The Level of Anti-Viral Antigen-Specific Antibodies to EBNA-1 in the Serum of MS Patients Does not Depend on the Severity of the Disease.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease leading to inevitable disability and primarily affecting the young and middle-aged population. Recent studies have shown a direct correlation between the risk of MS development and Epstein-Barr virus (EBV) infection. Analysis of the titer of EBV-specific antibodies among patients with MS and healthy donors among Russian population confirmed that MS is characterized by an increased level of serum IgG binding EBNA-1 (EBV nuclear antigen 1). The number of patients with elevated levels of EBNA-1-specific antibodies does not differ statistically significantly between two groups with diametrically opposite courses of MS: benign MS or highly active MS. It can be assumed that the primary link between EBV and the development of MS is restricted to the initiation of the disease and does not impact its severity.

[Clinical characteristics and short-term outcomes of autoimmune encephalitis in adults]. / Klinicheskie kharakteristiki i kratkosrochnye iskhody autoimmunnogo entsefalita u vzroslykh.

OBJECTIVE: To characterize clinical, paraclinical features and short-term outcomes in different types of autoimmune encephalitis (AE) in a one-center cohort of Russian patients, as well as to evaluate the frequency and significance of the joint expression of antineuronal and anti-glial antibodies (Abs) in AE. MATERIAL AND METHODS: Forty-one patients were diagnosed with AE at the Research Center of Neurology from November 2020 to December 2022. Demographic, clinical characteristics, results of laboratory tests, MRI of brain, treatment and outcomes of disease were analyzed. The analysis of Abs to glial antigens (myelin-oligodendrocyte glycoprotein - MOG, glial fibrillar acidic protein - GFAP, aquaporin 4 - AQP-4) was performed by indirect immunofluorescence assay (Euroimmun, Germany). RESULTS: In 24 (58.5%) patients was established definite AE, confirmed by specific Abs detection; in 2 (4.9%) - definite limbic encephalitis, in 15 (36.6%) - seronegative probable AE (including 3 cases of Hashimoto's encephalitis). GFAP-Abs in cerebrospinal fluid (CSF) were detected only in two patients - with clinical and MRI-picture of autoimmune GFAP-astrocytopathy (A-GFAP-A). GFAP- and MOG-Abs in the blood were detected in 25.7% and 6%, respectively, AQP-4-Abs were not detected. There were no correlations between co-expression with glial Abs and clinical characteristics. Systemic and antithyroid Abs were present in 15% and 31%, respectively. Paraneoplastic AE accounted for 22%. For the first time in the Russian population, 2 cases of A-GFAP-A, 6 cases of AE associated with COVID-19 were described. The most common first syndrome were epileptic seizure (34%), psychiatric (29%) and cognitive (14%) disorders. Relapses of AE was observed in 22%. Inflammatory changes in CSF were detected in 41%, focal changes on MRI in 68%. First-line immune therapy was performed in all patients, 85% of cases received pulse therapy with methylprednisolone. Second-line immune therapy (rituximab or cyclophosphamide intravenously) was performed in 19.5%, 78% of patients achieved significant improvement during treatment (scores ≤2 on the modified Rankin scale). CONCLUSIONS: The results allow us to consider COVID-19 as a trigger of AE. The absence of detection of GFAP-Abs in CSF in patients with other types of AE contributes to the confirmation of the specificity of GFAP-seropositivity of CSF for the diagnosis of A-GFAP-A. The expression of GFAP- and MOG-Abs in AE can serve as confirmation of the immuno-mediated etiology of the disease, which is especially important for the AE diagnosis in the absence of antineuronal Abs.

[Acute hemorrhagic leukoencephalitis with a subacute onset]. / Ostryi gemorragicheskii leikoentsefalit Khersta, variant podostrogo techeniya.

Acute hemorrhagic leukoencephalitis (AHLE), also called Hurst's encephalitis, is a rare demyelinating disease of the central nervous system characterized by rapid progression and acute inflammation of the white matter of the brain and spinal cord. AHLE is currently considered as a rare, most severe variant of acute disseminated encephalomyelitis. Clinically AHLE is characterized by a fulminant course with a rapid development of encephalopathy and multifocal neurological symptoms. AHLE is associated with high mortality rate that requires immediate and aggressive treatment initiation. This article describes a case of AHLE with an atypical course, a subacute form, which is extremely rarely described in the literature, with the progressive symptoms' development over several months. Due to delayed treatment initiation, unfortunately, a fatal outcome has been observed. Subsequent histological examination of the autopsy material confirmed the presence of a subacute form of AHLE in the patient.

