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.

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.

The effect of retinyl-palmitate on the level of pro and anti-inflammatory cytokines in multiple sclerosis patients: A randomized double blind clinical trial.

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-1ß, 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-ß) (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.

A systematic review and meta-analysis of randomized controlled trials to evaluating the trend of cytokines to vitamin A supplementation in autoimmune diseases.

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-ß 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.

Safety and Efficacy of Nanocurcumin as Add-On Therapy to Riluzole in Patients With Amyotrophic Lateral Sclerosis: A Pilot Randomized Clinical Trial.

The objective of present study was to assess the safety and efficacy of nanocurcumin as an anti-inflammatory and antioxidant agent in adults with amyotrophic lateral sclerosis (ALS). We conducted a 12-month, double-blind, randomized, placebo-controlled trial at a neurological referral center in Iran. Eligible patients with a definite or probable ALS diagnosis were randomly assigned to receive either nanocurcumin (80 mg daily) or placebo in a 1:1 ratio. A computerized random number generator was used to prepare the randomization list. All patients and research investigators were blinded to treatment allocation. The primary outcome was survival, and event was defined to be death or mechanical ventilation dependency. Analysis was by intention-to-treat and included all patients who received at least one dose of study drug. A total of 54 patients were randomized to receive either nanocurcumin (n = 27) or placebo (n = 27). After 12 months, events occurred in 1 patient (3.7%) in the nanocurcumin group and in 6 patients (22.2%) in the placebo group. Kaplan-Meier analysis revealed a significant difference between the study groups regarding their survival curves (p = 0.036). No significant between-group differences were observed for any other outcome measures. No serious adverse events or treatment-related deaths were detected. No patients withdrew as a result of drug adverse events. The results suggest that nanocurcumin is safe and might improve the probability of survival as an add-on treatment in patients with ALS, especially in those with existing bulbar symptoms. Future studies with larger sample sizes and of longer duration are needed to confirm these findings.

Retinyl Palmitate Supplementation Modulates T-bet and Interferon Gamma Gene Expression in Multiple Sclerosis Patients.

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.

Effect of Vitamin A Supplementation on fatigue and depression in Multiple Sclerosis patients: A Double-Blind Placebo-Controlled Clinical Trial.

Decreasing the population and activation of inflammatory T helper cells in multiple sclerosis (MS) patients using vitamin A derivatives (retinoic acids) has been well documented. The present study determined the effect of vitamin A supplementation on psychiatric signs in MS patients. The subjects were 101 relapsing-remitting MS patients enrolled in a placebo-controlled randomized clinical trial. The treatment group was administered 25000 IU/d retinyl palmitate (RP) for 6 months followed by 10000 IU/d RP for another 6 months. The results for baseline characteristics, modified fatigue impact scale and Beck Depression Inventory-II were recorded at the beginning and end of the one-year study. The non-normal distribution data was compared between groups using a nonparametric test and normal distribution data was analyzed using a parametric test. (ClinicalTrials.gov Identifiers: NCT01417273). The results showed significant improvement in the treatment group for fatigue (p=0.004) and depression (p=0.01). Vitamin A supplementation helped during interferon therapy in the treatment process and improved psychiatric outcomes for anti-inflammatory mechanisms.

Multiple sclerosis influences on the augmentation of serum Klotho concentration.

We have already shown that the concentration of secreted form of Klotho decreases in the cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis (RRMS). The current study aimed at assessing possible changes in the serum Klotho concentration of MS patients. Participants involved 15 new cases of RRMS patients in the relapse phase, 15 RRMS patients who had been suffering from the disease for more than three years and were under regular treatments (interferon beta-1a) and, finally, 15 non-MS patients who constituted the control group. Beside thorough neurological examinations, demographic and clinical data (e.g. gender, age, duration of disease and expanded disability status scale) were obtained. Serum Klotho concentration was measured using ELISA method. The results showed no statistically meaningful difference between new cases of RRMS (585.56pg/ml±153.99) and control group (556.81pg/ml±120.36; P=0.859). The serum Klotho level, however, was significantly higher in patients with prolonged disease duration (696.94pg/ml±170.52; P=0.037) in comparison with the subjects in the control group. In conclusion, this study showed that serum Klotho concentration tends to be higher in MS patients when compared to control group. This finding might be attributed to treatment of MS patients with immunomodulatory drugs or a compensatory response to enhance CNS regeneration and/or vitamin D biosynthesis. Further studies are required to elucidate the role of Klotho in MS pathophysiology.

Impact of Vitamin A Supplementation on Disease Progression in Patients with Multiple Sclerosis.

