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Objective Cognitive impairment (CI) and executive dysfunction (ED) are prevalent in patients with multiple sclerosis (PwMS). The Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) is the gold standard neuropsychological battery (NPB) for detecting CI. Delis-Kaplan Executive Function System (DKEFS) NPB evaluates ED. We aimed to find practical test(s) from DKEFS with acceptable diagnostic utility for early detection of impairment in cognitive and executive domains. Methods Cognitive and executive tasks, physical disability, and depression scores of 30 PwMS were assessed (17 women, age: 38.1). Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and Controlled Oral Word Association Test (COWAT) from MACFIMS and Trail Making Test (TMT), Design Fluency Test (DFT), and Verbal Fluency Test (VFT) from DKEFS were selected. The association between patients' characteristics and performance in tests, and diagnostic accuracy of DKEFS tests in detecting impairment in cognitive tasks were evaluated, using Pearson correlation and receiver operator characteristic curve analyses, respectively. Results A significant correlation was found between disease duration and SDMT and TMT subtests. Expanded Disability Status Scale was significantly related to SDMT, VFT-switching, and TMT subtests. Beck Depression Inventory was significantly related to DFT. TMT-switching detected abnormalities in SDMT and PASAT with 100% sensitivity, 93.3% (for SDMT), and 85.7% specificity (for PASAT). TMT-letter showed 100% sensitivity and 90% specificity in identifying abnormalities in COWAT. Conclusions TMT, particularly the switching condition, is a practical paper-based test that could predict impairment in cognitive tasks. Clinicians may use TMT as a screening tool among PwMS.

Background: Coronavirus Disease 2019 (COVID-19) is a highly contagious disease that resulted in 4533645 deaths until September first, 2021. Multiple Sclerosis (MS) patients receive immunosuppressive drugs. Thus, there is a concern that these drugs will reduce the patient’s immune system resistance against COVID19. Objectives: This study aimed to evaluate the epidemiology of COVID19 and its impact on MS patients in our university hospital in Tehran City, Iran. Materials & Methods: A cross-sectional study was conducted based on hospital-based registry data from May 2020 to March 2021. Among more than 500 registered MS patients in Imam Khomeini Hospital in Tehran City, Iran, referring within our study period, 84 patients reported SARS-COV2 infection. The diagnosis of MS was confirmed by the McDonald criteria. Moreover, the diagnosis of COVID-19 in MS patients was established by the real-time-PCR technique and chest computed tomography. Results: Out of 84 MS patients with SARS-COV2 infection, 55(65.5%) were women, and their mean age was 37.48 years. The most commonly used medications by MS patients were Rituximab 20 (26.3%) and Dimethyl Fumarate 14(18.4%). Totally, 9(10.8%) of the patients needed to be hospitalized due to COVID-19, with a mean hospitalization duration of 5.88 days. A total of 1 (1.2%) death was reported. Conclusion: Compared to the healthy population, COVID-19 is not more serious in MS patients. Most MS patients with COVID-19 infection were not hospitalized and continued their medication during the infection.

Background: Fatigue is a common complaint of patients with multiple sclerosis (MS), adversely affecting their quality of life. There is a lot of evidence showing that carnitine deficiency is linked to fatigue development and severity in some conditions. This study aimed to evaluate the association between free L-carnitine serum levels and the severity of fatigue in patients with MS. Methods: This case-control study included 30 patients with relapsing-remitting MS (RRMS) in two age-matched equal-number groups according to the presence or absence of fatigue. Fatigue was scored using the valid questionnaire of Fatigue Severity Scale (FSS) and serum level of free L-carnitine was measured simultaneously. Finally, the association between serum level of free L-carnitine and fatigue severity was evaluated in patients with MS. Results: The mean value of FSS in patients with fatigue was 48.80 ± 8.55, which was nearly two-fold higher than the group without fatigue. We found a significant correlation between the serum level of free L-carnitine and FSS and showed that the patients with fatigue had a significantly lower serum level of free L-carnitine compared to patients without fatigue (P < 0.001). Conclusion: Present study demonstrated that patients with lower serum levels of free L-carnitine were more likely to experience fatigue. We recommend that a higher dietary intake of carnitine might be a useful complementary treatment for MS-related fatigue.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). Myelin-autoreactive T cells have been implicated in the initiation of an inflammatory cascade. Dendritic cells (DC) are key modulators of this immuno-pathological cascade. The interaction between immune complexes (IC) and FcγRs results in activation of the immune system and induction of host inflammatory responses. Otherwise, monocytes differentiate into DCs after ligation of their FcγRs to IgG. We investigated circulating immune complexes levels (CIC) and differentiation of monocytes onto immature dendritic cell (iDC) via FcγR by Plate-bound human IgG in MS patients compared to healthy individuals. Our results showed that the concentration of CIC in patients with MS was significantly higher than healthy controls. Human IgG alone differentiate monocytes into DCs with a phenotype, including up-regulation of CD1b, CD86 and down-regulation of CD14. Also, the ability of LPS/MBP matured DCs in activation and cytokine production of autologous T cells was evaluated by MLR assay and ELISA. The level of IL-17 was significantly higher in MS patients when IgG derived DCs cocultured with T cells. Also, a correlation between IL-17 levels and circulating immune complexes level was observed in MS patients. Therefore, activation of FcγR on monocytes triggers differentiation into specialized iDC with the capacity to induce auto-reactive T cells that may contribute to the pathogenesis of MS.

