[Autoimmune hearing loss and a chance of its development in children: literature review and own observations]. / Autoimmunnaya tugoukhost' i veroyatnost' ee formirovaniya v detskom vozraste: obzor literatury i sobstvennye nablyudeniya.

Autoimmune sensorineural hearing loss (AiSNHL) is an uncommon auditory disorder characterized by rapidly progressive bilateral hearing loss and a positive clinical response to treatment with corticosteroids and cytostatics. The prevalence of the disease in the adult population is less than 1% among all cases of subacute and permanent sensorineural hearing loss (precise data are unknown), it is even rarer in children. AiSNHL can be primary (isolated, organ-specific) or secondary (manifestation of another systemic autoimmune disease). The pathogenesis of AiSNHL is based on the proliferation of autoaggressive T cells and the pathological production of autoantibodies to the protein structures of the inner ear, which leads to damage to various parts of the cochlea (possibly also to the retrocochlear parts of the auditory system), less frequently to the vestibular labyrinth. Pathologically, the disease is most often represented by cochlear vasculitis with degeneration of the vascular stria, damage to hair cells and spiral ganglion cells, and endolymphatic hydrops. In 50% of cases, the result of autoimmune inflammation may be fibrosis and/or ossification of the cochlea. The most characteristic symptoms of AiSNHL at any age are episodes of sudden progression of hearing loss, fluctuations of hearing thresholds, and bilateral, often asymmetric impairments. The article presents contemporary ideas of the clinical and audiological manifestations of AiSNHL, the possibilities of diagnosing and treating the disease, and highlights the current approaches to (re)habilitation. Along with literature data, two own clinical cases of an extremely rare pediatric AiSNHL are given.

Dependence of blood biochemical parameters on various genotypes of the UGT1A1 gene associated with gilbert's syndrome.

Diagnosis of Gilbert's syndrome is based on the detection of homozygous carriage of an additional TA-repeat in the promoter of the UGT1A1 gene, leading to a decrease in the activity of the UGT enzyme. No large studies have been done in the Russian Federation on the prevalence of carriage of Gilbert's syndrome, as well as the biochemical and molecular profile of such patients. The aim of the study is to evaluate biochemical and molecular genetic parameters in patients with Gilbert's syndrome in Russia. The study included 124 healthy volunteers (group 1) and 5650 patients with suspected Gilbert's syndrome (group 2). The number of TA-repeats of the promoter region of the UGT1A1 gene was determined by the method of fragment analysis for all participants. The following biochemical parameters were analyzed for 299 patients from group 2: the level of bilirubin and its fractions, AST, ALT, cholesterol and LDL. In group 1 the prevalence of genotype (TA)6/(TA)6 was 39,52%, (TA)6/(TA)7 - 53,23%, (TA)7/(TA)7 - 7,26%, no rare forms were found. In group 2 the prevalence of genotype (TA)6/(TA)6 was 6,04%, (TA)6/(TA)7 - 20,05%, (TA)7/(TA)7 - 73,7%, rare alleles - 0,2%. Rare alleles included (TA)5/(TA)6, (TA)5/(TA)7, (TA)6/(TA)8 and (TA)7/(TA)8, as well as a new genotype not described in the literature previously - (TA)7/(TA)9. When assessing the level of total bilirubin and its fractions, a difference was revealed between the genotype of Gilbert's syndrome (TA)7/(TA)7 and the reference genotype (TA)6/(TA)6, and between genotypes (TA)7/(TA)7 and (TA)6/(TA)7. A significant increase in total bilirubin was demonstrated in carriers of a larger number of TA-repeats. There was no significant difference in the concentration of ALT, AST, cholesterol or LDL between different genotypes.The number of TA-repeats of the UGT1A1 gene affects the increase of total bilirubin and its indirect fraction, including the cases of rare allelic variants (TA≤5, TA≥8), but not the activity of ALT and AST and the lipid profile.

[Acute disseminated encephalomyelitis]. / Ostryi rasseyannyi entsefalomielit.

Acute disseminated encephalomyelitis (AEM) is an immune-mediated inflammatory demyelinating disease of the central nervous system (CNS), usually single-phase. In WREM, multiple lesions of the central nervous system of an inflammatory-demyelinating nature accompanied by extremely polymorphic neurological disorders develop acutely or subacutely. The review considers the issues of epidemiology, trigger factors of the inflammatory process, clinical manifestations, differential and molecular diagnostics of WECM, and outlines the ways for further study of this pathology.

[Actual issues of serum aquaporin-4 autoantibodies evaluation in the diagnostics of neuromyelitis optica spectrum disorders]. / Aktual'nye voprosy diagnostiki zabolevanii spektra optikoneiromielita pri opredelenii antitel k akvaporinu-4 v syvorotke krovi.

