OBJECTIVE:To compare efficacy of the new drug divozilimab with other second-line treatment options for relapsing remitting multiple sclerosis (RRMS) that have been already included or submitted application to be included into the «14 high-cost nosologies» program in the Russian Federation. MATERIAL AND METHODS:We conducted systematic literature review (PROSPERO ID CRD42022310082) and frequentist network meta-analysis of 2-years efficacy of divozilimab and other second-line therapies to treat RRMS. RESULTS:Annualized relapse rate ratio in divozilimab vs fingolimod was 0.4 (95% CI 0.3-0.7), divozilimab vs cladribin 0.5 (95% CI 0.3-0.9), divozilimab vs alemtuzumab 0.7 (95% CI 0.3-1.7), divozilimab vs ocrelizumab 0.7 (95% CI 0.3-1.6), divozilimab vs ofatumumab 0.7 (95% CI 0.4-1.1), divozilimab vs natalizumab 0.4 (95% CI 0.4-1.1) respectively. Divozilimab had the highest SUCRA rank (0.9) while fingolimod had the lowest (0.4). CONCLUSION:Systematic literature review and network meta-analysis revealed statistically significant superiority of divozilimab over cladribine and fingolimod and absence of statistically significant differences with alemtuzumab, ocrelizumab, ofatumumab and natalizumab in the annual relapse rate during 2 years of treatment.

Primary central nervous system lymphoma (PCNSL) is a rare neoplasm that can affect the brain, eyes, and, rarely, the spinal cord. Clinical presentation and MRI findings can mimic a variety of diseases, including high-grade gliomas, infectious and granulomatous diseases, and demyelinating diseases. We describe three cases where the diagnosis of PCNSL was difficult due to an ambiguous clinical, radiological and laboratory results. The role of stereotactic biopsy remains leading in differential diagnosis; however, the invasiveness and frequent limitations of this method determine the search for additional biological markers of the disease. New evidence suggests a potential role for cerebrospinal fluid (CSF) cytokine profiles and proteomic analysis in differential diagnosis, disease progression, and treatment response.

This study is a continuation of our previous research aimed at investigating changes in the pools of amino acids in the myocardium of the ground squirrel during winter torpor. Neurochemical profiles of amino acids and the secondary metabolites (taurine, phosphoserine, and cysteic acid) were explored in the neocortex of the ground squirrel at different stages of torpor: in the beginning of torpor (2–3 days) and during prolonged torpor (9–10 days), as well as during short-term winter arousal (winter activity, euthermia). Reduced excitatory neurotransmitter levels (glutamate by 7% and 14%; aspartate by 25% and 52% in a coordinated manner and the increased level of GABA, the main transmission inhibitor (by 50% and 67%) were observed from the onset of the torpor entry and at the end of the torpor arousal, respectively. Alanine, which was formed in negligible amounts in the neocortex in the summer season, increased at the initial stage of hibernation and after multiday torpor bout (by 98% and 126%, respectively), indicating a partial switch to anaerobic glycolysis. Short-term inter-bout euthermia returned levels of these substances back to normal. The behavior of glutamate and aspartate, the anaplerotic substrates, that supported cycling of the tricarboxylic acid cycle during torpor and winter activity periods was like their responses in the myocardium, though differed quantitatively. The responses of the neuromodulators such as glycine, threonine, and lysine differed radically when compared to their responses in the myocardium. No changes in taurine and phosphoserine pools were detected, but the level of cysteic acid decreased compared to the summer control from 0.51 ± 0.06 μmol/g to 0.07 ± 0.01 μmol/g at the end of torpor, while during winter euthermia it became 2 times lower than the summer level. Our data suggest that metabolic pathways, involving anaplerotic amino acids of the neocortex, are more active than the myocardium during winter torpor, while the pools of neuromodulators that regulate inhibition processes, increase.

