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• Risk profiles of familial and sporadic MS could differ. • Breastfeeding could reduce future risk of MS in infants with family history of MS. • This associacion was found in males, but not in females. Multiple sclerosis (MS) is an immune-mediated disease that affects the central nervous system, which most likely results from the interplay between environmental and genetic factors. The aim of our study was to assess the effect of breastfeeding on the risk of developing familial multiple sclerosis (fMS) in persons with positive MS history, being the first such investigation performed in fMS cohort. A case-control study based on the Belgrade population MS Registry was conducted. Cases for the sporadic MS (sMS) control group were randomly selected from the Registry, and matched with individuals with fMS at a ratio of 1:1. Spouses of the persons with fMS were included as a healthy control (HC) group. A specific questionnaire that was previously validated was used to obtain the data. To evaluate risk factors associated with breastfeeding for fMS occurrence compared with sMS and HC, multinomial regression analysis was performed to compute the relative risk ratios (RRR) along with 95% confidence intervals (95% CI). The analysis was afterwards repeated, stratified by sex. Both models were adjusted for potential confounding factors. A total of 393 participants were included in our case-control study, 131 per group. There were more individuals who were exclusively breastfed longer than six months in the sMS group compared to fMS group (RRR 2.01, 95% CI 1.22–3.32). After stratification by sex, exclusive breastfeeding was shown to be a protective factor for fMS only in male population, for individuals breastfed ≥4 months. The results of both the main and stratified analysis remained robust after adjustment. Our study findings indicate that breastfeeding reduces the risk of MS in infants with family history of the disease, although this protective effect may be limited to the male population. Further investigation into the differences in risk factors between fMS and sMS is warranted to gain a more comprehensive understanding of the disease. [ABSTRACT FROM AUTHOR]

• The presence of ANS dysfunction occurs in almost all NMOSD and MS patients. • ANS dysfunction correlates with decreased quality of life, in both NMOSD and MS. • Lower autonomic burden independently predict better quality of life in MS and NMOSD. A substantial autonomic nervous system (ANS) dysfunction has been described in multiple sclerosis (MS) and recently, also in neuromyelitis optica spectrum disorder (NMOSD). The prevalence of ANS symptoms contributes to the chronic symptom burden in both diseases. The aim of our study was to assess ANS dysfunction in people with (pw) NMOSD and MS, using the Composite Autonomic Symptom Score-31 (COMPASS-31), and additionally, to evaluate if ANS dysfunction have impact on the quality of life of these patients. We conducted cross-sectional study at three national referral neurological clinics in Serbia, Croatia, and Montenegro. A total of 180 consecutive subjects, 80 pwNMOSD and 100 pwMS, followed-up at these clinics, were enrolled in the study. Subjects included in the study completed: the validated versions of the COMPASS-31 and the Multiple Sclerosis Quality of Life-54 (MSQoL-54), and the Beck Depression Inventory (BDI). This study demonstrated that the total COMPASS-31 score > 0.0, implicating the presence of ANS dysfunction, was detected in almost all NMOSD and MS study participants tested (80/80, and 97/100, respectively). Our findings showed that autonomic symptom burden was statistically significantly correlated with decreased quality of life, in both NMOSD and MS cohorts. The independent predictors of the better quality of life in pwNMOSD were lower autonomic burden, particularly the absence of the orthostatic intolerance (p = 0.005), along with lower EDSS and BDI score (p ≤ 0.001). Similarly, in pwMS, independent predictors were EDSS, BDI, orthostatic intolerance, and the total COMPASS-31 (p ≤ 0.001). Our study demonstrated that a significant proportion of persons with both NMOSD and MS have considerable dysautonomic symptom burden which is correlated with the decreased quality of life. Further investigations are warranted in order to optimize treatment interventions in MS and NMOSD. [ABSTRACT FROM AUTHOR]

