Time interval between the onset of symptoms and diagnosis of multiple sclerosis and the influential factors: A national registry-based study.

OBJECTIVE: The time to diagnosis of multiple sclerosis (MS) is of great importance for early treatment, thereby reducing the disability and burden of the disease. The purpose of this study was to determine the time from the onset of clinical symptoms to the diagnosis of MS and to evaluate the factors associated with a late diagnosis in Iranian MS patients. METHODS: The present cross-sectional study was conducted on patients with MS who were registered in the National MS Registry System of Iran (NMSRI). RESULTS: Overall, 23291 MS patients registered in 18 provinces of Iran were included in this study. The mean (standard deviation) interval between the onset of the disease and diagnosis of MS was 13.42 (32.40) months, and the median was one month. The diagnostic interval of 41.6% of patients was less than one month, and 14.8% of them had a one-month time to diagnosis. Patients with an age of onset below 18 years and those diagnosed after the age of 50 years had a longer time to diagnosis (P<0.001). Patients with primary progressive MS (PPMS) had the longest time to diagnose and those with relapsing-remitting MS (RRMS) had the shortest time (P<0.001). The results of negative binominal regression showed that the average rate of delay in diagnosis in women was 12% less than that in men. The average delay in diagnosis in patients with a positive family history of MS was 23% more than that in others. The rate of delay in the diagnosis of patients with PPMS and secondary progressive MS was 2.22 and 1.66 times higher, respectively, compared with RRMS. CONCLUSION: The findings of the present study revealed that more than half of the MS patients were diagnosed within a one-month interval from the symptom onset, which is an acceptable period. More attention should be paid to patients' access to medical facilities and MS specialists.

The association of serum carnitine levels with severity of fatigue in patients with multiple sclerosis: A pilot study.

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.

Late-onset multiple sclerosis in Iran: A report on demographic and disease characteristics.

BACKGROUND: Today, it is estimated that around 5% of multiple sclerosis (MS) patients are in the late-onset category (age at disease onset ≥ 50). Diagnosis and treatment in this group could be challenging. Here, we report the latest update on the characteristics of Iranian patients with late-onset MS (LOMS). METHODS: This cross-sectional study used the information provided by the nationwide MS registry of Iran (NMSRI). The registrars from 14 provinces entered data of patients with a confirmed diagnosis of MS by neurologists. Patients with disease onset at or later than 50 years of age were considered LOMS. RESULTS: Of 20,036 records, the late-onset category included 321 patients (1.6%). The age-standardized LOMS prevalence was around 75 per 100,000 people. 215 patients (67%) were female. Median Expanded Disability Status Scale (EDSS) was 3 (interquartile range: 1.5-5). The majority of the cases (56%) suffered from relapsing-remitting (RR) course while 20% were diagnosed with primary progressive (PP) MS. Significantly higher proportion of male sex, PPMS, and higher EDSS were seen in the late-onset group compared with early-onset and adult-onset cases (p-value < 0.05). Seventy-five (23%) patients did not receive any disease-modifying treatment. DISCUSSION: The more prominent degenerative pathology of LOMS may be the underlying mechanism of the observed differences in comparison to non-LOMS. CONCLUSION: There are substantial differences and knowledge gaps regarding LOMS which could be the subject of further research.

Biomechanical changes of the common carotid artery and internal jugular vein in patients with multiple sclerosis.

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.

Trail Making Test Could Predict Impairment in Cognitive Domains in Patients with Multiple Sclerosis: A Study of Diagnostic Accuracy.

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.

Effects of Nonconsecutive Sessions of Transcranial Direct Current Stimulation and Stationary Cycling on Walking Capacity in Individuals With Multiple Sclerosis.

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.

Mindfulness-based cognitive therapy combined with repetitive transracial magnetic stimulation (rTMS) on information processing and working memory of patients with multiple sclerosis.

