Comparing the effects of cerebellar and prefrontal anodal transcranial direct current stimulation concurrent with postural training on balance and fatigue in patients with multiple sclerosis: a double-blind, randomized, sham-controlled trial.

Fatigue and balance disorders are common challenges experienced by Multiple Sclerosis (MS) individuals. The purpose of this study was to compare the concurrent effects of cerebellar and prefrontal anodal trans-cranial direct current stimulation (a-tDCS) with postural training on balance and fatigue in MS patients. 51 patients were evaluated to randomly allocation to a-tDCS over cerebellum, a-tDCS over dorsolateral prefrontal cortex (DLPFC) and sham group. 46 individuals (n = 16 in experimental groups and n = 14 in control group) followed treatment. All the groups received 10 sessions of postural training. The experimental groups underwent a-tDCS with a current of 1.5 mA for a period of 20 min. While, in the sham group, tDCS was only activated for 30 s and then turned off. The treatment included 10 sessions for four weeks. Before and after intervention, fatigue and balance were assessed using Fatigue Severity Scale (FSS), Timed Up and Go (TUG) test and Berg Balance Score (BBS), respectively. There was found a significant reduction in fatigue in the group receiving a-tDCS over the prefrontal cortex with postural training compared to the other two groups (P < 0.001). Additionally, a significant improvement was found in balance in the group receiving a-tDCS over the cerebellum concurrent with postural training in comparison to the other two groups (P < 0.001). Besides, in the sham group, the significant results were not reported in the variables. (P > 0.001). The results demonstrated that a-tDCS enhances the effects of postural training on balance and fatigue in MS patients.

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.

Effects of a novel probiotic mixture on the modulation of brain and intestine Aquaporin-4 gene expression in rats exposed to Cadmium.

Cadmium (Cd) is a toxicant metal that risks human and animal health. Nowadays, the vital role of Aquaporin-4 (AQP-4) in brain and gut cell permeability has gathered too much attention to protecting against heavy metals. Studies have shown that heavy metals can harm the body due to oxidative stress. Probiotics are known for their health-beneficial effects and establish as dietary adjuncts mainly for their antioxidant properties. This study investigated the impact of a novel probiotic combination including Lactobacillus casei IBRC-M10783, Lactobacillus rhamnosus IBRC-M10782, and Lactobacillus helveticus TG-34 on the AQP-4 gene expression in CdCl2-induced Wistar rats. Rats were divided into three groups and received a specific dose of CdCl2 or probiotics. The AQP-4 expression level had estimated by Real-Time PCR in both the intestine and brain. These results showed a significant reduction in AQP-4 gene expression in the probiotic treatment group compared to the CdCl2 control group in the intestine and brain for the first time. Our research showed that consuming a probiotic mixture of L. casei, L. rhamnosus, and L. helveticus can reduce the expression of the aquaporin-4 gene in the brain and intestine of rats exposed to Cadmium, which can be promising in the field of aquaporin-4 regulation.

Low carbohydrate diet score and odds of neuromyelitis optica spectrum disorder: A case-control study.

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating inflammatory disease of The Central nervous system. We aimed to investigate the association between low carbohydrate diet (LCD) and NMOSD odds. Method: Seventy NMOSD patients with definite diagnosis and 164 hospital-based controls were enrolled in this case-control study. Dietary data was obtained using a validated 168-item food frequency questionnaire. To determine the LCD score, participants were stratified into 11 groups according to carbohydrate, protein, fat, animal fat, animal protein, vegetable fat and vegetable protein intakes. Higher intake of protein and fat, and lower intake of carbohydrate received a higher score between 0-10. Macronutrients scores were summed together and LCD scores calculated. The association between LCD scores and likelihood of being assigned to NMOSD group was investigated using multiple regression models. Results: Total LCD scores increased from the median of 21.00 in the first decile to 53.00 in the tenth decile of LCD score. After adjustment for confounding factors including age, gender, BMI, energy intake, cigarette smoking and alcohol consumption, an inverse association was detected between LCD scores and odds of NMOSD. The odds of suffering from NMOSD declined significantly about 78% (OR: 0.22; 95% CI: 0.05-0.87) and 76% (OR: 0.24; 95% CI: 0.06-0.93) in the fifth and sixth deciles of LCD score compared to the first decile. Conclusion: From the obtained results it can be speculated that higher carbohydrate and lower protein and fat intakes may be associate with the increased odds of NMOSD. However, further studies are needed to confirm these results.