BACKGROUND: Many studies have shown that active vitamin A derivatives suppress the formation of pathogenic T cells in multiple sclerosis (MS) patients. The aim of the present study is to determine the impact of vitamin A on disease progression in MS patients. METHODS: A total of 101 relapsing-remitting MS (RRMS) patients were enrolled in a 1-year placebo-controlled randomized clinical trial. The treated group received 25000 IU/d retinyl palmitate for six month followed by 10000 IU/d retinyl palmitate for another six month. The results of the expanded disability status scale (EDSS) and multiple sclerosis functional composite (MSFC) were recorded at the beginning and the end of the study. The relapse rate was recorded during the intervention. Patients underwent baseline and follow up brain MRIs. RESULTS: The results showed "Mean ± SD" of MSFC changes in the treated group was (-0.14 ± 0.20) and in the placebo group was (-0.31 ± 0.19). MSFC was improved significantly (P < 0.001) in the treatment group. There were no significant differences between the "Mean ± SD" of EDSS changes in the treated (0.07 ± 0.23) and placebo (0.08 ± 0.23) groups (P = 0.73). There were also no significant differences between the "Mean ± SD" of annualized relapse rate in the treated group (-0.36 ± 0.56) and placebo (-0.53 ± 0.55) groups (P = 0.20). The "Mean ± SD" of enhanced lesions in the treatment (0.4 ± 1.0) and in the placebo (0.2 ± 0.6) groups were not significantly different (P = 0.26). Volume of T2 hyperintense lesions "Mean ± SD" was not significantly different between treatment (45 ± 137) and placebo (23 ± 112) groups after intervention (P = 0.23). CONCLUSION: Vitamin A improved total MSFC score in RRMS patients, but it did not change EDSS, relapse rate and brain active lesions.

The Effect of Vitamin A Supplementation on FoxP3 and TGF-ß Gene Expression in Avonex-Treated Multiple Sclerosis Patients.

Multiple sclerosis (MS) is an autoinflammatory condition of the central nervous system with impaired T helper (Th)17 and regulatory T cell (Treg) balance that is involved in disease immunopathogenesis. The vitamin A active metabolite, retinoic acid, can re-establish this imbalance through the modulation of gene expression of specific nuclear receptors including Forkhead box P3 (FoxP3). At present, few data exist on the impact of vitamin A supplementation on T cell balance. This study reports the results of a clinical trial, over a 6-month period, of 36 relapsing-remitting MS (RRMS) patients that received vitamin A (25,000 IU retinyl palmitate) or placebo (one capsule of placebo per day). Peripheral blood mononuclear cells were isolated from patients, and the expression of FoxP3 and transforming growth factor (TGF)-ß gene expression was measured using real-time PCR at the beginning and end of the study. The results of this study showed that vitamin A upregulated TGF-ß and FoxP3 gene expression. Therefore, vitamin A supplementation can be considered as a new approach in MS prevention and treatment.

Impact of Melatonin on Motor, Cognitive and Neuroimaging Indices in Patients with Multiple Sclerosis.

A series of preclinical and clinical studies have shown the immunomodulatory effect of  melatonin, especially in the state of chronic inflammation. A double-blind, randomized, parallel-group, placebo-controlled clinical trial was designed to study the tolerability and efficacy of supplemental therapy with melatonin (3 mg/day) in comparison to placebo in relapsing-remitting MS (RRMS) patients receiving once weekly interferon beta. Patients were followed up for 12 months. Primary outcomes consisted of the number of relapses, change in Extended Disability Status Scale (EDSS), and the number and volume of new T2 and gadolinium-enhancing brain lesions. Secondary outcomes included change in performance on Multiple Sclerosis Functional Composite (MSFC) as well as change in fatigue and depression. The outcomes were evaluated every three months. Twenty-six patients (13 in each group) were recruited in the study. All participants, except for one patient in the placebo group, completed the study. No patient reported serious adverse events. There was no significant difference either in primary or secondary outcomes between melatonin and placebo arm. However, a trend for beneficial effect was observed for melatonin on change in MSFC performance and the cognitive subscore of the Modified Fatigue Impact Scale (p=0.05 and 0.006, respectively, not corrected for multiple comparisons). We found no significant effect for treatment with melatonin on measures of clinical and functional disability and development of brain lesions in our small sample-size study. Studies with higher statistical power and longer follow up are needed to further evaluate the potential immunomodulatory effect of melatonin in RRMS treatment.