• LETM very rarely occurs in patients with viral infections. • This is one of the few described cases of LETM associated with West Nile virus infection. • West Nile virus infection should be considered in patients with LETM. Until now, longitudinally extensive transverse myelitis (LETM) was reported in association with various viral infections. We describe the case in which a diagnosis of LETM was established as a clinical manifestation of West Nile virus (WNV) infection. We report a 39-year old man with WNV infection and LETM. In neurological examination, there was a left periscapular hypotrophy, moderate weakness of left arm, decreased left brachioradialis reflex, tandem instability and gait ataxia. Cervical spine MRI showed enhancing intramedullary lesion extending from C3-C7 level. According to the neurological, EMG and MRI findings, a diagnosis of LETM, with affection of anterior horn cells of the cervical spinal cord, induced by WNV infection was established. The patient was treated with antibiotics, acyclovir and high dose-steroids, methylprednisolone (MP) 1 g/daily in intravenous infusion, for 5 consecutive days, followed by tapering doses of prednisone during the next four months. Six weeks after onset of symptoms, previously described lesion on cervical spine MRI resolved, and the patient gradually clinically improved. [ABSTRACT FROM AUTHOR]

Highlights • LETM very rarely occur in patients with the systemic malignancy. • This is the first case of paraneoplastic LETM associated with carcinoma of the cervix. • LETM may have extremely rarely excellent treatment response and nearly full recovery after TPE. Abstract Longitudinally extensive transverse myelitis (LETM) is defined as a spinal cord lesion that extends over three or more vertebrae. LETM very rarely occurs in patients with the systemic malignancy. We report a 38-year old woman with adenocarcinoma of the cervix and LETM. Cervical and thoracic spine MRI showed hyperintense signal on T2W involving predominantly central spinal cord from the C4 level distally, including conus medullaris. In this patient corticosteroid therapy and therapeutic plasma exchange (TPE) courses were performed. On discharge, five weeks after TPE initiation, patient could walk with bilateral assistance. After a 16-month follow-up, her neurological finding was almost normal and MRI lesions disappeared. Thus, we present our patient as one of the rare cases of paraneoplastic LETM with excellent treatment response. [ABSTRACT FROM AUTHOR]

Background Gait pattern is frequently impaired in multiple sclerosis (MS), however gait characteristics in patients with different MS phenotypes have not been fully elucidated. Methods We analyzed spatio-temporal gait pattern characteristics in patients with relapsing-remitting (RR, n=52) and primary-progressive (PP, n=18) MS in comparison with age-matched healthy controls (HC, n=40). All subjects performed a standardized simple walking task, a dual motor- motor task, a dual motor-mental task, and a triple combined motor-mental task at a GAITRite electronic walkway of 5.5 m active area. We measured: cycle time (CT), stride length (SL), swing time (ST), double support time (DST), gait velocity (GV) and calculated symmetry index (SI) for CT, SL and ST. Results With each task performed, CT and DST in the total MS group were significantly longer while SL was significantly shorter and GV significantly lower than in HC. ST was similar in the total MS patient group and HC. In both MS patients and HC, CT and DST increased and SL and GV decreased over repeated assessments. Dual and triple tasks while walking influenced walking performance in both MS patients and HC. Although patients with PPMS differed significantly from those with RRMS in the majority of gait parameters, the subgroup analysis in patients matched for age and disability (Expanded Disability Status Scale Score -EDSS, 3.0–5.0) showed similar gait performance in RRMS and PPMS patients having the same level of disability, except for CT and ST- symmetry parameters that were more impaired in the PPMS group. The EDSS score correlated significantly with CT, DST, SL and GV, but no significant correlation was found with ST except at the triple combined motor-mental task. Conclusion A disturbed gait pattern in MS patients with different MS phenotypes depends on disability and reflects a cognitive-motor interference. [ABSTRACT FROM AUTHOR]