OBJECTIVE: To analyze the usage and timeliness of aquaporin-4 antibodies (AQP4-IgG) serology test in the diagnostics of neuromyelitis optica spectrum disorders (NMOSD) in routine clinical practice. MATERIAL AND METHODS: 27 patients with NMOSD were included in the study. All patients had a positive serum test for AQP4-IgG. A retrospective study of neurological manisfestations of attacks, timing and results of serology for AQP4-IgG was performed. The results were analyzed taking into account two types of attacks identified: a) HS (with highly specific manifestations for NMOSD), which are considered as indications for conducting the AQP4-IgG test and b) NS (with non-specific manifestations for NMOSD). RESULTS AND CONCLUSION: A comparison of the time from HS attack to the AQP4-IgG test administration (T1, years), from HS attack to NMOSD diagnosis (T2, years) was undertaken as well as the number of attacks during these periods (N1, N2) were counted in three groups of patients. Group 1 - with the first HS attack before or in 2008 (n=6), group 2 - from 2009 to 2013 (n=12), group 3 - from 2014 to 2018 (n=9) accordingly. A statistically significant decrease in T1, T2, N1, N2 was found in successive time intervals of 5 years (p<0.05). In 8 of 27 (28.6%) patients the first attack of NMOSD was presented with non-specific symptoms (NS attack). In 7 patients (77.8%) of 9 misdiagnosed as multiple sclerosis (MS) an increase in attack frequency was found while on disease modifying therapies (DMTs) and increase in attack severity was found in 8 (88.9%). In all 9 cases the diagnosis was revised to NMOSD after AQP4-IgG test was performed with positive result. The time interval from disease course worsening while on DMTs until the test was 7 [4; 37] months, and the number of relapses - 2 [0; 3]. In 4 of 27 patients with suspected NMOSD, the repeated AQP4-IgG test only was positive for increased antibodies titer. The time interval between first test negative and retest administered was 20 [6.1; 47.8] months. In 3 of 4 patients (75%) one or more attacks occurred during this time period. In 4 patients the presence of AQP4-IgG in the first analysis was not followed by the diagnosis of NMOSD. In recent years, apropos AQP4-IgG test administration improved, but the problem remains with the timeliness for retest with first result negative. It is advisable to expand the indications for its use. The timeliness for serum AQP4-IgG retest in cases of unexplained deterioration in the course of proposed MS on DMTs and the lack of awareness of the test diagnostic value are still relevant.

[Diagnostic value of immunoglobulin free light chains at the debut of multiple sclerosis]. / Rol' opredeleniia svobodnykh legkikh tsepei immunoglobulinov v diagnostike debiuta rasseiannogo skleroza.

AIM: To evaluate the diagnostic value of determination of free immunoglobulin light chains (IgG) in the debut of multiple sclerosis (MS). MATERIAL AND METHODS: Data from 226 patients, including 111 patients with clinically isolated syndrome with conversion to multiple sclerosis within the first 2 years of the disease (group 1), 49 patients with clinically isolated syndrome who did not develop multiple sclerosis within the first 2 years of the disease (group 2), 20 patients with other inflammatory diseases of the central nervous system (group 3) were analyzed. The control group consisted of 46 patients with non-inflammatory diseases of the central nervous system. The clonality of immunoglobulins in the CSF, concentration of kappa and lambda free light chains and their ratio were studied. RESULTS: Concentrations of free light chains were significantly higher in the first group in comparison with group 2 and the control group, but didn't differ from group 3. In group 3, concentrations of free light chains were significantly higher compared to group 2 and controls. In oligoclonal-positive patients with clinically isolated syndrome (groups 1 and 2), concentrations of kappa and lambda free light chains were significantly higher than in oligoclonal-negative patients. The production of free light chains in patients from the first group was considerably higher than in group 2 regardless of the oligoclonal status. The concentration of kappa chains and quotient of kappa free light chains in the CSF had the best diagnostic characteristics. Their use, along with the evaluation of IgG clonality, reduced the risk of false-negative results by 50%. Regardless of other factors, elevated concentrations of kappa chains increase the likelihood of MS diagnosis by 9.718 times. CONCLUSION: The use of free light chains as a laboratory marker can increase the accuracy of MS diagnosis. These markers can help indirectly assess the risk of transformation of a clinically isolated syndrome into definite multiple sclerosis within the first 2 years of disease.

[The association of intrathecal production of immunoglobulin free light chains and progression of multiple sclerosis]. / Sviaz' intratekal'noi produktsii svobodnykh legkikh tsepei immunoglobulinov s progressirovaniem rasseiannogo skleroza.