A controlled, randomized phase II clinical trial for efficacy and safety evaluation of mannuronic acid in secondary progressive form of multiple sclerosis.

BACKGROUND: The ß-D-Mannuronic acid (M2000) as a novel immunosuppressive drug, patented (PCT/EP2017/067920), has shown positive effects in experimental model of multiple sclerosis (MS). In this study, our aim was to assess efficacy and safety outcomes in MS treated patients with mannuronic acid compared to the conventional drug. METHODS: In a 6-month, randomized controlled, phase II trial, we enrolled patients who had secondary progressive multiple sclerosis (SPMS), were 21-54 years of age, with a score of 1-7 on the Expanded Disability Status Scale (EDSS), and who had at least one relapse in the previous 6 months. Patients were administered orally 1000 mg/day (two 500 mg/capsule daily) of M2000. Endpoints included changes in brain magnetic resonance imaging (MRI) measures and the EDSS score, as compared to the conventional drug (interferon beta-1a, interferon beta-1b). RESULTS: A total of 25 (92.5%) of the M2000 treated patients and 25 conventionally treated patients completed the study. M2000 had better performance compared to the conventional drug regarding to MRI-related measurements, however, the differences between groups were not statistically significant. M2000 decreased the disability progression over the 6-month period. The EDSS score was decreased in the M2000 treated group in the sixth month versus the conventional drug (p < 0.009). Furthermore, we did not observe any short-term side effects. CONCLUSIONS: As compared with the conventional drug, mannuronic acid (M2000) improved the rate of disability progression. This clinical trial demonstrated the efficacy and safety of mannuronic acid in patients with SPMS. (Registered Clinical Trials number, IRCT2016111313739N6).

MRI but not demographic or clinical characteristics differ between familial and sporadic MS cases.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease. The prevalence and incidence of MS in Iran is high and is rising over time. This study was conducted to compare the demographic, clinical features and MRI findings of MS patients with history of the disease in the first-degree family members (fMS) with sporadic MS patients (sMS) to determine the importance of genetic or non-genetic factors in the development of the disease and its effect in diagnostic and therapeutic modalities. METHODS: Among the 185 patients admitted to the study, 62 were fMS patients and 123 were sMS patients. All patients underwent clinical examination and data was gathered on age, sex, age of onset, symptoms, number of attacks, disease course, family history, disease-modifying drugs, and other accompanying diseases as well as MRI findings and EDSS scores. RESULTS: In this study, we demonstrated that the frequency of plaques in the periventricular area was significantly higher in sMS patients (97.56% vs 88.71%, p = 0.01) while the callosal plaques were more common in fMS patients (62.9% vs 47.97%, p = 0.05) which was statistically borderline and nonsignificant. In other evaluated parameters, no significant difference was observed. CONCLUSION: In our study, no significant difference was observed between the demographic and clinical characteristics of fMS and sMS patients, while there was a significant difference between the two groups in MRI findings.

Assessment of Biochemical Determinants in Multiple Sclerosis Patients Following the Oral Administration of ß-D-Mannuronic Acid (M2000).

BACKGROUND: Multiple sclerosis is an autoimmune chronic inflammatory disease of the central nervous system that can lead to some serious disabilities. Despite using various immunomodulatory and anti-inflammatory drugs that have therapeutic effects, they cannot reduce its progression completely and have some unwanted side effects too. The immunomodulatory and anti-inflammatory effects of the ß-D-Mannuronic acid (M2000) have been proven in several surveys, and the present research was designed to determine its toxicity and therapeutic effects in MS patients. METHODS: This study was performed on 15 MS patients who took 25 mg/kg/day the oral form of the ß-D-Mannuronic acid for six months, and 15 healthy people as a control group. Serum levels of Urea, Creatinine, GGT, Vitamin D3, Uric acid, and Anti-Phospholipids were compared to evaluate the therapeutic and possible toxic effects of this drug after this period. RESULTS: Non- toxic effects through the study of urea, creatinine, GGT, and non-significant changes in uric acid and anti-Phospholipids levels, besides a significant rise in vitamin, D3 levels in the M2000 treated cases were found. CONCLUSIONS: Our results suggested that ß-D-Mannuronic acid is a safe drug and has no toxicity when administered orally and also has some therapeutic effects in MS patients.

