Progressive Course Of Multiple Sclerosis Research Articles

A comparative study of human endogenous retrovirus <i>HERV-E λ 4-1</i> activation in autoimmune pathology

Considering the presence of immunomodulatory properties of human endogenous retroviruses, namely (i) the ability to activate the innate immune response by HERVs nucleic acids; (ii) the antigenicity of transcriptionally competent endogenous retroviruses envelope protein molecule, which causes polyclonal activation of lymphocytes; (iii) the absence of HERVs expression and protein production in the thymus during the immune tolerance formation, which allows us to consider these proteins as autoantigens or neoantigens, it seemed relevant to investigate the association of replication-competent human endogenous retrovirus HERV-E λ 4-1 with course of some of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. The aim of this work was a comparative study of the human endogenous retrovirus HERV-E λ 4-1 activation frequency in blood mononuclear cells in multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, as well as in chronic nervous system non-progressive diseases and the degenerative-dystrophic disease of the musculoskeletal system. The peripheral blood mononuclear cells were isolated by the venous blood centrifugation on Ficoll density gradient of 1.078 g/cm3. Expression of the HERV-E λ 4-1 envelope gene was detected by reverse transcriptase polymerase chain reaction. It was found that the HERV-E λ 4-1 envelope gene expression frequency in the chronic non-progressive diseases of nervous system, as well as in degenerative-dystrophic joint disease, is comparable to the expression frequency in conditionally healthy individuals. However, the HERV-E λ 4-1 envelope gene expression frequency in autoimmune diseases significantly exceeded that in conditionally healthy individuals and in non-inflammatory diseases. The maximum values of expression frequency were observed in active multiple sclerosis, significantly higher than in systemic lupus erythematosus and rheumatoid arthritis in the acute stage. Moreover, the expression frequency in the remission stage of multiple sclerosis was significantly lower than in the acute stage of the relapsing-remitted course, as well as in the progredient course. Estimation of HERV-E λ 4-1 envelope gene expression frequency at different severity levels of multiple sclerosis revealed its maximum rates at III and IV-V severity levels, both in relapsing-remitting and progressive course of multiple sclerosis. Thus, activation of the human endogenous retrovirus HERV-E λ 4-1 is associated with the course of autoimmune diseases, namely multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus; it positively correlates with the activity and severity of multiple sclerosis.

Значення часових етапів при різних типах перебігу розсіяного склерозу для формування прогнозу