[Hereditary optic neuropathy associated with demyelinating diseases of the central nervous system]. / Nasledstvennaya opticheskaya neiropatiya v sochetanii s demieliniziruyushchimi zabolevaniyami tsentral'noi nervnoi sistemy.

Demyelinating optic neuritis and hereditary optic neuropathy (HON) take a leading place among the diseases, the leading clinical syndrome of which is bilateral optic neuropathy with a simultaneous or sequential significant decrease in visual acuity. Optic neuritis can occur at the onset or be one of the syndromes within multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD). HON are a group of neurodegenerative diseases, among which the most common variants are Leber's hereditary optic neuropathy (LHON), associated with mitochondrial DNA (mtDNA) mutations, and autosomal recessive optic neuropathy (ARON), caused by nuclear DNA (nDNA) mutations in DNAJC30. There are phenotypes of LHON «plus¼, one of which is the association of HON and CNS demyelination in the same patient. In such cases, the diagnosis of each of these diseases causes significant difficulties, due to the fact that in some cases there are clinical and radiological coincidences between demyelinating and hereditary mitochondrial diseases.

[The need to validate translations into Russian of objective neurological scales, symptoms and syndromes]. / K voprosu o neobkhodimosti validizatsii perevodov na russkii yazyk ob"ektivnykh nevrologicheskikh shkal, simptomov i sindromov.

The article discusses the possibility and expediency of validating translations into Russian of objective and subjective neurological scales, the advantages and disadvantages of such translations, which is extremely relevant at the present time. As an example, the expediency of «validating¼ the translation into Russian of the objective neurological scale for assessing the severity of symptoms of the Expanded Disability Status Scale, which is widely used in patients with multiple sclerosis is discussed. The results of assessing the severity of neurological disorders according to these neurological scales do not depend on translation into other languages and therefore do not need validation.

[Optic neuropathies as an interdisciplinary subject of research]. / Opticheskie neiropatii kak predmet mezhdistsiplinarnogo izucheniya.

Despite the wide range of clinical, instrumental and laboratory methods used in modern ophthalmology, the problem of diagnosing optic neuropathy and identifying its etiology remains relevant. A complex multidisciplinary approach involving various specialists is required in the differential diagnosis of immune-mediated optic neuritis, for example in multiple sclerosis, neuromyelitis optica spectrum disorder, and MOG-associated diseases. Of special interest is differential diagnosis of optic neuropathy in demyelinating diseases of the central nervous system, hereditary optic neuropathies and ischemic optic neuropathy. The article presents a summary of scientific and practical results of differential diagnosis of optic neuropathies with various etiologies. Timely diagnosis and early therapy start reduces the degree of disability in patients with optic neuropathies of different etiologies.

[Long-term Efficacy and Safety of Sampeginterferon-ß1a in the Treatment of Relapsing Remitting Multiple Sclerosis: a Randomized, Double-Blind Clinical Trial 104-Week Results]. / Dolgosrochnye dannye po effektivnosti i bezopasnosti preparata sampeginterferon-ß1a u patsientov s remittiruyushchim rasseyannym sklerozom: rezul'taty 104-nedel'nogo randomizirovannogo dvoinogo slepogo klinicheskogo issledovaniya.

OBJECTIVE: To assess the efficacy and safety of sampeginterferon-ß1a (samPEG-IFN-ß1a) 180 µg and 240 µg administered once every 2 weeks compared to placebo and low dose interferon beta-1a (LIB) 30 µg administered once weekly. MATERIAL AND METHODS: Patients with relapsing-remitting multiple sclerosis aged 18-60 years, with Expanded Disability Status Scale score ≤5.5 were randomized at a ratio of 2:2:2:1 to the following groups: samPEG-IFN-ß1a 180 µg, samPEG-IFN-ß1a 240 µg, LIB, placebo. After 20 weeks, the placebo group completed the study. After week 52, the final analysis was performed, which included the primary endpoint analysis, the LIB group patients completed their participation in the study. The patients in samPEG-IFN-ß1a groups continued to receive therapy with samPEG-IFN-ß1a 240 µg until week 100 inclusive. The results of the final analysis after 52 weeks have been previously published. The current article presents a long-term efficacy and safety of samPEG-IFN-ß1a after 104 weeks of the trial. RESULTS: The annualized relapse rate over the second year was 0.16 in the samPEG-IFN-ß1a 180 µg group and 0.09 in the samPEG-IFN-ß1a 240 µg group. By week 104, the proportion of relapse-free patients was 77.0% (87/113) and 83.3% (95/114) in the samPEG-IFN-ß1a 180 µg and 240 µg groups, respectively. There were no negative dynamics of MRI markers, neurological deficit parameters and cognitive functions by scales and tests. The safety profile of samPEG-IFN-ß1a was consistent with the known safety profile of IFN-ß therapy. CONCLUSION: Treatment with samPEG-IFN-ß1a is an effective and safe first-line therapy for relapsing-remitting multiple sclerosis patients.