AIM: To assess an impact of immunoglobulin free light chains (FLC) on short-term and long-term prognosis of clinical and radiological activity and progression of disability in multiple sclerosis (MS). MATERIAL AND METHODS: A sample of 381 patients with definite MS was divided into 2 groups. In group 1, lumbar puncture was performed at the time of clinically isolated syndrome, and patients were prospectively followed up to 2 years (short-term prognosis group, n=97). In group 2, MS was diagnosed immediately after lumbar puncture, and retrospective analysis of the disease course with the duration not less than 5 years was performed (long-term prognosis group, n=284). The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS) were used to assess patient's status. Concentrations of kappa and lambda FLC in the CSF (K-FLCCSF, L-FLCCSF) and serum (K-FLCSERUM, L-FLCSERUM) as well as quotients of concentrations (Q-K and Q-L) were determined. Patients were stratified into subgroups with high and low concentrations of K-FLC and L-FLC using cut-offs from our previous studies: K-FLCCSF=0.595 mcg/l and L-FLCCSF=0.127 mcg/l. RESULTS: In group 1, significant correlations were found only between EDSS score and concentrations of K-FLCCSF (r=0.377, p=0.00019) and Q-K (r=0.366, p=0.0012). FLC concentrations did not correlate with the number of relapses and new T2 lesions. The age and EDSS score at the disease onset didn't differ between patients with high and low K-FLC and L-FLC (K-FLCCSF: р=0.2658; L-FLCCSF: р=0.5502). A significant decrease of EDSS score after the disease onset was observed in all groups except for patients with high concentrations of K-FLCCSF (p=0.1844), so the EDSS score after 2 years was significantly higher in this subgroup of patients (p=0.0006). In group 2, significant correlations of K-FLC with EDSS score (r=0.181, p=0.002) and MSSS score (r=0.121, р=0.044) for long-term prognosis (median (IQR) = 8 (6-13) years) were found. No correlations of FLC concentrations with the number of relapses during the first 5 years were found. Survival analysis showed that high concentrations of K-FLCCSF were associated with the high risk of progression to EDSS 6 (HR=2.055, p=0.026) but not with EDSS 4 (HR=2.388, p=0.08). CONCLUSION: Concentrations of kappa FLC can help to define the prognosis of MS early at the disease course. Although low concentrations of FLC do not exclude a severe disease phenotype, patients with high K-FLCCSF concentrations are at greater risk for faster MS progression, probably, due to impaired reparation of neural tissue. Measurement of FLC concentrations can be used to determine a therapeutic tactics in patients with MS.

Immunogenicity of Human Interferon-Beta-Containing Pharmaceuticals.

Multiple sclerosis is a severe autoimmune disease with inflammatory component that continues to be resistant to treatment. One of the approaches retarding its progression is based on using nonspecific therapy with human interferon-beta (IFN-ß)-containing pharmaceuticals. Neutralizing antibodies (NAbs) against genetically engineered pharmaceuticals developed by the patient's immune system, which reduce their therapeutic and biological activity, pose a serious problem. Cell lines sensitive to IFN-ß activity also quantifying NAb level are applied because direct measurement of IFN-ß antiviral activity is complicated. This study was aimed at standardization and validation of a reporter cell system for measuring anti-human IFN-ß NAb titers, and evaluation data were obtained with samples from 33 patients with multiple sclerosis.

[The methods of detection of binding and neutralizing antibodies to preparations of interferon-beta].

The human recombinant ß-interferon is most frequently applied for treatment of remittent recurrent form of multiple sclerosis using pharmaceuticals. The clinical response to applied therapy is absent in some of patients that can be conditioned by development of antibodies too preparations. Depending on possibility of blocking binding of human recombinant ß-interferon with its receptor, all antibodies are divided on binding and neutralizing ones. The purpose of study is to investigate analytical and clinical diagnostic parameters of tests using for detection of different types of antibodies synthesized against human recombinant ß-interferon. The study sampling consisted of 33 patients with remittent recurrent form of multiple sclerosis receiving therapy with human recombinant ß-interferon and also of 40 donors and 15 patients with multiple sclerosis without therapy with human recombinant ß-interferon. The concentration of binding antibodies was measured by enzyme-linked immunosorbent assay. Also immune blotting assay was applied. The titer of neutralizing antibodies was determined using cell line HL-116 sensitive to human recombinant ß-interferon. The binding and neutralizing antibodies were not detected in donors and patients without human recombinant ß-interferon therapy. The prevalence of binding antibodies to human recombinant ß-interferon amounted to 57.6% when analysis of samples using immune blotting assay was used and 60.6% when commercial testing system was applied. The statistical analysis of results demonstrated high convergence and correlation of values of concentrations of binding antibodies obtained using immune blotting assay and enzyme-linked immunosorbent assay (r=0.9159, p<0.0001). The clinically significant titers of neutralizing antibodies were detected in 21.21°% of patients. All patients with clinically significant titer of neutralizing antibodies were positive in relation to binding antibodies measured by immune blotting assay and enzyme-linked immunosorbent assay. The high correlation between values of titers of neutralizing antibodies and concentration of binding antibodies measured by immune blotting assay (r=0.7909, p=0.0055). The application in clinical practice of data concerning presence of binding and neutralizing antibodies to human recombinant ß-interferon can input into optimization of therapy with expensive biologic preparations in patients with multiple sclerosis and other autoimmune diseases.