Background Long-term treatment adherence to disease-modifying drugs (DMDs) may have significant impact on clinical outcomes in multiple sclerosis (MS). It has been recently emphasized that low treatment satisfaction (TS) may be an important factor for achieving high rates of treatment adherence. Interferon (IFN) beta-1b was the first DMD approved for the treatment of MS. The aims of our study were to assess TS in subjects with relapsing-remitting (RR) MS treated with IFN beta-1b in Serbia, Montenegro and the Republika Srpska, Bosnia and Herzegovina (B&H), and additionally, to evaluate the impact of patient support program on TS and adherence. Methods This is a cross-sectional survey performed in order to examine TS and adherence with IFN beta-1b in seven MS centers across three countries (Serbia, Montenegro and B&H). Included in the study were 296 adult patients with RRMS treated with IFN beta-1b for at least 6 months. They were invited to complete the Treatment Satisfaction Questionnaire for Medication (TSQM). Additional two treatment adherence questions were also asked. Patient support program (Betaplus®) was available exclusively for patients in Serbia and not for those in Montenegro and the Republika Srpska, B&H. In order to assess the potential impact of this program on TSQM, we combined two groups of patients from Montenegro and B&H and compared their results with those from patients in Serbia. Statistical analysis includes multivariable linear regression analysis in order to assess the differences between three MS patients groups in terms of the TSQM scores, adjusted for potential confounders. For the evaluation of the effects of Betaplus® program, multivariable logistic regression was used, controlling for the same confounding factors. Results Each of the TSQM summary scores in all three countries implicated high level of patients' satisfaction. There was statistically significant group difference on the Effectiveness summary score (p=0.001) and the Side effects summary score (p=0.006) between the group of subjects from Serbia and the combined group of subjects from Montenegro and B&H, in favor of the former cohort. There was statistically significant group difference neither on the Convenience summary score nor on the Overall satisfaction summary score. Results of adjusted logistic regression analysis based on the availability of patient support program (dependent variable) implicate that it had the most significant impact on the Effectiveness summary score (p=0.008). According to the correlation coefficients in the total patient cohort, all TSMQ summary scores except Effectiveness significantly correlated with the decreased adherence (Side effects: p=0.037; Convenience: p=0.016; Overall satisfaction: p=0.046). Conclusion TS with IFN beta-1b was high in our MS patients. Additionally, these results have demonstrated that patient support program have significant impact on TS with IFN beta-1b in the Balkan cohort of RRMS patients. [ABSTRACT FROM AUTHOR]

• First assessment on real-world operation of MS centres in Central-Eastern Europe • A self-report questionnaire was used to assess MS care unit recommendations • Data on DMT and registry use, and MS care systems were collected • Homogeneously and heterogeneously available and absent conditions were identified • A strictly regulated centre-system might ensure appropriate care for people with MS In 2018 multiple sclerosis (MS) care unit (MSCU) recommendations were defined. Nevertheless, the information on MS care, and whether MS centres fulfil the international recommendation is limited. Thus our objectives were to assess whether centres meet the MSCU recommendations and gain a comprehensive overview of MS care in Central-Eastern European countries. A self-report questionnaire assessing aspects of the MSCU recommendations, disease-modifying therapy (DMT) and registry use and the patient number was assembled and sent to nine Central-Eastern European countries. Furthermore, one Danish and one German centre were contacted as a reference. In 9/9 countries, MS care was pursued in centres by MS neurologists and MS nurses. In Austria and the Czech Republic, management of MS was conducted under strict regulations displaying a referral centre system, fundamentally similar to but independent of the MSCU criteria. Several centres fulfilled all aspects of the MSCU criteria, while others had similar insufficiencies consisting of a speech therapist, continence, pain and spasticity specialist, neuro-ophthalmologist, and oto-neurologist. In 9/9 countries, DMTs were reimbursed. However, some centres did not provide every available DMT. A national registry was available in 4/9 countries with mandatory registry use only in Austria and the Czech Republic. In countries where MSCU recommendations are not fulfilled, a strictly regulated centre system similar to the Austrian and Czech model with a registry-based quality control might ensure appropriate care for people with MS. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the humoral response to the SARS-CoV-2 infection and vaccination in the NMOSD patients, treated with various immunosuppresants (ISs). Serum IgG against the complete sequence of the receptor binding domain of the spike protein was measured using ELISA SARS-CoV-2 IgG, INEP, Belgrade. Seroconversion occurred in 8/10 patients with COVID-19, and in 5/9 after vaccination. One out of four patients treated with inebilizumab seroconverted (after COVID-19); antibodies were not detected in any of the remaining 3 patients who were vaccinated. Antibodies developed after COVID-19 in 4/5 patients treated with azathioprine and all treated with mycophenolate-mofetil, and after vaccination, in 5/6 patients treated with these ISs. Post-vaccination humoral response was impaired in our NMOSD patients treated with B-cell depleting therapies; seroconversion occurred in almost all patients treated with conventional synthetic disease modifying ISs. [ABSTRACT FROM AUTHOR]