The temperature coefficients of heart rate (Q10 HR) or oxygen consumption (Q10 Ox) were analyzed upon arousal from natural hibernation in long-tailed ground squirrels Urocitellus undulatus and during the rewarming of artificially precooled adult rats and rat pups. The Q10 Ox value was calculated using a standard equation, whereas for calculating Q10 HR, the equation was empirically modified to track changes in this parameter over a wide range of body temperatures (T b). It was found that during the initial period of arousal from torpor, at T h ≤ 10°C, ground squirrels demonstrated a sharp increase in the temperature coefficients up to Q10 HR = 40–50 and Q10 Ox = 6–7. Even higher values of Q10 HR (>100) were recorded at the onset of rewarming of rat pups, although they had a low level of Q10 Ox (1.2). Adult rats could not tolerate cooling below 16°C and demonstrated a moderate variability of both Q10 HR = 2.0–4.0 and Q10 Ox = 2.0–2.2. During the recovery of normal T b, the Q10 HR values in all animals approximated to 2.0, as predicted by the van’t Hoff–Arrhenius rule for chemical reactions in both living and inanimate nature. We assume that high values of Q10 HR and Q10 Ox, detected in the early period of ground squirrel’s arousal from hibernation, may indicate the functioning of adaptive processes aimed at accelerating body warming. Resistance to cooling and a high Q10 HR in rat pups may suggest the rudimentary adaptability to hibernation in the juvenile period of rats as representatives of the order Rodentia, which also includes such natural hibernators as ground squirrels.

Temporal and parahippocampal glial tumors at early morphological stages of their development may mimic the clinical and neuroimaging picture of limbic encephalitis. Delayed diagnosis of glioblastoma can have a negative impact on the prognosis of the disease, which is why there is a need to find approaches for its earlier detection. The aim of this paper is to analyze possible difficulties and errors in the differential diagnosis of autoimmune encephalitis (AE) and glioblastoma based on literature data and our own clinical observations. Features such as onset of the disease at a young age, subacute development of symptoms, response to immunosuppressive therapy and the MRI imaging of bilateral T2 hyperintense changes in the limbic areas are typical for AE, but do not exclude the diagnosis of a primary tumor of the central nervous system. Therefore, caution should be exercised regarding the likelihood of a primary brain tumor when patients of any age group present with symptoms characteristic of AE, especially if no specific for AE antibodies are detected. To shorten the time to diagnosis, a multidisciplinary approach, critical analysis of clinical data, a shortening of the examination interval and an increase in the frequency of imaging follow-up examinations are required.

Planning for pregnancy and possibility of disease modifying treatment (DMTs) is an important question in female patients of reproductive age who suffer from multiple sclerosis (MS). The frequency of refusals to plan pregnancy is 14%. This is due to numerous concerns about the course of pregnancy, its outcomes, as well as the possible effect of DMTs on the fetus and the probability of disease transmission to a child. The article discusses immunological reactions taking place in MS patients during pregnancy, which are protective in its nature. Data for all groups of DMTs regarding pregnancy planning, possible risks of their impact on fertility and teratogenicity is presented.

Previously, it has been shown that a series of physiological and biochemical changes occur in Yakutian long-tailed ground squirrels during autumn (the pre-hibernation period), involving the brain, heart, skeletal muscles, and other organs. This study was conducted to analyze the composition of peripheral blood cells obtained from Yakutian ground squirrels in autumn. For the first time, an increase in the total number of leukocytes, particularly granulocytes, and a decrease in the number of lymphocytes were observed when compared with samples obtained in summer; a leukogram shift from the lymphocytic to the granulocytic fraction was revealed. Significant increase in platelet counts and thrombocrit with preservation of the percentage ratio of mature and young cell fractions was shown. To date, information on the cellular components of blood during the autumn season when hibernators prepare for winter months of hibernation remains scarce. Nonetheless, the results of our study indicate that very significant adaptive changes occur in leukocytes and platelets of ground squirrels in this period. Possible causes of these changes are discussed.

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.

Background. Assessment of short-interval intracortical inhibition (SICI) using paired-pulse transcranial magnetic stimulation (TMS) and the threshold tracking technique is a promising approach to develop biomarkers of motor cortex damage in amyotrophic lateral sclerosis (ALS). Both high sensitivity and specificity of this approach were shown previously; however, almost all studies in this field were conducted by one group of authors.Aim. The replication of data showing impairment of SICI assessed by threshold tracking technique in patients with ALS.Materials and methods. 18 patients with ALS and 13 healthy volunteers were included into the study. Functional state of the patients was assessed as well as disease duration, form, stage and progression rate. Following values were determined in all participants using TMS: 1) resting motor threshold (MT); 2) mean motor evoked potential (MEP) amplitude of 30 stimuli applied with an intensity of 120 % MT; 3) SICI assessed using an algorithm based on paralleled optimized threshold tracking with interstimulus interval (ISI) of 1.0 ms, 1.5 ms, 2.0 ms, 2.5 ms, 3.0 ms, 3.5 ms, 4.0 ms, 5.0 ms, 7.0 ms, as well as mean inhibition for values with ISI from 1.0 to 3.0 ms and from 1.0 to 7.0 ms.Results. No significant differences between groups were observed for MT and MEP amplitude. Significant decrease of SICI with ISI 1.0 and 2.0 ms as well as mean SICI from 1.0 and 3.0 ms was observed in ALS. No significant correlations of MT, MEP amplitude or SICI with clinical values were found.Conclusion. This replication study has shown the ability of paired-pulse TMS with threshold tracking technique to identify the impairment of intracortical inhibition in patients with ALS.