Objectives: There is some inconclusive evidence for the role of fish consumption in susceptibility to multiple sclerosis (MS). The present study aimed to systematically review and determine the ass...

Background Quantitative magnetization transfer imaging (qMTI) 1 is an efficient technique that is sensitive to the density of the macromolecular protons which are found mainly in white matter myelin. Objective The aim of this study is to investigate the statistical significance of complementary qMTI parameters including magnetization transfer rate (Ksat) 2 and longitudinal relaxation time under MT saturation pulse (T1sat) 3 compared to magnetization transfer ratio (MTR) 4 and longitudinal relaxation time (T1) 5 in relapsing remitting multiple sclerosis (RRMS) 6 patients. Methods In this study, conventional MRI protocols as well as MT-3DSPGR imaging were performed on twelve clinically definite RRMS patients and twelve age-matched controls. Two general methodologies were utilized for qMTI calculations, including global volumetric measurement of MTI-T1 parameters using a pixel-based analysis method throughout the brain white matter and the regional assessments within classified MS lesions with respect to their hypointensities on T1-weighted scans. MTI-T1 parameters of segmented lesions and normal appearing white matter (NAWM) 7 in RRMS patients were evaluated in comparison with normal white matter (NWM) 8 of control subjects. Results Significant reductions of MTR and Ksat values in isointense ( p 0.0001 ), mild ( p 0.0001 ) and severe hypointense lesions in comparison with NAWM on T1-weighted scans, were associated with considerable increases in both tissue relaxation times with and without MT pulse, T1sat ( p 0.0001 ) and T1 ( p 0.0001 ) respectively. Similar significant changes of quantitative MT imaging parameters and T1 values were also seen in non-lesion areas of NAWM in MS patients compared to those of NWM in healthy volunteers. Conclusion Complementary qMT imaging parameter contributes to the magnetization transfer phenomenon including Ksat and T1sat can provide more reliable information about the magnitudes and mechanisms of myelin destruction in multiple sclerosis compared to the conventional MTR and T1 relaxation time values.

Background: A growing number of clinical trials have investigated the role of diet in multiple sclerosis (MS) patients. We systematically reviewed the literature for clinical trials to assess the impact of different kinds of diets on MS-related outcomes. Methods: We searched MEDLINE, EMBASE, and Web of Science for relevant studies published before July 2019. The clinical trials included a defined dietary intervention and MS outcomes, including fatigue, relapse rate (RR), quality of life (QOL), and disability. Results: In the present review, 15 trials on 669 MS patients were included. The 2 plant-based diet trials, 1 was low-fat and the other was low-calorie, included in the review showed a large effect (ES: 0.6 to 0.7) on fatigue compared to the regular diet. The other plant-based diet was a low-protein diet and showed moderate to large effects on disability and RR compared to the Western diet. Moreover, 2 studies showed the clinically meaningful effects of the ketogenic diet (KD) on QOL and disability compared to the regular diet. In addition, 2 studies compared fish oil (FO) to placebo and found a small effect on disability (ES: 0.1 to 0.3). There were 2 studies that evaluated evening primrose oil and hemp seed oil and showed medium to large effect (ES: 0.7 to 1.5) on RR compared to olive oil. Finally, we found 2 studies that showed high flavonoid cocoa had a moderate effect (ES: 0.4) on fatigue and a small effect (ES: 0.04) on QOL compared to low flavonoid cocoa. Conclusion: Plant-based diet is a backbone for dietary recommendations in MS patients although low-fat, low-calorie, and KD diets with the addition of fish oil, vegetable oil, and flavonoids could be helpful.

Purpose: Investigations of the hemodynamic changes of the venous system in patients with multiple sclerosis (MS) have shown contradictory results. Herein, the biomechanical parameters of the internal jugular vein (IJV) and common carotid artery (CCA) of MS patients were extracted and compared to healthy individuals.Methods: B-mode and Doppler sequential ultrasound images of 64 IJVs and CCAs of women including 22 healthy individuals, 22 relapsing-remitting multiple sclerosis (RRMS) patients, and 20 primary-progressive multiple sclerosis (PPMS) patients were recorded and processed. The biomechanical parameters of the IJV and the CCA walls during three cardiac cycles were calculated.Results: The IJV maximum and minimum pressures were higher in the MS patients than in the healthy subjects, by 31% and 19% in RRMS patients and 39% and 24% in PPMS patients. The venous wall thicknesses in RRMS and PPMS patients were 51% and 60% higher than in healthy subjects, respectively. IJV distensibility in RRMS and PPMS patients was 70% and 75% lower, and compliance was 40% and 59% lower than in healthy subjects. The maximum intima-media thicknesses of the CCAs were 38% and 24%, and the minimum intima-media thicknesses were 27% and 23% higher in RRMS and PPMS patients than in healthy individuals, respectively. The shear modulus of CCA walls in RRMS and PPMS patients was 17% and 31%, and the radial elastic moduli were 47% and 9% higher than in healthy individuals.Conclusion: Some physical and biomechanical parameters of the CCA and IJV showed significant differences between MS patients and healthy individuals.