Мета дослідження: розробити систему оцінки характеру прогнозу на основі клініко-математичного аналізу показників, що виникають на різних етапах при різних типах перебігу розсіяного склерозу. Матеріали та методи. Використані клінічні (клініко-неврологічний і метод анкетування — за анкетою, розробленою у відділі аутоімунної і дегенеративної патології нервової системи ДУ «Інститут неврології, психіатрії та наркології Національної академії медичних наук України») і математико-статистичні (метод пермутації) методи. За допомогою методу пермутації (перестановочного тесту) в групах хворих з різними типами перебігу обчислювалися відмінності в середніх значеннях клінічних показників, що характеризують перебіг розсіяного склерозу на різних часових етапах: доклінічному етапі, етапі дебюту, рецидивному етапі для рецидивуючого й вторинно-прогредієнтного перебігу, етапі прогресування — для вторинно- і первинно-прогредієнтного. На цій підставі було виділено клінічні показники, які з високою вірогідністю (рівень зв’язку 0,95) на кожному часовому етапі перебігу розсіяного склерозу визначають кінцевий варіант прогнозу захворювання. Результати. Обстежено 280 хворих, серед них: 80 (50 жінок і 30 чоловіків) — з рецидивуючим перебігом, 140 (80 жінок і 60 чоловіків) — із вторинно-прогредієнтним і 60 (30 жінок та 30 чоловіків) — із первинно-прогредієнтним. Характер прогнозу (сприятливий і невизначений при рецидивному перебігу, невизначений і несприятливий при прогредієнтних типах перебігу) оцінювався на основі клініко-діагностичних критеріїв, розроблених з урахуванням особливостей перебігу захворювання в цілому. Проведені дослідження показали, що сприятливий прогноз при рецидивуючому перебігу з високою вірогідністю зустрічався при поєднанні таких клінічних показників, як легка тяжкість дебюту, повна ремісія після дебюту, легкі рецидиви, що розвиваються швидкими темпами, і тривалі ремісії між рецидивами на рецидивному етапі; невизначений прогноз — за наявності дебютів середньої тяжкості, стовбурової симптоматики в дебюті, тяжких і середньої тяжкості рецидивів і тенденції до обтяження й подовження рецидивів на рецидивному етапі. Несприятливий прогноз при вторинно-прогредієнтному перебігу вірогідно пов’язаний з перенесеною вітряною віспою на доклінічному етапі в преморбідному анамнезі, блискавичними темпами розвитку дебюту, неухильним варіантом прогресування, що перебігає без клінічно окреслених періодів стабілізації; невизначений прогноз — із швидкими темпами розвитку дебюту. Несприятливий прогноз при первинно-прогредієнтному перебігу був тісно асоційований з перенесеною тяжкою черепно-мозковою травмою на доклінічному етапі в преморбідному анамнезі, мозочковою симптоматикою в дебюті, формуванням етапу прогресування безпосередньо після дебюту, минаючи етап стабілізації, неухильним варіантом прогресування на етапі прогресування; невизначений прогноз — із перенесеними герпетичними інфекціями на доклінічному етапі в преморбідному анамнезі, легкою тяжкістю дебюту, формуванням етапу прогресування після періоду стабілізації, що настала слідом за дебютом, поступальним варіантом прогресування на етапі прогресування, який перебігає у вигляді чергування періодів повільного накопичення неврологічного дефіциту, що має, як правило, локальний акцент, і етапів стабілізації різної тривалості. Висновки. Отже, за допомогою клініко-математичного аналізу було показано, що формування альтернативних варіантів прогнозу при різних типах перебігу розсіяного склерозу відбувається шляхом вибіркового залучення до єдиного патерну клінічних показників, які мають діагностичне значення на різних часових етапах перебігу захворювання.

Порівняльна ефективність гормональної пульс-терапії при рецидивуючому та вторинно-прогредієнтному типах перебігу розсіяного склерозу з різним характером прогнозу

Досліджено ефективність пульс-терапії глюкокортикоїдами (ГКТ) у 70 хворих на етапі прогресування при вторинно-прогредієнтному типі перебігу (ВПТ) розсіяного склерозу з невизначеним (30 осіб, 21 жінка і 9 чоловіків) і несприятливим (40 осіб, 36 жінок і 4 чоловіки) прогнозом. Проведено 249 курсів ГКТ-терапії, у тому числі при невизначеному прогнозі — 75 і несприятливому прогнозі — 174. Аналіз ефективності лікування проводився з урахуванням наступних клінічних показників: тривалість етапу прогресування до моменту проведення дослідження; варіанти і темпи прогресування; швидкість прогресування, ступінь інвалідизації за шкалою EDSS. Ефективність лікування на етапі прогресування при ВПТ у хворих з різним характером прогнозу оцінювалася з урахуванням наступних критеріїв: тривалість етапу прогресування до моменту останнього курсу ГКТ; варіанти прогресування (неухильне, рецидивуюче, поступальне); порівняльна оцінка тривалості ремісій (на рецидивуючому етапі при майбутньому ВПТ) і/або стабілізації (на етапі прогресування) після першого і перед останнім курсом ГКТ; динаміка балів за шкалою інвалідизації EDSS після першого і перед останнім курсом ГКТ; швидкість прогресування. Результати лікування у хворих з невизначеним прогнозом ВПТ показали помірну ефективність (21 особа) з формуванням більш доброякісного поступального варіанту прогресування і низьку ефективність (9 осіб) з менш сприятливим — рецидивуючим варіантом прогресування. Значно менш ефективною (низька ефективність — у 12 осіб, відсутність ефективності — у 28 осіб) ГКТ-терапія виявилася у хворих з несприятливим прогнозом ВПТ, які характеризувалися найменш сприятливим неухильним (21 особа), рецидивуючим (17 осіб) і чергуванням неухильного і рецидивуючого (2 особи) варіантів прогресування. Таким чином, проведені дослідження показали, що ефективність ГКТ-терапії при ВПТ залежить від характеру прогнозу, який визначається складною взаємодією клінічних показників, що мають прогностичне значення, а також рядом генетичних факторів, що вимагають свого подальшого вивчення.

