demyelination (9%), syndrome of multifocal degenerative leucoencephalopathy (8%), syndrome of combined multifocal diffusive leucoencephalopathy (4%). The similarity and differences in MRT semiotics of the above diseases and MS are described.

[Interferon-beta treatment in patients with childhood-onset and juvenile multiple sclerosis]. / Lechenie rasseiannogo skleroza u detei i podrostkov preparatami beta-interferona.

Prospectively observed natural history in 10 cases of pediatric multiple sclerosis (MS), with respect to prognosis comparing to that of adult-onset MS (n=100) is presented. Poor-prognosis with severe disability was found in juvenile MS (age at onset 10-16 years old) with high annual rate of relapses in 2 years after the disease onset. The results of the long-term (2.0 to 3.5 years) beta-interferon treatment in patients with juvenile MS and the factors affecting these results are analyzed. Based on these data, together with those of published controlled clinical trials in adult-onset MS, indications for beta-interferon therapy and peculiarities of the treatment are discussed.

[Multiple sclerosis in children and adolescents: history and current experience of immunomodulating treatment]. / Rasseiannyi skleroz u detei i podrostkov: istoriia izucheniia problemy i sovremennyi opyt immunomoduliruiushchego lecheniia.

An agreement accepted worldwide for treatment of multiple sclerosis (MS) in adult patients has not been achieved so far for children and adolescents, mostly due to the insufficient information on the features of MS with early age-at-onset. New methods of immunomodifying treatment and the conception of early MS treatment have changed the attitude to prognosis of MS with early onset. In such cases, a course of the disease is less aggressive and characterized by more intensive remyelination as well as brain plasticity and less neurological deficit that may predict highest efficacy of the disease modifying treatment timely started in these patients. Such drugs, as beta-interferons, glatiramer acetate and high-dosage intravenous immunoglobulines G, which are able to decrease MS relapse frequency and disability progression in adult patients, are poorly studied in children and adolescents. Preliminary positive results of international and Russian investigations on the efficacy and tolerability of immunomodulating therapy of MS with early age-at-onset require further investigations in this field.

[Results of a multicenter study of Rebif-22 mcg administration in Russia]. / Rezul'taty multitsentrovogo issledovaniia éffektivnosti preparata Rebif-22 mkg v Rossii.

The results of multicenter study of Rebif 22 micrograms in Russia have been reported. 167 multiple sclerosis patients have received Rebif 22 micrograms three times a week for 1 year. This study provides evidence for reduction of the relapse rate in patients with relapsing/remitting and secondary progressive multiple sclerosis. The tendency to the decrease of the severity of relapses, less need for steroid use and the decrease of EDSS score in patients with relapsing/remitting multiple sclerosis have been shown. In general Rebif 22 micrograms was tolerated well.

[Possibilities of magnetic resonance visualization in the diagnosis of multiple sclerosis]. / Vozmozhnosti metodov magnitno-rezonansnoi vizualizatsii v diagnostike rasseiannogo skleroza.

Magnetic-resonance imaging (MRI) is considered to be the most informative non-invasive method in diagnosis, differential diagnosis and estimation of activity of multiple sclerosis (MS). MRI data of 270 patients with clinically and laboratory definite MS were analyzed to assess diagnostic MRI-criteria for MS, MRI presentations at the time of first clinical manifestation of the disease, neuroimaging patterns in children and elderly persons with MS. The MRI variants of MS are substantiated. Neuroimaging data of cervical spinal cord in 28 patients with MS are presented in parallel with corresponding clinical data. The most typical patterns are singled out. The data of brain 1H-magnetic-resonance spectroscopy (MRS) in 20 patients with MS and 8 patients with inflammatory and vascular disorders were analyzed to reveal biochemical distinction between MS and non-MS lesions as well as changes in normal appearing white matter in MS. The differential-diagnostic value of MRS is limited although decreased N-acetyl-aspartate peak is characteristic for MS lesions and in some cases in normal appearing white matter in primary-progressive MS.

[Multiple sclerosis with childhood onset]. / Rasseiannyi skleroz s debiutom v detskom vozraste.