The role of opening CSF pressure in response to treatment for idiopathic intracranial hypertension (IIH).

The aim of the current study was to assess the risk factors, clinical symptoms and Cerebrospinal fluid (CSF) pressure of idiopathic intracranial hypertension (IIH) with emphasis on determining the risk factors which involved in poor response to treatment. We retrospectively included 202 patients who were diagnosed with IIH. Disease severity was classified according to prescribed therapeutic option into 4 groups: acetazolamide (group 1), Acetazolamide plus topiramate or Lasix (group 2), repeated LP (group 3) and surgical intervention (group 4). Being in the higher group was considered as a higher severity of disease and poor response to treatment. Among the evaluated features of IIH, the strongest association were observed between opening CSF pressure and disease severity. So that, the highest CSF pressure was observed in patients who underwent surgery, which represent the highest severity of disease (group 4) and poor response to therapy (mean ± SD: 43.9 ± 21.1 cm H2O). Headache was the most prevalent symptom of IIH in our series which was significantly higher among acetazolamide group. Blurred vision was the second most common symptoms which, unlike the headache was more reported in surgery group. Our results suggested that higher CSF pressure could be the risk factors of poor response to therapy, which may raise need for more intensive treatment. Furthermore, suffering of headache without blurred vision can consider as a prognostic factor for mild severity and good response to treatment.

Effects of guluronic acid (G2013) on gene expression of TLR2, TLR4, MyD88, TNF-α and CD52 in multiple sclerosis under in vitro conditions.

Context: Multiple sclerosis (MS) is an autoimmune and chronic inflammatory disease of CNS. The α-L-guluronic acid (G2013) as novel NSAID with immunomodulatory effects has shown its positive effects in various investigations.Objective: Present research aimed to study the potency of G2013 on gene expression of TLR2, TLR4, MyD88, TNF-α and CD52 in PBMCs of MS patients under in vitro conditions. Materials and methods: 24 blood samples from MS patients and healthy controls were considered for RT-PCR and flow cytometry techniques under two different doses of G2013.Results: Our research indicated that this drug could significantly decrease the gene expression of TLR2, TLR4 and TNF-α compared to untreated group. Conclusion: Data demonstrated that the guluronic acid is able to modify the expression levels of TLR2, TLR4 and TNF-α genes to less than the pathogenic boarder line level, which it might be recommended for reducing the pathological process in multiple sclerosis.

Vitamin K2 in multiple sclerosis patients.

BACKGROUND: Vitamin K2 (VK2) belongs to the vitamin K family and comprises a number of subtypes differing in length of side chains consisting of isoprenoid groups (menaquinone-n, MK-n). It is essential for a number of physiological functions although the full spectrum of activity has not yet been elucidated. Due to its role in protection of mitochondrial damage, VK2 could be relevant in preventing disease progress in multiple sclerosis (MS). METHODS: We measured VK2 serum levels by the double antibody sandwich Enzyme-linked Immunosorbent Assay (ELISA) technique in MS patients and age and sex matched controls, both under vitamin D supplementation, and related it to disease characteristics and treatment. RESULTS: Overall, 45 MS patients (31 females and 39 of the relapsing-remitting type) and 29 healthy controls (19 females) were included in the analysis. The MS patients had vastly lower VK2 blood levels than controls (235 ± 100 ng/ml vs. 812 ± 154 ng/ml, respectively). Female patients had significantly lower VK2 levels than males and a decrease with age by approximately 10% per decade was found. The VK2 levels were lower with increasing numbers of attacks per year and were higher in patients with optic nerve lesions. No consistent relationship with medications was detected. CONCLUSION: The substantially lower levels of VK2 in MS patients could be due to depletion, lower production in the gut, diminished absorption or, less likely, reduced intake of precursor vitamin K1. The role of VK2 in MS development and progress deserves further study.