BACKGROUND Exercise has been demonstrated to be safe and well-tolerated in individuals with multiple sclerosis (MS). Physical activity has been shown to enhance the therapeutic effects of transcranial direct current stimulation (tDCS). This study aimed to determine the efficacy of intermittent tDCS combined with riding a stationary bicycle to improve walking capacity in individuals with MS. METHODS This double-blind randomized controlled trial enrolled 50 eligible participants. Thirty-nine participants completed the study: 21 in the active group and 18 in the control group. Participants were assigned randomly to exercise on a stationary bike in conjunction with anodal tDCS or to exercise combined with a sham tDCS protocol. Walking capacity tests (2-Minute Walk Test, 5-Meter Walk Test, Timed Up and Go test), manual muscle testing, the Fatigue Severity Scale, and the Multiple Sclerosis Quality of Life–54 were used to determine outcomes. RESULTS In terms of observed changes in 2-Minute Walk Test and 5-Meter Walk Test values, the exercise + tDCS group achieved significantly higher posttreatment values than the exercise + sham tDCS group. After the intervention and 1 month later, the intervention group's mean Timed Up and Go test value decreased significantly (P = .002) compared with that of the control group. There was no difference in Fatigue Severity Scale score, Multiple Sclerosis Quality of Life–54 score, or manual muscle testing improvement between the 2 groups. CONCLUSIONS Nonconsecutive sessions of anodal tDCS combined with stationary cycling may have a greater effect on the walking capacity of individuals with MS than exercise alone

Summary Background & aims Vitamin A is considered as a supplement that effect on autoimmune diseases. We aimed to systematically review the effect of vitamin A on cytokines in patients with autoimmune disease. Methods Two researchers searched Scopus and PubMed until May 2018. Researchers extracted data from 6 eligible published papers. Extracted data included the gene expression of the inflammatory and anti-inflammatory cytokines. Results Fixed effect analysis of the WMD (95% CI) of the changes in gene expression showed that gene expression of the inflammatory (IL-17, IFN-γ and T-bet) and anti-inflammatory (TGF-β and FOXP3) cytokines significantly decreased and increased due to vitamin A supplementation in patients with autoimmune (Multiple sclerosis and atherosclerosis) diseases. Conclusions Vitamin A supplementation effects on gene expression and may improve serum level of cytokines and clinical signs of autoimmune disease but there is no adequate evidence.

MS is a demyelinating disease that can result in significant disability. Along with physical complications, this disease is associated with significant psychological complications, including cognitive decline. Therefore, this study aimed to determine the efficacy of mindfulness-based cognitive therapy in combination with rTMS on information processing and working memory in patients with MS.The current study used a single-case experimental design and included a follow-up (A-B-A). The statistical population of the present study was all MS patients in Tehran who referred to Imam Khomeini Hospital in Tehran in 2020. The present study sample consisted of 5 MS patients selected by the sampling methods availableThe current study's findings indicate that combining mindfulness with rTMS has a beneficial effect on the information processing and working memory of MS patients. Overall, 67.24% recovered following the intervention stage, 53.64% recovered following the follow-up for information processing, 104.04% recovered following the intervention stage, and 76.98% recovered following the follow-up for working memory.The study shows the effect of mindfulness combined with rTMS on cognitive problems in MS patients. Significant improvements in MS patients' information processing, working memory, and therapeutic outcomes were observed throughout the follow-up period.

Objective: The use of an appropriate contrast agent performs a major role in brain magnetic resonance imaging (MRI) of multiple sclerosis (MS) patients. The present study aimed to make a comparison between the diagnostic values of Gadovist and Magnevist considering the successive imaging times in contrast-enhanced brain MRI of MS patients. Materials and Methods: A total of 62 relapsing-remitting MS patients (56 females, mean age of 31 years) were enrolled in the present study. All of them underwent two sessions of standard contrast-enhanced brain MRI upon enrollment and 48 h later. The participants were randomly assigned to each contrast agent. T1-weighted (T1W) images were taken 30 sec, as well as 5, 10, 15, and 30 min after the contrast injection. For all of the images, two neuro-radiologists who were blinded to the contrast type counted the number of plaques in the brain. In addition, for the enhanced plaques larger than 10 mm, the signal intensity (SI) was determined using its region of interest. Results: The mean plaque number significantly increased from 30 sec to 15 min for both contrasts separately (P0.25). The mean plaque number in the Gadovist group was higher, compared to that in the Magnevist group at both 15 and 30 min, and the differences were statistically on the borderline (both P-Values=0.07). The mean SI of enhanced plaques gradually increased in the course of imaging in both contrast groups. Except for 30 sec, in all other time sessions, the mean SI was higher in Gadovist-enhanced MR images, compared to Magnevist-enhanced MR images (P

Background and Purpose: Stroke is reported as a consequence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in several reports. However, data are sparse regarding the details of these patients in a multinational and large scale. Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke, intracranial hemorrhage, and cerebral venous or sinus thrombosis among SARS-CoV-2–infected patients. We further investigated the risk of large vessel occlusion, stroke severity as measured by the National Institutes of Health Stroke Scale, and stroke subtype as measured by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria among patients with acute ischemic stroke. In addition, we explored the neuroimaging findings, features of patients who were asymptomatic for SARS-CoV-2 infection at stroke onset, and the impact of geographic regions and countries’ health expenditure on outcomes. Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least 1 eligible stroke patient. Of 432 patients included, 323 (74.8%) had acute ischemic stroke, 91 (21.1%) intracranial hemorrhage, and 18 (4.2%) cerebral venous or sinus thrombosis. A total of 183 (42.4%) patients were women, 104 (24.1%) patients were P =0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; P Conclusions: We observed a considerably higher rate of large vessel occlusions, a much lower rate of small vessel occlusion and lacunar infarction, and a considerable number of young stroke when compared with the population studies before the pandemic. The rate of mechanical thrombectomy was significantly lower in countries with lower health expenditures.