Level of attitude toward complementary and alternative medicine among Iranian patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an unpredictable neurological disease leading to severe disability in young adults. The majority of MS patients use complementary and alternative medicine (CAM) as adjunct to conventional therapies. This study aimed to investigate the prevalence of CAM utilization among Iranian patients with MS and their attitude toward the CAM usage. METHODS: A cross-sectional study was conducted on 119 definite MS patients referred to Tehran's Imam Khomeini and Sina hospitals. A questionnaire was used to examine the association between participants' health-related factors and usage of CAMs interventions. P value < 0.05 was considered statistically significant. RESULTS: Among the enrolled patients, 60% of the participants agreed with using CAM, 42% experienced the usage of these treatments; out of whom 41% believed its efficiency and 18% reported exacerbation of symptoms. The mean duration of disease diagnosis and mean time from symptoms onset were both longer in users of CAM (P = 0.001). Most socio-demographic factors had no significant effect on the type of used CAM. However, Yoga was significantly more applied in those with higher degree of education (P = 0.002). CONCLUSION: Regarding the widespread use of CAM by Iranian patients with MS, further researches about the safety and efficacy of each treatment on the special outcomes is recommended.

Impact of vitamin A supplementation on RAR gene expression in multiple sclerosis patients.

Vitamin A and its derivatives have been shown to modulate the immune system via retinoic acid receptor (RAR). This study explored the impact of retinyl palmitate supplementation on RAR subtype gene expression in peripheral blood mononuclear cells (PBMCs) in multiple sclerosis (MS) patients. The study designed as a double-blind randomized clinical trial in which relapsing remitting multiple sclerosis patients were evaluated. Both groups received one capsule 50,000 IU vitamin D3 per 2 weeks and one intramuscular injection interferon beta-1a per week. The intervention group received one 25,000 IU retinyl palmitate capsule daily for 6 months and the placebo group received one placebo capsule daily. The PBMCs were isolated from participants and the expression level changes of RAR-α and RAR-γ genes were determined by real-time PCR. After supplementation, in the intervention group, the RAR-α gene expression level was significantly decreased compared to the placebo group (p = 0.03); however, the expression of RAR-γ gene did not significantly change (p = 0.10). These results show that vitamin A supplementation can significantly downregulate the expression of RAR-α gene in PBMCs of MS patients that suggest the presence of in vivo regulatory mechanisms for the action of vitamin A on the immune system.

The effect of vitamin a supplementation on biochemical parameters in multiple sclerosis patients.

BACKGROUND: Vitamin A has different functions in the body and after being converted to acid form; it can play many roles in immune system regulation. Therefore, this vitamin can be used as a supplement in the treatment of diseases, such as cancer and autoimmune diseases. Vitamin A is a fat-soluble compound and its long-term consumption in high doses can have some adverse effects. OBJECTIVE: The current study aimed to investigate the possible complications and find solutions to minimize the adverse effects. PATIENTS AND METHODS: This study was a double blind randomized clinical trial. In the main study, vitamin A (as retinyl palmitate) was given to 35 multiple sclerosis (MS) patients in order to regulate their immune system with a dose of 25000 IU/day for a period of six months. To investigate the possible biochemical complications, lipid profiles, fasting blood sugar (FBS), liver enzymes, and C-reactive protein (CRP) were tested. RESULTS: Vitamin A did not have a significant difference in lipid profiles, FBS and liver enzymes between the two groups receiving vitamin A and the placebo, but CRP increased in patients who were taking vitamin A, 1.65±0.43 (mg/L) and 2.88±0.67, (Mean±SEM), before and after the intervention respectively (P=0.029), and statistical analysis showed significant differences with the group receiving placebo (P=0.011) and CRP level in vitamin A group was 1.3 mg/L more than those of the placebo group after intervention (P=0.011). CONCLUSIONS: Considering that no significant difference was found in the proven vitamin A side effects, due to the increase in CRP, frequent clinical and biochemical controls are required along with vitamin A supplementation.

Vestibular evoked myogenic potential for diagnoses of multiple sclerosis: is it beneficial?