• NMOSD patients are at higher risk of COVID-19. • Older age and higher disability affect the development of severe COVID-19. • Relation between immunosuppressants and COVID-19 severity is not confirmed. • The most common adverse event after vaccination is injection site pain. Reports on outcomes of COVID-19 in patients with neuromyelitis optica spectrum disorder (NMOSD) are scarce, as well as those related to the safety profile of the vaccines in this population. The aim of this survey is to present demographic and clinical characteristics of patients with NMOSD who developed COVID-19 and safety data of the COVID-19 vaccines in these persons. This study comprise all patients from the Hospital registry of NMOSD, of the Clinic of Neurology in Belgrade, who fulfilled the 2015 NMOSD diagnostic criteria, and who after invitation by phone call, from April 10 to May 10, 2021, accepted to participate and provide information regarding COVID-19 and vaccination against Sars-CoV-2 (n = 53). Sixteen out of 53 enrolled NMOSD patients were diagnosed with COVID-19. In three cases (18.8%), severity of COVID-19 clinical manifestations warranted hospitalization, and one of these patients, died due to COVID-19 (case fatality ratio = 6.25%), after invasive mechanical ventilation. The remaining two patients had grade II COVID -19 severity and were hospitalized because of pneumonia, not requiring supplemental oxygen. Median EDSS in patients requiring hospitalization was 4.5, and in the non-hospitalized group, it was 3.0. Nine out of 53 patients received two doses of vaccine against Sars-Cov-2 (8 Sinopharm and one Pfizer). Pain at the site of application was the only vaccine-related adverse effect. Our survey indicates overall favourable COVID-19 outcome and encouraging safety profile of the vaccines in persons with NMOSD, in our cohort. Prospective studies are warranted to confirm these data. [ABSTRACT FROM AUTHOR]

• All MS patients under cladribine, had IgG antibodies after COVID-19. • All MS patients under cladribine, vaccinated with mRNA develop seroconversion. • All MS patients under alemtuzumab, develop seroconversion after vaccination. • Seroconversion occurs independent of absolute lymphocyte count. It has been generally accepted that people with MS (PwMS) should be vaccinated against COVID-19. The aim of our investigation was to evaluate the humoral response to natural SARS-CoV-2 infection and to two COVID-19 vaccines (BNT162b2 Pfizer-BioNTech and Beijing/Sinopharm BBIBP-CorV) in our cohort of PwMS under high efficacy disease modifying therapies (DMTs), cladribine and alemtuzumab. Twenty two PwMS treated at the Clinic of Neurology, in Belgrade, who developed COVID-19 and/or were vaccinated against SARS-CoV-2, during treatment with cladribine and alemtuzumab, were included. Out of 18 patients treated with cladribine, 11 developed COVID-19, and 11 were vaccinated against SARS-CoV-2 (four with mRNA vaccine, 7 with Sinopharm). Four MS patients under alemtuzumab were vaccinated against SARS-CoV-2; three with mRNA, and one with Sinopharm vaccine. SARS-Cov-2 IgG response was measured using ELISA anti-spike protein-based serology (INEP, Belgrade, Serbia). All 7 patients under cladribine treatment who suffered from COVID-19, developed IgG antibodies, 2.0-5.5 months after last symptoms. All four (100%) patients under cladribine who were vaccinated with Pfizer-BioNTech vaccine, and three out of seven (42.9%) vaccinated with Sinopharm, developed antibodies. All 4 patients under alemtuzumab developed antibodies after vaccination. In all cases, seroprotection occurred, irrespective of timing of vaccination and absolute lymphocyte count. Our findings in a small number of highly active PwMS in whom, lymphodepleting, immune reconstitution therapies, were applied in order to successfully manage MS, indicate that in a number of these patients it was possible to develop at the same time seroprotection in these patients after COVID-19 vaccination in these complex circumstances. [ABSTRACT FROM AUTHOR]