Background Multiple sclerosis (MS) is the most common immune mediated disorder of the central nervous system (CNS). This study compares the worldwide occurrence and epidemiologic burden of MS in the Middle East and Northern Africa (MENA) region and Western Europe from 1990 to 2017. Methods This study used data from the global burden of disease (GBD) studies. Initially, all age and age-specific values were estimated and then, these values were compared among the mentioned areas. In addition, the changes of sex distribution of MS according to incidence, prevalence, and disability-adjusted life years (DALYs) were calculated. The trend of MS incidence was also compared among the MENA region countries. Results According to MS incidence per 100,000 populations during 1990 to 2017, the occurrence of new cases has decreased slightly in the world (from 0.7 to 0.65) and Western Europe (from 2.55 to 2.50). Except Iran with a sharp rise of 2 to 2.8, there was a slow increase in the MENA region (from 0.9 to 1). The MS prevalence, between 1990 and 2017, in all ages was stable in the world and the MENA region except a steady increase in Iran and highest value in Western Europe. In this study, we determined the age-specific incidence of MS in all regions from 1990 to 2017. Although data showed a different trend of changes between age groups and regions, the group age 25–29 years had the highest risk of MS incidence. Based on gender, the incidence, prevalence, and DALY of MS in all regions were higher in female. Conclusion From 1990 to 2017, Western Europe had the highest MS prevalence and the MENA region had a relatively stable trend for MS incidence. In particular, in Iran, the MS incidence has been constantly increasing and has surpassed Western Europe since 2013.

Background: Studying different pathological aspects of lesions in multiple sclerosis (MS) patients could be useful to modify the diagnosis and treatment of this neurological disorder. Magnetic resonance imaging (MRI) modalities have the potential to investigate variations in brain tissue because of inflammatory and neurodegenerative processes in various types of MS-related lesions. Objectives: This study was done to investigate the quantitative changes in MRI-based parameters, like perfusion and magnetization transfer ratio (MTR) of different types of brain lesions, to demonstrate the ability of MRI to detect structural and pathological differences in MS lesions. Methods: Quantitative MRI modalities were performed on 18 patients with five different kinds of lesions (T1 holes, acute and chronic white matter (WM), and acute and chronic gray matter (GM) lesions) using a 3 T MRI scanner. The following protocols were used to characterize the pathology of lesions: (I) fluid-attenuated inversion recovery (FLAIR); (II) pre- and post-contrast T1-weighted; (III) dynamic contrast-enhanced (DCE); and (IV) MTR imaging. Quantitative comparison of Ktrans, cerebral blood volume (CBV), cerebral blood flow (CBF), and MTR was done to find the best parameter to distinguish different lesions. Finally, a multivariate classifier was applied to introduce the best parameter to indicate differences in lesions. Results: Five lesions were characterized by perfusion and MTR parameters. The pathological changes were measured, including: (I) the highest value of parameters in both acute WM and GM lesions; (II) the lowest value of four parameters in both chronic WM and GM lesions; (III) MTR had the highest rank among parameters using the classifier. Conclusions: The degree of pathological alterations due to inflammatory and neurodegenerative processes in MS-related lesions was indicated through the used parameters in different kinds of lesions. Inflammation was the dominant process in acute lesions, while neurodegeneration and tissue loss were observed mostly in chronic lesions. Both inflammation and neurodegeneration were detected in T1 holes. Perfusion parameters and MTR were reasonable parameters to describe differences in brain lesions. Thus, it could be confirmed that magnetization transfer imaging (MTI) and DCE-MRI are high-sensitivity methods to detect microstructural changes in the brain and subtle changes in the blood-brain-barrier. Classification of the parameters indicated that MTR was the best biomarker than others to show variations in lesions pathology.

Objective: Multiple sclerosis (MS) is a chronic neurological disease that could aggressively affect patients’ quality of life in most instances. This study aimed to compare the effectiveness of an existential-spiritual psychotherapy with a cognitive-behavioral therapy on quality of life and meaning in life in women with multiple sclerosis. Method: A convenience sample of 43 women with multiple sclerosis participated in this quasi-experimental study. They were randomly assigned into 3 groups: an existential-spiritual intervention, a cognitive-behavioral intervention, and the control group. Participants were assessed for outcome measures (quality of life and meaning in life) at 3 points in time: pretest, posttest, and 5-months follow-up. The Multiple Sclerosis Quality of Life-54 (MSQOL-54) and the Meaning in Life Questionnaires (MLQ) were used as outcome measures. To compare outcomes among the study groups, repeated measures analysis of variance was performed. Results: The results showed that while no difference was observed for the control group, scores for meaning in life improved significantly for existential-spiritual intervention and cognitive-behavioral therapy (p = 0.027, p = 0.039). Also, both mental (p < 0.001, p = 0.014) and physical (p = 0.001, p = 0.013) health dimensions of quality of life increased significantly in the 2 intervention groups. However, the results indicated that women in the existential-spiritual intervention group showed greater improvement in some aspects of meaning in life (search for meaning) and quality of life (role physical and role emotional, pain and energy) compared to women in the cognitive-behavioral intervention group. However, the latter group showed better improvements on 2 subscales (physical function and health distress). Conclusion: Both existential-spiritual and cognitive-behavioral interventions can improve quality of life and meaning in life among women with multiple sclerosis. However, the findings suggest that although both interventions were effective, the existential-spiritual intervention resulted in more positive improvements in some aspects of meaning in life and quality of life.