Background: 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. Methods: 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 available. Subjects were assessed three times before, during, and after the intervention using the Zahlen-Verbindongs and n-back tests in the two-back position. Subjects received cognitive therapy based on mindfulness and rTMS at a frequency of 10 Hz. Visual and graphical recovery percentage and effect size methods were used to analyze the data. Results: The 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. Conclusion: 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.

Prescription trends of disease-modifying treatments for multiple sclerosis in Iran over the past 30 years.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Epidemiology of familial multiple sclerosis in Iran: a national registry-based study.

BACKGROUND: Admittedly, little is known about the epidemiological signatures of familial multiple sclerosis (FMS) in different geographical regions of Iran. OBJECTIVE: To determine the epidemiology and the risk of FMS incidence in several provinces of Iran with a different ethnic population including, Fars, Tehran, Isfahan (Persians), and Mazandaran (Mazanis), Kermanshah (Kurds), and Chaharmahal and Bakhtiari (Lors). METHODS: This cross-sectional registry-based study was performed on nationwide MS registry of Iran (NMSRI) data collected from 2018 to 2021. This system, registers baseline characteristics, clinical presentations and symptoms, diagnostic and treatments at regional and national levels. RESULTS: A total of 9200 patients including, 7003 (76.1%) female and 2197 (23.9%) male, were participated. About 19% of patients reported a family history of MS; the order from highest to lowest FMS prevalence was as follows: Fars (26.5%), Chaharmahal and Bakhtiari (21.1%), Tehran (20.5%), Isfahan (20.3%), Mazandaran (18.0%), and Kermanshah (12.5%). Of all FMS cases, 74.7% (1308 cases) were female and 25.3% (442 cases) were male. FMS occurrence was much more common in females than males (P-value = 0.001). Further, the mean age at onset was 30 years among FMS cases. A substantially higher probability of relapsing-remitting MS and secondary-progressive MS was found among FMS cases than sporadic MS (SMS) (P_value = 0.001). There was no significant difference in Expanded Disability Status Scale (EDSS) scores between FMS and SMS. The majority of FMS cases were observed among first-degree relatives, with the highest rate in siblings. There was a significant association between MS risk and positive familial history in both maternal and paternal aunt/uncle (P_value = 0.043 and P_value = 0.019, respectively). Multiple sclerosis occurrence among offspring of females was higher than males (P_value = 0.027). CONCLUSIONS: In summary, our findings imply a noteworthy upward trend of FMS in Iran, even more than the global prevalence, which suggests a unique Atlas of FMS prevalence in this multi-ethnic population. Despite the highest rate of FMS within Persian and Lor ethnicities, no statistically significant difference was observed among the provinces.

Diet and disease-related outcomes in multiple sclerosis: A systematic review of clinical trials.

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.

Dietary fish intake and the risk of multiple sclerosis: a systematic review and meta-analysis of observational studies.

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 association between dietary fish intake and risk of MS.Methods: A systematic search with related keywords was carried out in PubMed-MEDLIN, Scopus-EMBASE, and OVID-MEDLINE from inception up to September 2019 to find observational studies that evaluated the association between dietary fish intake and the risk of MS. Random effect and subgroup analyses were performed to calculate pooled estimates at 95% CIs.Results: Six articles met the inclusion criteria for systematic review and meta-analysis. The results of this study indicated that the consumption of fish decreases the risk of MS [OR (95% CIs): 0.77 (0.64, 0.92); p-value = 0.004; I2 = 54.7%] compared with controls.Discussion: Dietary intake of at least 0.5 servings of fish per week during adolescence and after might reduce the risk of MS; however, further studies are required to prove this preventive effect.

Safety and efficacy of fingolimod in Iranian patients with relapsing-remitting multiple sclerosis: An open-label study.