Anti-CD20 treatment effectively attenuates cortical pathology in a rat model of widespread cortical demyelination

BackgroundCortical demyelination represents a prominent feature of the multiple sclerosis (MS) brain, especially in (late) progressive stages. We recently developed a new rat model that reassembles critical features of cortical pathology characteristic to progressive types of MS. In persons affected by MS, B-cell depleting anti-CD20 therapy proved successful in the relapsing remitting as well as the early progressive course of MS, with respect to reducing the relapse rate and number of newly formed lesions. However, if the development of cortical pathology can be prevented or at least slowed down is still not clear. The main goal of this study was thus to increase our understanding for the mode of action of B-cells and B-cell directed therapy on cortical lesions in our rat model.MethodsFor this purpose, we set up two separate experiments, with two different induction modes of B-cell depletion. Brain tissues were analyzed thoroughly using histology.ResultsWe observed a marked reduction of cortical demyelination, microglial activation, astrocytic reaction, and apoptotic cell loss in anti-CD20 antibody treated groups. At the same time, we noted increased neuronal preservation compared to control groups, indicating a favorable impact of anti-CD20 therapy.ConclusionThese findings might pave the way for further research on the mode of action of B-cells and therefore help to improve therapeutic options for progressive MS.

Screening of Cognitive Impairment in Patients with Multiple Sclerosis: A Cross-Sectional Study in Georgia.

Cognitive impairment (CI) is a common symptom of multiple sclerosis (MS), with a significant negative impact on the occupational and social functioning of patients. This study aimed to estimate the prevalence and characteristics of CI among MS patients in Georgia. Sixty-eight patients with MS attending a neurology outpatient clinic in Tbilisi, Georgia, were enrolled in the study. Cognitive status was evaluated using two screening tools: the Brief International Cognitive Assessment for MS and the Montreal Cognitive Assessment. The overall prevalence of CI in our MS patients was 47%. We found negative associations between cognitive test results and patients' age, disability status, and depression. Lower education, higher scores on the Expanded Disability Status Scale, and the progressive course of MS were the main predictors of CI in the logistic regression analysis. This is the first study in Georgia to evaluate CI in patients with MS. The prevalence of CI in our study was comparable with those reported in other countries; however, we found greater impairment of the executive system compared to other cognitive domains. In our study, patients who were on continuous DMT showed significantly better performance on the cognitive tests used, indicating possible favorable effect of immunomodulatory drugs on cognition.

The Factors Associated With Olfactory Dysfunction in Patients with Multiple Sclerosis.

Introduction:An impaired sense of smell has a remarkable impact on the quality of life. It is seen in a variety of neurodegenerative diseases such as Parkinson disease. In this study, we assessed the olfactory function in patients with Multiple Sclerosis (MS) by Sniff Magnitude Test (SMT).Methods:A cross-sectional study was conducted on 48 patients with MS. A questionnaire, including demographic and clinical variables, was completed for each patient. The SMT was used for the evaluation of olfactory function.Results:Olfactory dysfunction was found in 14.6% of patients (8.3% hyposmia and 6.3% anosmia). Older age, longer disease duration, higher hospital admission rate, lower minimental status examination score, and secondary progressive course of MS were significantly related to olfactory dysfunction.Conclusion:Secondary progressive MS and markers of advanced disease toward neurodegenerative phase (including older age, longer disease duration, and lower cognitive function) can be associated with olfactory dysfunction in MS patients.