Objective Multiple sclerosis (MS) is an inflammatory and autoimmune disease associated with the imbalance of cytokines secreted from CD4+ T cells. Studies have shown that vitamin A and its active derivatives are able to modulate the immune system in MS patients. The aim of the present study was to investigate the effect of supplementation of retinyl palmitate (RP), the dietary form of vitamin A, on pro- and anti-inflammatory cytokines in the plasma and supernatants of cultured peripheral blood mononuclear cells (PBMCs) of MS patients. Patients and methods Thirty-six relapsing-remitting MS patients were enrolled in this double-blind randomized clinical trial. Participants received one capsule of 25,000 IU RP or a placebo per day for six months. Blood samples were taken before and after intervention. After intervention, the PBMCs were isolated and cultured. The levels of pro- and anti-inflammatory cytokines in the plasma and supernatant of cells stimulated with myelin oligodendrocyte glycoprotein, phytohemagglutinin or vehicle (media) were determined. The sample t-test and Mann Whitney U test were used to compare data between groups. Results The changes in pro-inflammatory cytokine levels (IL-1β, TNF-α, IFN- γ, IL-2, IL-6, and IL-17) in the serum and supernatant of MS patients were not significant (p > 0.05). There were also no significant changes in the levels of anti-inflammatory cytokines (IL-10, IL-13, IL-4, and TGF-β) (p > 0.05). Conclusion Unexpectedly, this study found no significant changes in cytokine levels after six months of RP supplementation in MS patients. The results of other studies by our team have shown significant changes in the gene expression of the cytokines in response to RP supplements. Therefore, we recommend that periodic follow-up of RP supplementation may be needed to reveal changes in the level of the cytokines in the plasma and PBMCs and to clarify the real effect of RP on the immune factor levels in the serum of MS patients.

Iran, as a middle income country, is one of the places with high and rising prevalence of multiple sclerosis (MS). Regarding the substantial economic burden, reviewing the trend in prescribed disease modifying treatments (DMTs) could be of help. Here we studied the DMT information of nearly 14000 MS cases and its trends change for 30 years to improve health services to patients.The population base of this descriptive-analytical (cross-sectional) study consisted of all MS patients in the nationwide MS registry of Iran (NMSRI), up to August 1, 2021. Registrars from 15 provinces, 24 cities, 13 hospitals,8 MS associations, 16 private offices, and 7 clinics had entered the data.Overall, 14316 cases were enrolled. The majority (76.1%) were female. The youngest and eldest patients were 5 and 78 years old, respectively. Diagnosis delay was under one year in most cases (median: 0, IQR: 0 - 1). Most (61.4%) had RRMS. Generally, platform injectables (IFN beta, glatiramer acetate) were the most used DMTs until 2010. It seems that introduction of newer agents (antiCD20s and oral DMTs) resulted in a decrease in the use of former drugs since around 2015. Some unusual practices are prominent such as using not approved DMTs for PPMS over the years, or administering high efficacy drugs like natalizumab for CIS. The results indicate the remaining popularity of first line injectable DMTs in female and pediatric patients.Mean age (SD) at onset in our study (29 ± 8.8) is near the statistics in Asia and Oceania (28 ± 0.7). Concerns about COVID-19 had a noticeable impact on administering high efficacy drugs like rituximab and fingolimod. However, in male patients this approach has not been the case. It may be related to more aggressive disease course in this group. The other possible explanation could be planning for pregnancy in female cases. The popularity of platform injectable drugs in pediatric MS may be related to its favorable safety profile over the years. Another point in this group, is the superiority of rituximab over other highly efficient medications.

Recently, we reported a positive correlation between Klotho, as an anti-aging protein, and the total antioxidant capacity (TAC) in cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. However, there is no information about the Klotho and TAC changes within the central nervous system (CNS). Thus, the current study aimed to employ an experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice using MOG35-55 peptide to examine the relationship between Klotho and TAC within the CNS. To this end, the brain and spinal cord were obtained at the onset and peak stages of EAE as well as non-EAE mice (sham/control groups). The Klotho expression was assessed in the brain and spinal cord of different experimental groups at mRNA (qPCR) and protein (ELISA) levels. Also, TAC level was determined in the tissues of different experimental groups. The results showed that Klotho expression in the brain at the onset and peak stages of EAE were significantly lower than that in non-EAE mice. Conversely, Klotho expression in the spinal cord at the onset of EAE was significantly higher than that of non-EAE mice, while Klotho was comparable at the peak stage of EAE and non-EAE mice. The pattern of TAC alteration in the brain and spinal cord of EAE mice was similar to that of Klotho expression. In conclusion, for the first time, this study demonstrated a significant positive correlation between Klotho and TAC changes during the pathogenesis of EAE. It is suggested that Klotho may have neuroprotective activity through the regulation of redox system.