BACKGROUND: Fingolimod was the first oral therapy approved for treating relapsing-remitting multiple sclerosis (RRMS) in 2010. This open-label study evaluated the safety and efficacy of fingolideR, 0.5 mg in Iranian MS patients during one-year follow-up. METHODS: A multicenter, open-label, longitudinal was designed to evaluate the safety and efficacy of fingolideR, 0.5 mg over a one-year follow-up period across 11 centers. The patients were visited by their neurologists every two months to evaluate possible adverse events and clinical disease activity considered by recording Kurtzke's Expanded Disability Status Scale (EDSS). RESULTS: A total of 252 patients with the mean treatment duration of 343±45.70 days were. 20 patients experienced adverse events (AEs) and serious adverse events (SAEs) such as resistant urinary tract infection (UTI), premature atrial contraction (PAC), skin allergic reaction, macular edema, chicken pox, zona, panic attacks, and exacerbations associated with steroids treatment, all of which led to FingolideR discontinuation. The mean EDSS decreased from (2.15±1.29, 95%CI: 1.99to2.32) at baseline to (1.85±1.22, 95%CI: 1.68to2.02) at 12th month (final visit) while a p-value revealed significant differences comparing baseline and final EDSS (p<0.001). Mean annualized relapse rate (ARR) of the patients in one year prior to the study was (0.006±0.016, 95%CI: 0.004to0.008) which changed to (0.005±0.016, 95%CI: 0.003to0.007) at the end of the study period. Patients with a 12-month period of fingolideR treatment experienced sustained ARR and disease progression (p<0.001). CONCLUSION: The obtained findings suggest that the administration of FingolideR, 0.5 mg (Fingolimod, Osvahpharma, Tehran, Iran) is safe and efficient for Iranian MS patients.

Developing a Multi-channel Beamformer by Enhancing Spatially Constrained ICA for Recovery of Correlated EEG Sources.

BACKGROUND: Brain source imaging based on electroencephalogram (EEG) data aims to recover the neuron populations' activity producing the scalp potentials. This procedure is known as the EEG inverse problem. Recently, beamformers have gained a lot of consideration in the EEG inverse problem. OBJECTIVE: Beamformers lack acceptable performance in the case of correlated brain sources. These sources happen when some regions of the brain have simultaneous or correlated activities such as auditory stimulation or moving left and right extremities of the body at the same time. In this paper, we have developed a multichannel beamformer robust to correlated sources. MATERIAL AND METHODS: In this simulation study, we have looked at the problem of brain source imaging and beamforming from a blind source separation point of view. We focused on the spatially constraint independent component analysis (scICA) algorithm, which generally benefits from the pre-known partial information of mixing matrix, and modified the steps of the algorithm in a way that makes it more robust to correlated sources. We called the modified scICA algorithm Multichannel ICA based EEG Beamformer (MIEB). RESULTS: We evaluated the proposed algorithm on simulated EEG data and compared its performance quantitatively with three algorithms scICA, linearly-constrained minimum-variance (LCMV) and Dual-Core beamformers; it is considered that the latter is specially designed to reconstruct correlated sources. CONCLUSION: The MIEB algorithm has much better performance in terms of normalized mean squared error in recovering the correlated/uncorrelated sources both in noise free and noisy synthetic EEG signals. Therefore, it could be used as a robust beamformer in recovering correlated brain sources.

The trend of incidence, prevalence, and DALY of multiple sclerosis in the Middle East and Northern Africa region compared to global, West Europe and, Iran's corresponding values during 1990-2017: Retrieved from global burden of diseases data.

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.

Impact of an Existential-Spiritual Intervention Compared with a Cognitive-Behavioral Therapy on Quality of Life and Meaning in Life among Women with Multiple Sclerosis.

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.

Safety and efficacy of memantine for multiple sclerosis-related fatigue: A pilot randomized, double-blind placebo-controlled trial.

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.

Inhibition of protein disulfide isomerase has neuroprotective effects in a mouse model of experimental autoimmune encephalomyelitis.

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 symptomsand 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.

Necrotizing fungal osteomyelitis and fingolimod, 4 years after treatment with fingolimod.

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.

The effects and side effects of laquinimod for the treatment of multiple sclerosis patients: a systematic review and meta-analysis of clinical trials.

PURPOSE: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.