[Typical and atypical optic neuritis]. / Tipichnyi i atipichnyi opticheskii nevrit.

Optic neuritis (ON) is one of the most common neuro-ophthalmic causes of vision loss worldwide. Demyelinating ON can be idiopathic or be one of the symptoms of autoimmune demyelinating diseases of the central nervous system (CNS) such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Demographic, clinical and radiological signs of ON in these CNS diseases have differences. In this regard, typical and atypical ON are currently distinguished. Recognizing the clinical features that differentiate typical MS-associated ON from atypical ON in NMOSD and MOGAD is important for choosing the correct disease management and treatment strategy. This review summarizes the data from clinical, laboratory, instrumental methods of management used for the differential diagnosis of optic neuritis.

[Mechanisms of Neurodegeneration in Multiple Sclerosis]. / Mekhanizmy neirodegeneratsii pri rasseyannom skleroze.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, which results in the formation of primary demyelinating lesions in the white and gray matter, as well as diffuse axonal and neuronal damage. Although there has been substantial progress in drug research in relapsing-remitting MS, treatment of progressive forms of the disease, can be challenging. Diffuse and compartmentalized lymphocyte and macrophage infiltration of the CNS tissue inhibits the differentiation of myelinating mature oligodendrocytes, disrupting the process of remyelination. Chronic inflammation that occurs behind a closed blood-brain barrier (BBB) leads to microglia activation, which increases mitochondrial damage to axons and neurons, and therefore triggers chronic oxidative stress and histotoxic hypoxia. Thus, raising awareness about the mechanisms of neurodegeneration appears relevant. In the late stages of MS, it is caused by chronic neuroaxonal damage, disruption of the regenerative ability of the CNS, and to a great extent determines the disease outcome.

[New opportunities in the treatment of patients with multiple sclerosis (Resolution of the Council of Experts on April 23, 2022, Moscow, JSC «BIOCAD¼)]. / Novye vozmozhnosti v terapii patsientov s rasseyannym sklerozom¼ (Rezolyutsiya soveta ekspertov 23 aprelya 2022 goda, Moskva, AO «BIOKAD¼).

One of the target areas for the development of the Russian pharmaceutical industry at present is the development of next-in-class drugs medicines. These are original, patent-protected drugs that act on known biological targets, improved or modified in structure and mechanism of action compared to existing, successfully proven medicine. The article presents the results of an expert council on the management of patients with multiple sclerosis and the place of new original medicines of the JSC BIOCAD company (SamPEG-IFN-ß1a and divozilimab) in multiple sclerosis therapy algorithm.

[Anti-Ma2 paraneoplastic autoimmune encephalitis]. / Anti-Ma2 paraneoplasticheskii autoimmunnyi entsefalit.

Paraneoplastic syndromes are a heterogeneous group of conditions affecting cancer patients, where the symptoms are not owing to the local effects of the tumor but instead owing to humoral or immunologic effects. Paraneoplastic neurological syndromes (PNS) develop in less than 1% of cancer patients and can affect any part of the nervous system. A variety of PNS phenotypes are associated with anti-Ma2 antibody, primarily encephalitis with a predominant involvement of brainstem, limbic and diencephalic structures. We describe a case of anti-Ma2 autoimmune encephalitis with a recurrent course in a patient with two different primary tumors in the anamnesis.

Multiple Sclerosis Is Associated with Immunoglobulin Germline Gene Variation of Transitional B Cells.

The regulatory functions of the B-cell compartment play an important role in the development and suppression of the immune response. Disruption of their anti-inflammatory functions may lead to the acceleration of immunopathological processes, and to autoimmune diseases, in particular. Unfortunately, the exact mechanism underlying the functioning and development of regulatory B cells (Breg) has not yet been fully elucidated. Almost nothing is known about their specificity and the structure of their B-cell receptors (BCRs). In this research, we analyzed the BCR repertoire of the transitional Breg (tBreg) subpopulation with the CD19+CD24highCD38high phenotype in patients with multiple sclerosis (MS), using next-generation sequencing (NGS). We show, for the first time, that the immunoglobulin germline distribution in the tBreg subpopulation is different between MS patients and healthy donors. The registered variation was more significant in patients with a more severe form of the disease, highly active MS (HAMS), compared to those with benign MS (BMS). Our data suggest that during MS development, deviations in the immunoglobulin Breg repertoire occur already at the early stage of B-cell maturation, namely at the stage of tBregs: between immature B cells in the bone marrow and mature peripheral B cells.