Functional and metabolic characteristics of peripheral blood mononuclear phagocytes in patients with different clinical courses of multiple sclerosis

Functional and metabolic features of intact and stimulated mononuclear phagocytes were studied in patients with different clinical courses of multiple sclerosis, the study included 66 patients with relapsing-remitting and 32 patients with progressive course of multiple sclerosis. The state of the mononuclear phagocytes was characterized by expression of costimulatory molecules and direction of L-arginine metabolism. Relative quantities of CD80, CD86 and PD-L1 positive monocytes were determined with Phycoerytrin-labeled monoclonal antibodies in immunofluorescence test in peripheral blood and after culture in parallel series with addition of: (a) E.coli lipopolysaccharide (a stimulator of TLR4), (b) a single-stranded RNA – preparation ssRNA40/LyoVec (a stimulator of TLR7/8), (c) IL-4 (an anti-inflammatory interleukin). The formation of NO was determined by the amount of nitrite in the culture supernatants, arginase activity was determined in cell lysates of the monocyte fraction. We showed that functional and phenotypic characteristics of monocytes depend on the clinical course of multiple sclerosis. In patients with progressive course, the relative number of CD86+ cells was significantly higher and PD-L1+ cells significantly lower than in patients with relapsing-remitting course and healthy persons, in patients with relapsing-remitting course the number of PD-L1+ cells was increased. The number of CD80+ cells did not show any significant difference in the investigated groups of patients relative to the control group. In vitro stimulation of peripheral blood monocytes with TLR4/8 produced a significant increase in the number of CD86+ and decrease in the number of PD-L1+ cells in patients with the progressive course. In patients with the relapsing-remitting course LPS produced an increase in number of PD-L1+ cells. We did not find any difference in activity of the arginase pathway of L-arginine metabolism in the intact monocyte fraction of peripheral blood in patients with multiple sclerosis versus the control group, but stimulation with TLR4 agonist of mononuclear cells of patients with progressive course caused significant increased arginase activity versus baseline. At the same time, versus control cells arginase activity in patients with the progressive course decreased after LPS treatment, but trended to increase after TLR7/8 treatment. In patients with the relapsing-remitting course these changes had a similar direction but were less expressed. The results may be considered as an indication of the activation of peripheral blood monocytes and their polarization trend in the M1 direction in patients with the progressive course of multiple sclerosis, these changes could be considered as signs of violation of autoimmune regulatory mechanisms in multiple sclerosis.

The window of opportunity for treatment of progressive multiple sclerosis.

Based on the knowledge of disease mechanisms in the progressive course of multiple sclerosis and the experience from randomized clinical trials, we assessed the timing of disease-modifying therapy in patients with progressive multiple sclerosis to define the optimal window of opportunity for treatment of progressive multiple sclerosis. In progressive multiple sclerosis both small molecules that cross the blood--brain barrier (siponimod) and monoclonal antibodies (ocrelizumab) have shown therapeutic efficacy and have been approved for treatment of progressive multiple sclerosis. However, the majority of phase II and phase III trials in progressive forms of multiple sclerosis have been negative, probably owing to either late start of treatment or use of drugs that are ineffective for treatment of progressive multiple sclerosis. Results from phase II and III trials suggest that the window of opportunity for treatment of progressive multiple sclerosis with anti-inflammatory drugs is predominantly in the early phase of the progressive disease course when patients have lower age, shorter duration of progressive multiple sclerosis, and more pronounced clinical and MRI inflammatory activity. Ongoing trials of neuroprotective drugs may widen the window of opportunity by expanding targeted pathophysiologies.