Neurological disease contributes significantly to morbidity and mortality in different ages and geographic areas around the world. The purpose of the current study was to investigate the incidence and disability-adjusted life years (DALYs) trend of neurological disease in Iran during 27 years ago. We used the data of the Global Burden of Disease (GBD) Study to estimate the incidence and DALYs of neurological disease in Iran in different age groups between 1990 and 2017. Age groups were defined in 5 groups including < 5 years, 5-14 years, 15-49 years, 50-69 years, and ≥ 70 years. The incidence number of neurological disease during 1990 to 2017 increased from 7.5 million to more than 12 million and the incidence rate grew as much as 1400 per 100000 populations in Iran. Totally, headache, epilepsy, and Alzheimer were the most common neurological diseases according to incidence and had the most values of DALY in Iran. The highest incidence and DALY of neurological disease was observed in the age group of 15-49 years. This study showed that the incidence and burden of neurological diseases had a dramatic increasing trend during 27 years ago in Iran. Consequently, it is necessary to investigate the causes of the growing trend in future studies.

Background Fatigue is one of the most common symptoms in patients with multiple sclerosis (MS). Currently, there is no approved medication for MS-related fatigue. Objective In this study, we aim to evaluate the safety and efficacy of memantine for improving fatigue in patients with MS. Methods This was a pilot randomized, double-blind, placebo-controlled clinical trial. Eligible patients with relapsing-remitting MS (RRMS) according to the McDonald criteria were randomized to receive either memantine (20 mg/day) or placebo and were assessed at baseline and three months after treatment. The change in the severity of fatigue was determined by the Modified Fatigue Impact Scale (MFIS). Results Sixty-four patients were randomly allocated to the memantine (n = 32) and placebo (n = 32) groups. Sixteen patients in the memantine group and 24 patients in the placebo group completed the study. The mean [95% CI] absolute change in MFIS scores from baseline did not differ significantly between the memantine (−5.8 [−12.7 to 1.0]) and placebo (−4.0 [−10.6 to 2.7]) groups (between-group difference: −1.9 [−11.7 to 7.8], P = .702). No serious adverse events were reported, except for dizziness and sedation in four patients in the experimental arm, which resulted in discontinuation. Conclusion This trial failed to prove any clinical efficacy of memantine for the management of MS-related fatigue. Although memantine was generally well-tolerated, adverse events were among the major causes of dropout in this study.

Background: In the pre-antiretroviral era, the frequency of neurologic complications was associated with low baseline CD4+ T-cell counts. Introduction of antiretroviral therapy (ART) has largely decreased the incidence of opportunistic infections and CNS neoplasia in the recent two decades; however, virus replication persists in the cerebrospinal fluid (CSF) and neuronal tissues due to variable drug penetration as well as development of drug resistance. Although many previous studies have addressed the presence of neurologic manifestations in the course of HIV infection; an update on the type of neurologic involvement, presenting signs and symptoms, radiologic findings, and response to treatment is essential. Methods: In a case series, we recruited 42 patients presenting with neurologic symptoms/signs and concomitant HIV infection in 12 months during 2015 and 2016 at a tertiary academic hospital. Information regarding the course of diagnosis, laboratory findings, radiologic findings, and final diagnosis were documented and analyzed in relation to the survival status of each patient during up to one month of hospitalization. Results: The mean age of the patients was 39.7; 25 were men, 19 were newly diagnosed. Thirteen patients (31%) died during treatment; from them, six were newly diagnosed. Median CSF white blood cell counts were significantly higher in nonsurvivors; the most common diagnosis was focal brain lesions; toxoplasmosis and tuberculosis were the first common etiologies; 79% recovered with the intended treatment regimen. History of drug abuse, not receiving antiretrovirals, low baseline CD4 counts, and loss of consciousness at the time of admission has been seen more among deceased patients. Conclusions: Neurologic presentations or complications of HIV infection lead to high mortality rates. Early diagnosis of infection and improvement of patient compliance with antiretroviral treatment can reduce the mortality associated with neurologic diseases.

Although studies have shown the efficacy of laquinimod (LAQ) on disease progression in patients with multiple sclerosis (MS), there is some controversy about whether it improves the types of outcomes and side effects. The main purpose of the present study was to systematically review and meta-analyze the efficacies and side effects of LAQ in patients with relapsing-remitting MS (RRMS).PubMed, Scopus, and Web of Science databases were searched with relevant keywords for articles published up to June 2019. Six randomized control trials that examined LAQ vs. placebo in adult patients with MS were included. Information on the effectiveness and side effects of LAQ were extracted. The quality of the included studies was appraised using Jadad scores, and the data were divided into subgroups according to different doses and periods.Efficacy of LAQ: The number of Gadolinium-enhancing (GDE) lesions significantly decreased after treatment with LAQ (SMD = -0.15, 95% CI: -0.23, -0.07), but there was no significant reduction in the number of T2 lesions (SMD = -0.38, 95% CI: -1.04, 0.28). The relapse rate (SMD = -0.13, 95% CI: -0.21, -0.04) and MS Functional Composite (MSFC) score significantly decreased with LAQ treatment (SMD =0.14, 95% CI: 0.05, 0.23). Risk of adverse events: The risk of diarrhea, nausea, abdominal pain, and all adverse events did not significantly increase (p 0.05) with treatment with LAQ; however, the risk of back pain, headache, and vomiting significantly increased (p 0.05). The change in mortality rate was not significant (OR = 0.25, 95% CI: 0.04, 1.50).LAQ can considerably improve clinical and imaging outcomes in RRMS patients. The most effective dose of LAQ with lower side effects may be 0.6 mg/day for at least 2 years, but more evidence is needed to confirm these results.Laquinimod can improve clinical and imaging outcomes in patients with multiple sclerosis.Back pain and headache are probable side effects of laquinimod in patients with multiple sclerosis.The most effective and safe dose of laquinimod for patients with multiple sclerosis may be 0.6 mg/day for 2 years.