The clinical manifestations, magnetic resonance imaging (MRI) data, blood and cerebrospinal fluid (CSF) tests were analyzed in 19 patients with early-onset (before the age of 17 years) multiple sclerosis (MS) and in 100 patients with the definite diagnosis of MS with adult onset. Between group differences in sex ratio and initial neurological symptoms, with the prevalence of acute brainstem dysfunction (37%) and optic neuritis (37%) in the patients with early onset MS, were revealed. In childhood, the disease course was poorer with early disablement on the background of attendant unfavorable conditions. A sensitivity of various MRI parameters was analyzed and the essential proportion of the tumor-like acute inflammatory lesions was shown in early onset MS (29%). Immunological tests (albumin coefficient evaluation) revealed that in early onset MS hematoencephalic barrier dysfunction was registered more often, comparing to adult onset MS (100% vs 50%). The peculiarities of biases in concentrations of kappa-free and lambda-free light immunoglobulin chains in blood and CSF were detected. Higher levels of the kappa-free light chains concentrations in CSF were mostly found in the patients both with early and adult onset MS (86% and 99%, respectively) that confirmed the diagnostic value of this index. The results obtained may improve MS diagnosis in children.

[Free light-chain immunoglobulins in the biological fluids of patients with multiple sclerosis]. / Svobodnye legkie tsepi immunoglobulinov v biologicheskih zhidkostiakh bol'nykh rasseiannym sklerozom.

15 patients with clinically significant multiple sclerosis (MS) were examined in terms of content of free light chains of immunoglobulins of kappa- and lambda-types in blood serum, cerebrospinal liquor, lacrimal fluid, saliva, urine, indices were compared with corresponding data of 12 patients with other neurological diseases and of 10 healthy individuals (control group). Significantly increased content of kappa-chains in cerebrospinal, lacrimal fluids and urine was revealed in patients with MS as compared with other two groups and in saliva of patients as compared with controls. The frequency of alterations was high in all biological fluids of the patients with MS. Elevated content of kappa-chains was most often observed in cerebrospinal fluid of the patients (13 individuals). The changes observed reflected systemic activation of humoral immune response in MS. Examination of cerebrospinal fluid was most informative for differential diagnosis.

[Antibodies to brain galactocerebrosides in the serum and cerebrospinal fluid of patients with disseminated sclerosis]. / Antitela k galaktotserebrozidam mozga v syvorotke i tserebrospinal'noi zhidkosti bol'nykh rasseiannym sklerozom.

The titers of antibodies (AB) to myelin's glycolipids galactocerebrosides (GC) as well as some other immunological indices were measured in 63 patients with multiple sclerosis (MS), in 14 patients with other similar neurological diseases and in 9 individuals with cerebellospinal ataxias. The correlation between the frequency of revelation of high serum AB titers and MS stage was observed. Thus the highest frequency was observed at primary progredient current of MS and at decline of its aggravation while the latter was found in steady remission. The correlation between level of AB to blood serum GC and blood immune complexes concentrations (complement and antistreptolysin O) was established too. Meanwhile these were not bound in patients with cerebellospinal ataxias and with other neurologic diseases or the titers of AB to GC were quite low in such cases. The titers of AB to GC in liquor were rather high in 2 patients with MS and in 1 patient with viral encephalitis while there were no AB to GC in other cases. That may be caused by determination of immunoglobulins of M class in reactions of complement binding. The determination of AB to GC in blood serum may be quite usefull in differential diagnosis of MS and other similar clinical conditions.

[The content of free light-chain immunoglobulins in the cerebrospinal fluid and the importance of its determination for the differential diagnosis of multiple sclerosis]. / Soderzhanie svobodnykh legkikh tsepei immunoglobulinov v likvore i znachenie ego opredeleniia dlia differentsial'noi diagnostiki rasseiannogo skleroza.

The serum and liquor of 70 patients with multiple sclerosis (MS), 54 patients with other neurological diseases and 20 controls were examined for free light chains (FLC) of immunoglobulins type chi and lambda. The findings were compared to blood-brain barrier competence, liquor pleocytosis, IgG intrathecal synthesis 86% MS patients exhibited high levels of liquor chi-type FLC which appeared early in the disease course irrespectively of MS phase and pattern. Simultaneous high content of lambda-type FLC was reported in 52% of the cases. Patients in need of differential diagnosis were characterized by normal or reduced (in spinocerebellar ataxia) concentrations of FLC except for the conditions with impaired blood-brain barrier.