[Clinical and epidemiological aspects of neuromyelitis optic spectrum diseases in the russian population]. / Kliniko-epidemiologicheskie aspekty zabolevanii spektra optikoneiromielita v rossiiskoi populyatsii.

OBJECTIVE: To present clinical and epidemiological aspects of neuromyelitis optica spectrum disorders (NMOSD) in the Russian Federation. MATERIAL AND METHODS: We studied 142 patients who met diagnostic criteria of 2015 for NMOSD. Sex, age at disease onset, presence or absence of aquaporin-4 immunoglobulin G antibodies (AQP4-IgG), mail clinical symptoms, oligoclonal IgG, therapy for the treatment of exacerbations and prevention of exacerbations, compliance with 2006 diagnostic criteria were assessed. RESULTS: The prevalence of women is 4.26:1, the most frequent age at disease onset is 18-29 years (36% of cases). The laboratory aspects of the disease are characterized and approaches to the treatment and prevention of exacerbations of NMOSD in patients of the Russian population are evaluated. Approaches to diagnostics are compared depending on the applied diagnostic criteria (34% of patients do not meet neuromyelitis optica 2006 diagnostic criteria). A prognosis for the prevalence of NMOSD in the Russian population has been proposed: 0.45-4.21/100000. CONCLUSION: This is the first published data on clinical and epidemiological characteristics of NMOSD in the Russian Federation.

[Rehabilitation of patients with multiple sclerosis]. / Reabilitatsiya patsientov s rasseyannym sklerozom.

Multiple sclerosis is a common cause of disability among young and middle-aged people. Despite the modern possibilities of diagnostics and therapy, over time, the disease acquires a secondary progressive character. Rehabilitation of patients at all stages of the disease plays an important role in improving well-being, improving the quality of life, adapting the patient and restoring motor skills. However, there is currently no clear recommendation for the application of specific techniques in each case. The aim of this work was to analyze the available methods of rehabilitation therapy, to highlight the most used and promising ones. Due to the progressive course of the disease, the benefits of rehabilitation measures are usually higher at the initial stages. Nevertheless, nowadays there is a large number of works devoted to rehabilitation measures in patients with moderate and high levels of disability. It has been shown that both inpatient and outpatient rehabilitation has a positive effect on the quality of life and improvement of clinical indicators. Our review describes the main techniques with recommendations for the scheme of application. A comprehensive assessment of the patient's health status, a multidisciplinary team and a personalized approach increase the quality and effectiveness of rehabilitation measures. We also describe our own experience in the treatment of spasticity in patients with a secondary progressive multiple sclerosis.

[Monoclonal antibody therapies for rapidly progressive and highly active multiple sclerosis in the era of the COVID-19 pandemic]. / Terapiya monoklonal'nymi antitelami bystroprogressiruyushchego i vysokoaktivnogo rasseyannogo skleroza v epokhu pandemii COVID-19.

As the COVID-19 pandemic continues, reducing the risk of infection for immunocompromised patients remains an important issue. Patients with aggressive multiple sclerosis (MS) require immunosuppressive therapy in order to control the overactive autoimmune response. Preliminary international and national trials demonstrate that older age, higher disability status and progressive MS are generally associated with a more severe clinical course of COVID-19. However, uncertainty remains about the effect of disease-modifying therapies on the COVID-19 clinical presentation. In this article, we pay special attention to monoclonal antibodies used for immune reconstitution therapy, which results in significant changes to the T-cell and/or B-cell repertoire. Based on the published data from registries in different countries, we attempted to estimate the benefits and risks of these therapies in a complicated epidemiological setting.

[C9orf72-associated frontotemporal dementia in the Russian population]. / C9orf72-assotsiirovannaya forma lobno-visochnoi dementsii v rossiiskoi populyatsii.