Current approaches to treating multiple sclerosis aim at controlling disease activity. Despite the variety of agents that have proven their effectiveness and were introduced in practice in the last decade, the use of the interferon β group remains relevant. The article presents clinical cases of long-term use of interferons β in treating multiple sclerosis.

Morphofunctional features of the bone marrow obtained from the femoral shaft and humeral diaphysis of long-tailed ground squirrels were studied in summer and fall, as well as during torpor bouts and short-term winter arousals (winter euthermic intervals). Histological analysis showed an increase in the count and size of bone marrow adipocytes in torpid animals, with a partial myeloid-to-adipose tissue replacement. Although the femoral bone marrow has a larger volume compared to the humeral, it contains significantly less nucleated cells, but significantly more erythroid islets, particularly during hibernation. In torpid ground squirrels, disc-shaped erythrocytes in the blood are replaced by atypical forms (oval- and target-shaped, macrocytes) whose counts drop significantly during winter euthermia. The reticulocyte count increases twofold during hibernation compared to the summer period. The results obtained are discussed in the context of maintaining high blood oxygen levels during torpor and erythropoiesis adaptation to conditions of prolonged hypothermia.

This article presents a clinical case of Gerstmann–Sträussler–Scheinker syndrome (GSS) – a progressive inherited prion disease with an extremely rare phenotype that changed dynamically during the course of the disease and eventually led to the misdiagnosis of a motor neurone disease. An important feature of this case is a progressive myelopathy, probably due to the deposition of prion protein plaques, with the development of symptoms of lower motor neuron involvement (muscle atrophy, areflexia, fasciculations and muscle hypotonia). Clinical, laboratory, electrophysiological and neuroradiological features of this case are presented. The final diagnosis was verified by whole-exome sequencing – a typical mutation p.P102L in the prion protein gene PRNP was identified. It is discussed whether GSS should be included in the differential diagnosis in patients with progressive motor disorders, a family history and unchanged long nerve conduction function according to electromyography.

In this study, changes in all blood formed elements of long-tailed ground squirrel Urocitellus undulatus (n=100) during different periods of their life activity were investigated. The hematological analysis was performed on an automatic veterinary analyser: a indices of leukocytes, platelets and erythrocytes were measured in summer (normothermia, june-july), autumn (preparatory period, october), winter torpid (hypothermia, december-february) and winter active periods (IBA, euthermia, short awakenings between hypothermia stages, december-february). It was shown that the total counts of platelets and leukocytes of ground squirrel increased by ~40 % in autumn compared to summer. During the torpor period, thrombocytosis and leukocytosis were replaced by extreme thrombocytopenia (~90 %) and leukopenia (~80 %). On awakening, the indices reached “summer” values, except for a slightly increased mean platelets volume. In autumn, an insignificant erythrocytosis (~10 %) was observed, which, together with changes in other parameters, could indicate an unexpressed autumn hypoxia. In torpor and in winter euthermia, the erythrocyte indices were no difference with summer control values; however, the presence of atypical forms of erythrocytes was detected both in the autumn period of preparation for hibernation and during hibernation. The results are discussed in the context of the adaptation of the blood-forming elements of the ground squirrel to the extreme conditions of hibernation and are valuable for the study of the adaptive abilities of homoeothermic animals and humans.