A pilot study of lncRNAs expression profile in serum of progressive multiple sclerosis patients.

Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease that affect both white and gray matter. The relapsing and the eventually progressive course of MS is heterogeneous; thus, a confident long-term prediction of individual prognosis is not possible yet. Recent studies have demonstrated the role of long non-coding RNA (lncRNAs) as potential biomarkers that could provide information to predict disease activity and progression. By qRT-PCR, we analysed the lncRNAs expression in the serum of 16 secondary progressive MS (SP-MS), 12 primary progressive (PP-MS) patients and 8 healthy controls. We found that TUG1 was upregulated in SP-MS, while the comparison of PP-MS vs. controls showed a downregulation of non-protein coding RNA 188 (LRRC75A-AS1) and a significant upregulation of two lncRNAs: long intergenic non-protein coding RNA 293 (LINC00293) and RP11-29G8.3. Moreover, we performed an in-silico analysis using DIANA-LncBase v2 and HMDD v3.0 software, in order to predict the possible interaction of these four lncRNAs with miRNAs. We identified 21 miRNAs prediction targets possibly involved in MS. Our data indicate a regulatory function of these lncRNAs in autoimmune and inflammatory processes related to MS suggesting their potential role in progressive MS pathogenesis.

Рассеянный склероз в Республике Татарстан: клинико-эпидемиологическая характеристика

The purpose — to clarify the clinical and epidemiological characteristics of multiple sclerosis (MS) in the Republic of Tatarstan (RT). Material and methods. A retrospective analysis of the register of MS patients in RT from 2015 to 2019 was carried out. The sample size was 2351 patients. The type of MS course, disease duration, clinical characteristics, including EDSS and MSSS scores, used by disease modifying therapies (DMT) were analyzed. Results and conclusions. The prevalence of MS in RT continues to grow and has increased by 29% over a 5-year period (from 46,6 to 60,3 per 100,000 population in 2015 and 2019, respectively). The incidence has relatively stabilized and averages 4,2 cases per 100,000 population per year. The dominant type of MS course in RT is remitting (51,3%), patients with progressive forms account for 48,7%, including those with primary progressive MS (6,9%). In RT, a positive tendency towards a more favorable course of the disease with a decrease in the degree of patients’ disability was traced, mainly due to early diagnosis and timely prescription of adequate treatment with DMT. The problem of timely diagnosis of MS in children and adolescents and in the primary progressive course of MS remains.

Variability of the MIR196A2 Gene as a Risk Factor in Primary-Progressive Multiple Sclerosis Development

Multiple sclerosis is a chronic disease of the central nervous system, combining in its pathogenesis both autoimmune and neurodegenerative components, and is characterized by a highly heterogeneous clinical phenotype. Genetic susceptibility to the development of the most common relapsing-remitting course of the disease is extensively studied, while the genetic architecture of the aggressive primary progressive course of multiple sclerosis remains poorly understood. We analyzed the association of polymorphic variants in miRNA genes MIR146A, MIR196A2, and MIR499A with the risk of primary progressive multiple sclerosis one by one and in biallelic combinations with variants of immune-related genes; the analysis was performed in comparison with healthy individuals and with relapsing-remitting multiple sclerosis patients. The allele MIR196A2*C was useful in discriminating between two main courses of multiple sclerosis, one by one and in combination with alleles of the IFNAR2, IL7RA, IL6, PVT1, CD86, CCL5, and PSMB9 genes. The data presented in the current work may be used for the construction of a biomarker panel, to differentiate primary progressive and relapsing-remitting courses of multiple sclerosis on the initial stages of the disease.