OBJECTIVE: To evaluate the frequency of C9orf72-associated frontotemporal dementia (FTD) in the Russian population and to study clinical features of GGGGCC-repeat expansion carriers. MATERIAL AND METHODS: Twenty-eight patients with FTD are included in the study: 15 with a behavioral variant of FTD (bvFTD) and 13 with a agrammatic/non-fluent variant of primary progressive aphasia (avPPA). The mean age was 62 years (34-80), the mean disease duration was 4 years (1-10). The positive family history was noted in 46% of cases. DNA diagnosis was performed using repeat-primed polymerase chain reaction. RESULTS: The frequency of the C9orf72 repeat expansion in patients with FTD was 14%, in patients with bvFTD 20%, in patients with avPPA 8%. The mean age of disease onset in the expansion carriers was 63 (55-75) years. The frequency of the C9orf72 repeats expansion in familial FTD cases was 31%, in sporadic cases 7%. bvFTD with parkinsonian syndrome was noted in two out of four cases, bvFTD with amyotrophic lateral sclerosis (ALS) was shown in one case, avPPA with ALS was shown in one case. One female patient with bvFTD with parkinsonian syndrome presented with cognitive fluctuations that required a differential diagnosis with Lewy body disease. CONCLUSION: This is the first study of the genetic structure of FTD in the Russian population. The prevalence and clinical characteristics of C9orf72-associated FTD were defined, in particular, the spectrum of motor symptoms was shown along with behavioral and aphasic disturbances. DNA diagnosis plays an important role in confirming the diagnosis and selection of patients for potential disease-modifying treatment.

C9orf72 Gene Expression in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We studied the expression of C9orf72 gene in pathologies associated with hexanucleotide repeats expansion in this gene: frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The study included 7 patients with hexanucleotide repeats expansion in the C9orf72 gene and 9 patients of the control group. The expression of C9orf72 mRNA was evaluated in blood leukocytes by real-time PCR. Methylation of CpG-sites in C9orf72 promotor region was evaluated by DNA sequencing after bisulfite conversion. A 2-fold decrease in the C9orf72 gene expression was found in patients with hexanucleotide repeats expansion in comparison with controls, though the difference did not reach statistical significance due to small sample size. The highest expression was shown for ALS in comparison with FTD and FTD-ALS phenotype. A trend to inverse correlation between C9orf72 mRNA level and promoter methylation of this gene as well as between mRNA level and age of disease onset was demonstrated.

[Myelin oligodendrocyte glycoprotein immunoglobulin G-associated encephalomyelitis]. / Entsefalomielity, assotsiirovannye s antitelami k mielin-oligodendrotsitarnomu glikoproteinu.

The article discusses the role of myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) in demyelinating diseases of the central nervous system. Clinical phenotypes of demyelinating syndromes associated with MOG-IgG that are currently included into neuromyelitis optica spectrum disorders (NMOSD) are described. However, it has been shown that encephalomyelitis associated with MOG-IgG (MOG-EM) has certain clinical, radiological, immunological and histopathological features that make it possible to single out these syndromes into a separate nosological form. We provide International recommendations that establish indications for testing MOG-IgG using cell-based assay. We discuss epidemiological issues and classification challenges of the disease. Various approaches to treatment and prevention of relapses of MOG-EM are analyzed.

[Experience in designing an electronic multiple sclerosis registry]. / Opyt sozdaniya elektronnogo registra patsientov s rasseyannym sklerozom.

OBJECTIVE: To develop an electronic registry of patients with MS in the Russian Federation and to analyze the collected epidemiological and clinical data. MATERIALS AND METHODS: Patients aged 18 and older with definite multiple sclerosis were included in the study. We designed a specialized electronic individual registration form (registry) to gather information about study participants. This paper presents data collected in the project between September 25, 2017 and March 25, 2020. RESULTS: We collected information on 2728 patients. This paper presents the results of data analysis from the registry of MS patients, including demographic, clinical and epidemiological characteristics, the type and timing of treatment received. Based on the data obtained, certain issues with primary diagnosis of multiple sclerosis and delayed initiation of disease-modifying therapy can be highlighted, which contribute to the transition of the disease to a secondary progressive course and disability increase.

[Updated recommendations of the Council of Experts on the use and safety of alemtuzumab (Lemtrada)]. / Obnovlennye rekomendatsii soveta ekspertov po primeneniyu i obespecheniyu bezopasnosti terapii preparatom alemtuzumab (Lemtrada).

Alemtuzumab (Lemtrada) is a recombinant humanized IgG1 kappa monoclonal antibody to the surface cell glycoprotein, a CD52 differentiation cluster. The drug is approved for use in more than 65 countries, including the Russian Federation. The drug is one of the most effective methods of treating patients with aggressive multiple sclerosis, but the risk management plan should be followed. The safety profile of the drug includes infusion-associated reactions, thyroid dysfunction, immune cytopenia, acute cardiovascular events, infections, and other autoimmune diseases. This publication provides updated practical recommendations for the use of the drug and ensuring the safety of patients treated with alemtuzumab.