AIM: To determine the sensitivity of the vestibular evoked myogenic potential (VEMP) in multiple sclerosis (MS) patients as well as its relation to clinical signs and symptoms, course of the disease and other evoked potentials. METHODS: This case-control study was conducted on 40 subjects (20 MS patients and 20 healthy participants). Participants were selected from Imam Khomeini Hospital, Tehran, Iran. Two hundred stimuli (clicks of 0.1 ms of duration and 2 Hz frequency) were applied to each ear. These stimuli were repeated in two consecutive cycles. In order to evaluate the reproducibility the stimulation intensity of 95dBNHL was applied. During the test, individuals were requested to be seated on a chair and rotate their head to the opposite side of the stimulated ear to activate the ipsilateral sternocleidomastoid muscle (SCM). RESULTS: A biphasic, initially positive, p13-n23 wave pattern was found in all patients. All of the parameters, including latencies and amplitudes fit the normal Kolmogorov-Smirnov (KS) distribution. Fourteen (70%) patients reported abnormal results, and VEMP abnormality was significantly related to disease duration also. In addition, there was a significant correlation between abnormality of VEMP and abnormality of visual evoked potential (VEP) as well as the abnormality of VEMP and brainstem auditory evoked potential (BAEP). CONCLUSION: Vestibular evoked myogenic potential has a high sensitivity (70%) in MS patients, and VEMP could be recommended as a useful complementary neurophysiological method to evaluate the MS patients.

The effect of vitamin A supplementation on retinoic acid-related orphan receptor γt (RORγt) and interleukin-17 (IL-17) gene expression in Avonex-treated multiple sclerotic patients.

The aim of this study was to investigate the role of vitamin A on RORγt and IL-17 gene expression in multiple sclerotic patients. Patients in the vitamin A group received 25,000 IU retinyl palmitate per day, while patients in the placebo group took one capsule of placebo per day for 6 months. Gene expression was measured by real-time PCR at the first and end of the study. The results of this study show that vitamin A downregulates IL-17 and RORγt gene expression. No changes in gene expression occurred in the placebo group.

The effect of vitamin A supplementation on stimulated T-cell proliferation with myelin oligodendrocyte glycoprotein in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease whereby myelin sheath of the central nervous system is destroyed. Vitamin A is known to play a role in the immune system. It has been recognized that some metabolites of vitamin A can be used effectively to treat experimental autoimmune encephalomyelitis (EAE). AIMS: The effect of vitamin A as retinyl palmitate on T-cell proliferation in MS patients. SETTING AND DESIGN: This study is a double blind clinical trial of two test groups over a period of 6 months. MATERIALS AND METHODS: Thirty five multiple sclerosis (MS) patients were divided into two groups. One group received 25,000 IU/day vitamin A (as retinyl palmitate) and the other group were administered a placebo. The peripheral blood mononuclear cells (PBMCs) were separated and stimulated with myelin oligodendrocyte glycoprotein (MOG) and phytohemagglutinin (PHA) before and after the trial period. BrdU calorimetric assay was performed to measure cell proliferation. STATISTICAL ANALYSIS: Analysis of covariance (ANCOVA) and paired t-test were used to analyze the data. RESULTS: Observations showed statistical significant differences in the reduction of cell proliferation in the presence of MOG and fetal calf serum (FCS) in the culture medium, between patients receiving vitamin A and the placebo (P = 0.046). Although, this difference was not significant between the two vitamin A and placebo groups in MOG treatment with human serum, a decrease was observed in the group of patients taking vitamin A supplements (P = 0.019). Phytohemagglutinin did not cause any change in cell proliferation between the two groups. CONCLUSION: The results suggest supplementation with retinyl palmitate in patients with MS reduce MOG stimulatory effects on T-cells.

A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer's disease.

RATIONALE: There is increasing evidence to suggest the possible efficacy of Crocus sativus (saffron) in the management of Alzheimer's disease (AD). OBJECTIVE: The purpose of the present investigation was to assess the efficacy of C. sativus in the treatment of patients with mild-to-moderate AD. METHODS: Fifty-four Persian-speaking adults 55 years of age or older who were living in the community were eligible to participate in a 22-week, double-blind study of parallel groups of patients with AD. The main efficacy measures were the change in the Alzheimer's Disease Assessment Scale-cognitive subscale and Clinical Dementia Rating Scale-Sums of Boxes scores compared with baseline. Adverse events (AEs) were systematically recorded. Participants were randomly assigned to receive a capsule saffron 30 mg/day (15 mg twice per day) or donepezil 10 mg/day (5 mg twice per day). RESULTS: Saffron at this dose was found to be effective similar to donepezil in the treatment of mild-to-moderate AD after 22 weeks. The frequency of AEs was similar between saffron extract and donepezil groups with the exception of vomiting, which occurred significantly more frequently in the donepezil group. CONCLUSION: This phase II study provides preliminary evidence of a possible therapeutic effect of saffron extract in the treatment of patients with mild-to-moderate Alzheimer's disease. This trial is registered with the Iranian Clinical Trials Registry (IRCT138711051556N1).