Therapeutic decision considering progressive course of multiple sclerosis in Japan

Therapeutic decision considering progressive course of multiple sclerosis in Japan

Markers of oxidative/nitrative damage of plasma proteins correlated with EDSS and BDI scores in patients with secondary progressive multiple sclerosis

ABSTRACTObjectives: The objective of the present study was to evaluate oxidative/nitrative stress in the plasma of 50 patients suffering from the secondary progressive course of multiple sclerosis (MS), and to verify its correlation with physical and mental disability as assessed by the Expanded Disability Status Scale (EDSS), and the Beck Depression Inventory (BDI).Methods: Oxidative and nitrative damage to proteins was determined by the level of carbonyl groups and 3-nitrotyrosine using ELISA test. Based on the reaction with Ellman’s reagent, we estimated the concentration of oxidized thiol groups. Additionally, we measured the level of lipid peroxidation.Results: In plasma drawn from MS patients, we observed a significantly higher level of 3-NT (92%; P < 0.0003), carbonyl groups (29%; P < 0.0001) and thiobarbituric acid reactive substances (73%; P < 0.0001), as well as a lower concentration of thiol groups (33%; P < 0.0001), in comparison to healthy subjects. We noted positive correlations between the level of carbonyl groups or 3-NT and both diagnostic parameters, EDSS and BDI. Negative correlations were observed between concentration of -SH groups and EDSS and BDI.Conclusion: Our results indicate that impaired red-ox balance can significantly promote neurodegeneration in secondary progressive MS.

Еvaluation data somatosensory evoked potentials and electromyography in patients with multiple sclerosis in the aspect comorbidity

The paper shows the results of electrophysiological methods of investigation in patients with multiple sclerosis (MS) in the aspect of comorbidity. The studies of somatosensory evoked potentials (SSEP) in 216 patients with MS and electroneuromyography in 158 patients with MS, together with the assessment of neurological and psychological status. It is shown that according SSEP increase latency peripheral response in a progressive course of MS compared to remitting associated with older age of patients with progressive MS, and due to involvement in the pathological process of the peripheral nervous system (PNS) and the prevalence of pain syndrome (PS) in patients MS with comorbidity. It is demonstrated, on the basis of electroneuromyographic that MS patients with comorbidity tends to be deeper shock PNS. The data electroneuromyographic clinically appropriate initial stage of sensory or sensorimotor polyneuropathy, which proceeded in 84.8% of patients with MS subclinical and 15.2% had a clear clinical signs.

Reliable volumetry of the cervical spinal cord in MS patient follow-up data with cord image analyzer (Cordial).

Spinal cord (SC) atrophy is an important contributor to the development of disability in many neurological disorders including multiple sclerosis (MS). To assess the spinal cord atrophy in clinical trials and clinical practice, largely automated methods are needed due to the sheer amount of data. Moreover, using these methods in longitudinal trials requires them to deliver highly reliable measurements, enabling comparisons of multiple data sets of the same subject over time. We present a method for SC volumetry using 3D MRI data providing volume measurements for SC sections of fixed length and location. The segmentation combines a continuous max flow approach with SC surface reconstruction that locates the SC boundary based on image voxel intensities. Two cutting planes perpendicular to the SC centerline are determined based on predefined distances to an anatomical landmark, and the cervical SC volume (CSCV) is then calculated in-between these boundaries. The development of the method focused on its application in MRI follow-up studies; the method provides a high scan-rescan reliability, which was tested on healthy subject data. Scan-rescan reliability coefficients of variation (COV) were below 1%, intra- and interrater COV were even lower (0.1-0.2%). To show the applicability in longitudinal trials, 3-year follow-up data of 48 patients with a progressive course of MS were assessed. In this cohort, CSCV loss was the only significant predictor of disability progression (p=0.02). We are, therefore, confident that our method provides a reliable tool for SC volumetry in longitudinal clinical trials.