Demyelinating diseases are a group of heterogeneous pathologies that affect the nervous system and reduce the quality of life. One of such diseases is multiple sclerosis (MS), an inflammatory autoimmune neurodegenerative disease of the central nervous system (CNS). At the initial stages, MS can mimic some infectious, neoplastic, genetic, metabolic, vascular, and other pathologies. Accurate differential diagnosis of this disease is important to improve the quality of life of patients and reduce possible irreversible damage to the central nervous system. In this work, we confirmed the possibility of using our previously proposed candidate panel of MS biomarkers to distinguish MS from neuromyelitis optica spectrum disorder (NMOSD) and amyotrophic lateral sclerosis (ALS). We have shown that our proposed panel (SPTAN1601-644 + PRX451-494 + PTK6301-344 + LMP1285-330) allows us to distinguish MS from ALS (AUC = 0.796) and NMOSD (AUC = 0.779).

OBJECTIVE:To assess the efficacy and safety of sampeginterferon-β1a (samPEG-IFN-β1a) 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-β1a 180 µg, samPEG-IFN-β1a 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-β1a groups continued to receive therapy with samPEG-IFN-β1a 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-β1a after 104 weeks of the trial.RESULTS:The annualized relapse rate over the second year was 0.16 in the samPEG-IFN-β1a 180 μg group and 0.09 in the samPEG-IFN-β1a 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-β1a 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-β1a was consistent with the known safety profile of IFN-β therapy.CONCLUSION:Treatment with samPEG-IFN-β1a is an effective and safe first-line therapy for relapsing-remitting multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), which leads to the formation of foci of primary demyelination in the white and gray matter and diffuse damage to axons and neurons. Despite significant progress in the development of drugs for relapsing-remitting MS, the impact on the progression of the disease remains insufficient. Diffuse and compartmentalized lymphocyte and macrophage infiltration of CNS tissue inhibits the differentiation of myelinating mature oligodendrocytes and disrupts remyelination processes. Chronic inflammation, which occurs when the blood–brain barrier (BBB) is intact, activates microglia, increasing axon and neuron damage and, as a result, triggers chronic oxidative stress and histotoxic hypoxia. It is currently important to clarify the mechanisms underlying neurodegeneration, which in the later stages of MS is caused by chronic neuroaxonal damage and impairment of regenerative capabilities and which largely determines disease outcome.

Optic neuritis (ON) can often occur at the onset of a demyelinating autoimmune CNS disease or as one of its clinical manifestations. The introduction of novel laboratory techniques, technical advances in magnetic resonance imaging (MRI), electrophysiologic studies, and ocular imaging have significantly expanded the spectrum of autoimmune optic neuropathies. Identification of different forms of ON based on clinical and instrumental data can lead to early diagnosis of the underlying neurologic disorder. According to current guidelines, one can distinguish between typical ON, which are mainly associated with multiple sclerosis (MS), and atypical ON, which are the main clinical manifestation of neuromyelitis optica spectrum disorders (NMOSD) and diseases associated with myelin oligodendrocyte glycoprotein antibodies (MOGAD). In this paper, we present four clinical cases of atypical ON at the onset of NMOSD and MOGAD and illustrate the high diagnostic value of a multidisciplinary approach.

Changes in the content of heat shock protein 90 (HSP90) in m. soleus (contains mainly fibers expressing the “slow” isoform I MyHC) and m. gastrocnemius (contains mainly fibers expressing the “fast” isoforms II MyHC) of a true hibernant, the long-tailed ground squirrel (Urocitellus undulatus), during different periods of the annual cycle, summer activity (seasonal control), hypothermia/winter torpor, and winter (interbout) activity, were studied. It was found that despite the development of atrophic changes that were more pronounced in the “fast” m. gastrocnemius, the content of HSP90 in both muscles did not change throughout the hibernation period. The role of HSP90 in maintaining the stability of the titin giant sarcomeric protein molecules during the periods of the animal’s entry into and exit from hypothermia, when the activity of calpain proteases increased due to the increased content of Ca2+ in the cytosol of muscle cells, as well as during hypothermia, when the activity of calpains most likely was not completely inhibited, was discussed. During the winter/interbout activity, when there was an increased titin turnover in the striated ground squirrel muscles, a constant content of HSP90 was apparently necessary for the correct folding of newly synthesized titin molecules and their embedding into sarcomeres, as well as for the removal of improperly folded and old titin molecules/fragments, as well as other proteins. Thus, HSP90 proteostasis in skeletal muscles of the long-tailed ground squirrel could contribute to maintaining a stable level of titin and, possibly, other sarcomeric proteins during hibernation, which, in turn, would contribute to maintaining a highly ordered sarcomeric structure and the necessary level of contractile muscle activity in different phases of the hibernation–wakefulness cycle.