• The prevalence of insulin resistance in MS patients is higher than in controls. • MS patients have significantly higher risk of impaired glucose metabolism. • Glucose level at 120′ during OGTT is independently associated with MS. • EDSS and disability progression are associated with glucose levels during OGTT. It has not been clarified yet if persons with multiple sclerosis (MS) are at increased risk to develop glucose metabolism dysregulation. The aims of the present study were to evaluate glucose metabolism characteristics in persons with MS and to compare it to the healthy individuals; to examine the association of glucose metabolism with the level of disability and its progression. The study enrolled 78 patients with MS and 26, comparable for age, gender and body mass index (BMI), healthy controls (HC). Disability and its progression were evaluated by the Expanded Disability Status Scale (EDSS) score, progression index (PI) and multiple sclerosis severity score (MSSS). All participants performed an oral glucose tolerance test (OGTT). Insulin and lipid parameters were analyzed. Fasting glucose concentrations (5.3±0.7 in MS patients vs. 4.5±0.9 mmol/L in HC, p=0.001) and 2 hour post-load glucose concentrations were statistically significantly higher in MS patients compared with controls. Glucose levels at all different time points during OGTT, baseline insulin, Homeostasis model assessment of insulin resistance (HOMA-IR), total cholesterol and LDL were statistically significantly (p<0.05) associated with MS, in univariable logistic regression analysis. Glucose level at 120' was independently associated with MS (OR=3.937, 95% CI 1.178-13.159, p=0.026), in the multivariable model. The prevalence of IR was 64.1% in the MS group compared to 30.8% in the control group (p=0.008), based on HOMA-IR. EDSS and Multiple sclerosis severity score (MSSS) were associated with glucose levels at different time points (p<0.05). According to the ROC analysis, best cut-off value for HOMA-IR is 2.3, providing both sensitivity and specificity of 66.7% in discriminating persons with MS and HC. Our results demonstrate the presence of higher prevalence of IR in MS patients compared to healthy individuals, and strong association between impaired glucose metabolism and disability. Finally, it has to be emphasized that further studies are warranted to confirm our findings implicating that MS patients have significantly higher risk of impaired glucose metabolism, which could suggest the potential importance of the performance of OGTT in patients with this disorder. [ABSTRACT FROM AUTHOR]

• 2015 NMOSD criteria increase the rate of diagnosis. • Higher EDSS at onset is an independent predictor of reaching severe disability. • Severe visual deficit is reached earlier after optic neuritis or opticospinal onset. • Longer time from NMOSD onset to maintenance treatment predicts severe disability. • NMOSD studies should utilize OSIS as an outcome disability measure. Neuromyelitis optica spectrum disorder (NMOSD) most commonly, although not exclusively, targets optic nerves and spinal cord. Untreated, early and severe disability is common. We evaluated the long-term outcome in NMOSD patients diagnosed according to the 2015 criteria. We retrospectively analyzed 74 patients from the hospital-based NMOSD cohort at the Clinic of Neurology, Belgrade, Serbia, who fulfilled the 2015 NMOSD criteria. We identified patients based on 2015 criteria; 51.4% of whom would not have fulfilled 2006 criteria. Median follow-up was 6.9 years. Aquaporin-4 (AQP4) IgG was tested in all patients using a cell-based indirect immunofluorescence assay. The level of neurological disability was assessed by the Expanded Disability Status Scale (EDSS) score, and by Opticospinal Impairment Scale (OSIS), visual acuity (VA) and motor function subscores. The disease course was monophasic in 17.6% patients and relapsing in the remainder; none developed progressive disease. AQP4-IgG was detected in 89.2% of patients. 45 of 74 patients were treated with immunosuppressants, 40 with azathioprine, 3 with mycophenolate mofetil, 1 with cyclophosphamide, 1 with mitoxantrone, and 2 patients with rituximab. The median intervals from onset to EDSS 4.0, 6.0 and 7.0 were 6.5 years, 11.9, and 22.0 years, respectively. Higher baseline EDSS was associated with risk of attaining EDSS 4.0, 6.0 and 7.0; a shorter first inter-attack interval for reaching EDSS 4.0 and 6.0; longer time to the start of treatment for reaching EDSS 7.0. Worse visual acuity at the disease onset predicted faster assignment of OSIS VA = 6 and VA = 8. Severe visual deficit (OSIS V A 6) was reached earlier after optic neuritis (median time, 10.0 years) or combined opticospinal onset (median time, 11.4 years) than after myelitis onset (median time, 18.0 years) (p = 0.002). Our results support the benefits of early diagnosis and treatment of NMOSD, especially in persons with severe optic and spinal disability at onset. [ABSTRACT FROM AUTHOR]