A COMPARATIVE ANALYSIS OF EFFICACY OF INTERFERON BETA 1-B AND NATALIZUMAB TREATMENT IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS

Background: Disease modifying drugs for multiple sclerosis have similar indications for use and at the same time, their specifics of the effect on the pathophysiological process. This complicates the choice of an optimal therapy for a given patient. Aim: To assess efficacy of treatment for multiple sclerosis with interferon beta-1b (IFN-β-1b) and natalizumab. Materials and methods: We performed an open label prospective study in 110 patients with multiple sclerosis who were followed up in the Moscow Regional Center of multiple sclerosis from 2012 to 2015. From those, 99 patients with relapsing-remitting multiple sclerosis (disease modifying drugs naïve) were treated with IFN-β-1b, 11 were non-responders to interferon (1 and more attacks for the previous year of therapy with IFN-β-1b) or had progressive course of multiple sclerosis (more than 2 attacks and an increase in the Expanded Disability Status Scale (EDSS) score by 1 and more within 1 year) and were treated with natalizumab. Analysis of treatment efficacy was performed with consideration of their past history, results of a 3-year neuromonitoring with Kurtzke EDSS and Functional System Scale, neuroophthalmologic testing with Farnsworth dichotomous test, and changes in optical coherent tomography parameters. Results: During 3 years of treatment with IFN-β-1b, the mean number of attacks decreased by over 70% (from 1.28±0.7 in the year before treatment to 0.35±0.09 in the 3rd year of treatment; p&lt;0.05), whereas the degree of disability assessed by EDSS increased nonsignificantly by 0.44 (p&gt;0.05). During the follow-up in the natalizumab group, the number of attacks decreased from 2.3±0.04 to 0.13±0.01 (p&lt;0.05), and the degree of disability by EDSS decreased by 0.8 (p&gt;0.05). There was a significant difference between changes in the thickness of peripapillar nervous fibers during 2 years of the follow up, this parameter decreasing by 2.5 mcm in patients treated with IFN-β-1b and by 0.1 mcm in those treated with natalizumab (p&lt;0.01). Conclusion: Although the patients from natalizumab group had initial more severe course of multiple sclerosis, both agents were highly effective, with the most prominent clinical effect observed for natalizumab. The results obtained may serve as a basis for recommendation of the 2nd line disease modifying drugs for patients with aggressive course of the multiple sclerosis and failure of the 1st line disease modifying drugs. Also, we were able to demonstrate the efficacy of neuroophthalmological monitoring in the assessment of disease modifying drugs efficacy. The strict safety policy is essential while using natalizumab.

ATROPHIC CHANGES OF THE CORPUS CALLOSUM IN MULTIPLE SCLEROSIS

The changes in the parameters of the corpus callosum, depending on the type of flow, duration of disease and degree disability in multiple saclerosis. Most sensitive with respect to the investigated indices proved trunk of the corpus callosum, to a lesser extent the knee. For the same period of the disease atrophy of the corpus callosum in patients with primary progressive course of multiple sclerosis is much more pronounced than in other types of flow. Reducing the size of the corpus callosum in progressive types of flow suggests ongoing secondary degeneration of fibers.

Cognitive assessment in MS.