Endoplasmic reticulum (ER) stress is strictly linked to neuroinflammation and involves in the development of neurodegenerative disorders. Protein disulfide isomerase (PDI) is an enzyme that catalyzes formation and isomerization of disulfide bonds and also acts as a chaperone that survives the cells against cell death by removal of misfolded proteins. Our previous work revealed that PDI is explicitly upregulated in response to myelin oligodendrocyte glycoprotein (MOG)-induced ER stress in the brain of experimental autoimmune encephalomyelitis (EAE) mice. The significance of overexpression of PDI in the apoptosis of neural cells prompted us to study the effect of CCF642, efficient inhibitor of PDI, in the recovery of EAE clinical symptoms. Using this in vivo model, we characterized the ability of CCF642 to decrease the expression of ER stress markers and neuroinflammation in the hippocampus of EAE mice. Our observations suggested that CCF642 administration attenuates EAE clinical symptoms and the expression of ER stress-related proteins. Further, it suppressed the inflammatory infiltration of CD4 + T cells and the activation of hippocampus-resident microglia and Th17 cells. We reported here that the inhibition of PDI protected EAE mice against neuronal apoptosis induced by prolonged ER stress and resulted in neuroprotection.

Methamphetamine (meth) is potently addictive and is closely linked to high crime rates in the world. Since meth withdrawal is very painful and difficult, most abusers relapse to abuse in traditional treatments. Therefore, developing accurate data-driven methods based on brain functional connectivity could be helpful in classifying and characterizing the neural features of meth dependence to optimize the treatments. Accordingly, in this study, computation of functional connectivity using resting-state EEG was used to classify meth dependence. Firstly, brain functional connectivity networks (FCNs) of 36 meth dependent individuals and 24 normal controls were constructed by weighted phase lag index, in six frequency bands: delta (1–4 Hz), theta (4–8 Hz), alpha (8–15 Hz), beta (15–30 Hz), gamma (30–45 Hz) and wideband (1–45 Hz).Then, significant differences in graph metrics and connectivity values of the FCNs were used to distinguish the two groups. Support vector machine classifier had the best performance with 93% accuracy, 100% sensitivity, 83% specificity and 0.94 F-score for differentiating between MDIs and NCs. The best performance yielded when selected features were the combination of connectivity values and graph metrics in the beta frequency band.

Background Amyotrophic lateral sclerosis (ALS) is an incurable progressive neurodegenerative disease and thus the assessment of quality of life (QOL) changes and factors that may influence its course is valuable in the meantime. Objectives The present study aimed to assess the deterioration rate of QOL and influencing factors in different subgroups of Iranian ALS patients. Methods 132 patients were evaluated in this prospective multicenter observational study. QOL was measured using ALS Assessment Questionnaire (ALSAQ-40) during 1year follow up and its progression rate was assessed in different subgroups of patients according to age, sex, stage of disease, riluzole consumption, onset type. Also physical disability and functional disability were measured using MMT and ALSFRS-R scores respectively and their progression rates were compared with ALSAQ-40 changes. Results Significant deterioration of the scores of ALSAQ-40 during study was consistent in all of its domains ( p =0.000). There was a significant negative correlation between ALSFRS-R and MMT changes and ALSAQ-40 change ( p =0.000) and this was consistently observed in all domains of ALSAQ-40 ( p =0.00). ALSAQ-40 deterioration rate was shown to be significantly lower in severe/terminal stages compared to mild/moderate stages ( p =0.00). Significantly higher deterioration rate was observed in bulbar onset versus limb onset patients [F (1,130)=4.52, p =0.04] but no significant difference was observed among other subgroups according to age, sex and riluzole consumption. Conclusion All domains of QOL significantly deteriorate during ALS course and there is a significant correlation between their changes and progression of physical and functional disabilities. Rate of degradation of QOL may be different at different stages of the disease. QOL worsens independent of factors such as sex, age and consumption of riluzole; but onset type (bulbar versus limb) is an imperative factor in quality of life changes during the disease course.

Vitamin A derivatives such as retinoic acid may improve the impaired balance of CD4+ T cells in autoimmune and inflammatory diseases. This study is a double-blind randomized trial to evaluate the effect of vitamin A (as form of retinyl palmitate) supplementation on multiple sclerosis (MS) patients. Thirty-nine patients were enrolled and randomly assigned to two groups. Both groups were followed for 6 months. The experimental group received 25,000 IU of retinyl palmitate daily, while the control group received a placebo. Before and after the study, the expression of interferon gamma (IFN-γ) and T-bet genes was evaluated in peripheral blood mononuclear cells of patients by RT-PCR. The results showed that after 6 months of supplementation, expression of IFN-γ and T-bet was significantly decreased. These data suggest that retinyl palmitate supplementation can modulate the impaired balance of Th1 and Th2 cells and vitamin A products that may be involved in the therapeutic mechanism of vitamin A in MS patients. This study provides information regarding the decreased gene expression of IFN-γ and T-bet in MS by retinyl palmitate supplementation.