Cognitive impairment has been demonstrated at all stages and in all subtypes of multiple sclerosis (MS) and has a wide-ranging impact on the lives of those affected. It can influence participative, safety and disease outcomes [1], with the net result being an overall reduction in quality of life. Worryingly, about half of patients with an Expanded Disability Status Scale (EDSS) score as low as 3 are unemployed [2] suggesting that physical disability is not the only contributing factor. Large unselected samples have identified cognitive impairment in around 60% of participants treated in clinics, with a slightly lower prevalence (50%) in community samples [3]. The strongest predictors of cognitive impairment are EDSS, progressive course of MS and age [3]. Cognitive domains most likely to be affected in MS are information processing speed and memory. Visual processing and executive function are less likely to be impaired, while language is largely intact. The profile is opposite to that usually seen in Alzheimer’s disease and, because language capability is mostly intact, diagnosis can be problematic. Cognition is affected by other MS symptoms such as fatigue and depression, although the link between objective measures and self-report is complex and unreliable for both symptoms [1]. Of current interest in this field is the relationship between intellectual enrichment (usually assessed by educational attainment) and cognitive reserve. It has been shown that people with lower cognitive reserve for specified disease burden, atrophy or lesions will lose more cognitive performance compared with people with the same level of disease burden, atrophy or lesions but with higher cognitive reserve [4]. Assessment of cognitive function in MS has traditionally been unavailable for patients outside specialist centers. This is partly because cognitive assessment requires specialist skills, can be time consuming to administer and the materials and validated measures have not been widely available in many countries. The Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) is a selfreported screening questionnaire that predicts neuropsychological deficiency with good sensitivity and specificity, but is confounded by depression [5]. Other tests such as the Brief Battery and the Minimal Assessment of Cognitive Function in MS (MACFIMS) are time consuming and require a specialist psychologist to complete, and are therefore not ideal for routine use. The Brief International Cognitive Assessment for MS (BICAMS [6]) initiative was designed to address these issues. An international expert consensus group was set up to develop a tool that could be used by healthcare professionals who are not cognitive specialists. BICAMS comprises a 15-min battery of tests developed from approximately 80 key scientific articles. Two commit tee members evaluated each article, and candidate scales were rated for psychometric standards (reliability, validity and sensitivity) and pragmatic standards (international applicability, ease of administration, feasibility in the specified context and acceptability to patients) [7]. A validation

Progressive multiple sclerosis.

The purpose of this study is to highlight the pathological features and clinical aspects of progressive multiple sclerosis (PMS) and also the results of clinical trial experience to date and review ongoing clinical trials and prospective new treatment options. This study will explain the challenges of clinical trial design in PMS. Multiple sclerosis (MS) has been identified as a chronic immune mediated disease, and the progressive phase of the disease appears to have significant neurodegenerative mechanisms. The classification of the course of PMS has been reorganized into categories of active vs. inactive inflammatory disease and the presence vs. absence of gradual disease progression. This differentiation allows clearer conceptualization of PMS and possibly even more efficient recruitment of PMS patients into clinical trials. Clinical trial experience to date in PMS has been negative with anti-inflammatory medications used in relapsing MS. Simvastatin was recently tested in a phase II trial and showed a 43% reduction of annualized atrophy progression in secondary progressive MS. Ongoing PMS trials are currently being conducted with the phosphodiesterase inhibitor ibudilast, S1P modulator siponimod and anti-B-cell therapy ocrelizumab. Several efforts for development of outcome measures in PMS are ongoing. PMS represents a significant challenge, as the pathogenesis of the disease is not well understood, no validated outcome metrics have been established and clinical trial experience to date has been disappointing. Advances in the understanding of the disease and lessons learned in previous clinical trials are paving the way for successful development of disease-modifying agents for this disease.

Cortical excitability changes over time in progressive multiple sclerosis.

In 25 patients with progressive forms of multiple sclerosis (MS), motor cortex excitability was longitudinally studied over one year by means of transcranial magnetic stimulation (TMS). The following TMS parameters were considered: resting and active motor thresholds (MTs), input-output curve, short-interval intracortical inhibition (SICI), and intracortical facilitation. Clinical evaluation was based on the Expanded Disability Status Scale (EDSS). In the 16 patients not receiving disease-modifying drugs, the EDSS score worsened, resting MT increased, and SICI decreased. By contrast, no clinical for neurophysiological changes were found over time in the nine patients receiving immunomodulatory therapy. The natural course of progressive MS appears to be associated with a decline in cortical excitability of both pyramidal neurons and inhibitory circuits. This pilot study based on a small sample suggests that disease-modifying drugs may allow cortical excitability to remain stable, even in patients with progressive MS.