Fingolimod has been the first approved oral medication in MS for its relapsing remitting type. It is a non-selective sphingosine1-phosphate (S1P) receptor modulator on lymphocytes. Engagement of this receptor blocks the T cells and B cells migration from the lymph nodes into the inflamed central nervous system (CNS) via bloodstream. In spite of this known immunomodulatory mechanism, there are some reports about serious infection following the initiation of fingolimod therapy like herpes types or infections associated to the immunosuppressed situation (cryptococcal meningitis, primary cutaneous cryptococcosis and visceral leishmaniasis). To the best of our knowledge, in contrary to many reports about opportunistic or serious infections with fingolimod, there has been no report on fungal osteomyelitis associated to fingolimod until now. Here, we aimed to describe a woman who developed necrotizing fungal osteomyelitis four years after starting fingolimod, as a disease modifying drug for MS.

We enthusiastically read the article in PNAS by Leibovitch et al. (1), in which they show that intranasal inoculations with human herpesvirus (HHV)-6A and HHV-6B accelerate the onset and severity of experimental autoimmune encephalomyelitis (EAE). They performed an outstanding job in utilizing marmosets to mimic the multiple sclerosis (MS)-like symptoms rather than female C57BL/6 mice. Although the creativity of their work is undeniable, several points exist that are worth mentioning. It is allegedly known … [↵][1]1To whom correspondence should be addressed. Email: harirchm{at}tums.ac.ir. [1]: #xref-corresp-1-1

The anti-inflammatory role of the active metabolite of vitamin D, namely 1, 25-dihydroxyvitamin D3 (calcitriol), has been reported in multiple sclerosis (MS). Moreover, recent studies have shown that fibroblast growth factor 23 (FGF23) is involved in the regulation of calcitriol biosynthesis. The probable changes of FGF23 and calcitriol concentrations in the CSF and serum of patients with MS were evaluated. Calcitriol concentration in the CSF and serum of MS patients was significantly higher than that in non-MS patients, while FGF23 concentration in MS patients was comparable to controls. We concluded that calcitriol concentration increases in the CSF and serum of MS patients independent of FGF23 status.

The role of endoplasmic reticulum (ER) stress has been proposed in several neurodegenerative and autoimmune diseases and may contribute to neural apoptosis. The complex role of ER stress-mediated apoptosis introduces a novel angle on multiple sclerosis (MS) research. Nevertheless, the mechanisms through which ER stress intermediates apoptosis are not entirely understood. To this aim, we examined the expression of C/EBP homologous protein (CHOP), caspase-12, and protein disulfide isomerase (PDI) in mice with experimental autoimmune encephalomyelitis (EAE). We found the upregulated expression of CHOP, caspase-12, and PDI in the brain of EAE mice in comparison to healthy mice. Furthermore, immunofluorescent dual-label staining verified elevated levels of caspase-12/CHOP in astrocytes, oligodendrocytes, and microglia in the hippocampus section of EAE mice. This study highlighted the presence of ER stress and increased activation of caspase-12 in the hippocampus of mice in response to EAE induction. Higher levels of caspase-12/CHOP in hippocampal oligodendrocytes as compared with microglia and astrocytes denote that oligodendrocytes are particularly sensitive to ER-mediated apoptosis. In conclusion, the regulation of ER stress pathway would be beneficial for the survival of oligodendrocyte.

The exact determination of endoplasmic reticulum (ER) stress-associated proteins is not completely elucidated in the multiple sclerosis (MS) patients. We measured CHOP concentrations in the serum and cerebro-spinal fluid (CSF) of relapsing-remitting MS (RRMS) patients (n = 20) in comparison with the non-MS control group (n = 20) to determine whether this marker could be detected in the body fluids of RRMS patients. CHOP marker was not detectable in all harvested CSF samples. However, its levels were detectable in all serums harvested from both non-MS and RRMS patients and its levels in the latter group were not significantly higher than those of the non-MS control group (P value = 0.265). CHOP was not detectable in the CSF of RRMS patients in spite of the recent reports on the RRMS autopsies. Additionally, there were not any significant correlations (Spearman's correlation) between both of EDSS score and age with CHOP serum concentrations in all subjects.

Introduction Neuromyelitis Optica (NMO) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) which predominantly involves optic nerves and spinal cord. Since the introduction of Neuromyelitis Optica Spectrum Disorders (NMOSD) as a separate entity, there have been many reports on its association with other disorders including systemic and organ-specific autoimmune diseases. Here, we reviewed other immune-mediated diseases associated with NMOSD and tried to categorize them. Methods The present review was conducted using the PUBMED database based on papers from 1976 (i.e., since the first NMO comorbidity with SLE was reported) to 2017. We included all articles published in English. The keywords utilized included Neuromyelitis optica, Neuromyelitis Optica Spectrum Disorders, Devic's disease, in combination with comorbidity or comorbidities. Results Diseases with immune-based pathogenesis are the most frequently reported co-morbidities associated with NMOSD, most of which are antibody-mediated diseases. According to literature, Sjogren's Syndrome (SS) and Systemic Lupus Erythematosus (SLE) are the most frequently reported diseases associated with NMOSD among systemic autoimmune diseases. Further, myasthenia gravis in neurological and autoimmune thyroid diseases in non-neurological organ-specific autoimmune diseases are the most reported comorbidities associated with NMOSD in the literature. Conclusions NMOSD may be associated with a variety of different types of autoimmune diseases. Therefore, systemic or laboratory signs which are not typical for NMOSD should be properly investigated to exclude other associated comorbidities. These comorbidities may affect the treatment strategy and may improve the patients' care and management.