Diagnosis and management of Neuromyelitis Optica Spectrum Disorder (NMOSD) in Iran: A consensus guideline and recommendations.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a relapsing neuro inflammatory disease of the central nervous system that typically presents with optic neuritis or myelitis and may cause severe disability. The diagnostic criteria have been updated and several immunosuppressive agents have been demonstrated to prevent acute exacerbations. As the disease rarely develops in a progressive course, management of acute attacks and proper prevention of exacerbations may change the long term out-come and prevent future disability. Consensus recommendations and guidelines will help the physicians to improve their practice and unify the treatment approaches in different communities. In order to develop a national consensus and recommendations for the diagnosis and management of NMOSD in Iran, a group of neurologists with long term experience in management of NMOSD were gathered to develop this consensus based on available national and international data. The primary draft was prepared and discussed to suggest the most appropriate treatment for these patients. We propose strategies for early diagnosis and treatment for prevention of relapses and minimizing consequences of attacks as a primary therapeutic goal. Attacks are currently treated with intravenous corticosteroids and, in refractory cases, with plasma exchange. All participants agreed on preventive treatment with currently available immunosuppressive agents such as azothioprin, rituximab and mycofenolate mofetil based on previous positive data in NMOSD in order to reduce attack frequency. The current consensus reviews the previous data and provides the clinicians with practical recommendations and advices for the diagnosis and management of NMOSD based on scientific data and clinical experience.

Can Salivary Acetylcholinesterase be a Diagnostic Biomarker for Alzheimer?

INTRODUCTION: The loss of brain cholinergic activity is a key phenomenon in the biochemistry of Alzheimer's Disease (AD). Due to the specific biosynthesis of Acetylcholinesterase (AChE) of cholinergic neurons, the enzyme has been proposed as a potential biochemical marker of cholinergic activity. AChE is expressed not only in the Central Nervous System (CNS), Peripheral Nervous System (PNS) and muscles, but also on the surface of blood cells and saliva. AIM: This study aimed to measure salivary AChE activity in AD and to determine the feasibility of creating a simple laboratory test for diagnosing such patients. MATERIALS AND METHODS: In this cross-sectional study, the recorded data were obtained from 15 Alzheimer's patients on memantine therapy and 15 healthy subjects. Unstimulated whole saliva samples were collected from the participants and salivary levels of AChE activity were determined by using the Ellman colorimetric method. The Mann Whitney U test was used to compare the average (median) of AChE activity between AD and controls. In order to adjust for possible confounding factors, partial correlation coefficient and multivariate linear regressions were used. RESULTS: Although the average of AChE activity in the saliva of people with AD was lower compared to the control group, we found no statistically significant differences using Mann Whitney U test (138 in control group vs. 175 in Alzheimer's patients, p value=0.25). Additionally, no significant differences were observed in the activity of this enzyme in both sexes or with increased age or duration of the disease. After adjusting for age and gender, there was no association between AChE activity and AD (regression coefficient ß=0.08; p value= 0.67). CONCLUSION: Saliva AChE activity was not significantly associated with AD. This study might help in introduce a new diagnostic aid for AD or monitor patients with AD.

Iranian consensus on use of vitamin D in patients with multiple sclerosis.

BACKGROUND: Accumulating evidences from experimental, epidemiologic and clinical studies support the potential linkage between poor vitamin D status and the risk of developing Multiple Sclerosis (MS), as well as, an adverse disease course. However, the results of the trials on the clinical outcomes of vitamin D supplementation in MS patients are less consistent which brought many discrepancies in routine practice. In this article we presented a summary of a symposium on vitamin D and MS. In this symposium we aim to review the current data about the relationship between vitamin D and MS, and suggest management guides for practicing neurologists. DISCUSSION: Generally, supplementation seems to be reasonable for all MS and clinically isolated syndrome (Rinaldi et al., Toxins 7:129-37, 2015) patients with serum 25(OH)D level below 40 ng/ml. In patients with vitamin D insufficiency or deficiency, a large replacing dose (e.g. 50,000 IU capsules of D per week for 8-12 week) is recommended. Panel also suggested: the checking of the serum vitamin D, and calcium level, as well as, patients' compliance after the initial phase; a maintenance treatment of 1500-2000 IU daily or equivalent intermittent (weekly, biweekly or monthly) Dose, considering the patient's compliance; routine check of serum vitamin D level at least two times a year especially at the beginning of spring and autumn; Serum vitamin D evaluation for first degree relatives of MS patients at high risk age and supplementation in case of insufficiency (25(OH)D less than 40 ng/ml); correction of vitamin D deficiency and insufficiency before pregnancy, as well as, a daily dose of 1500-2000 IU or equivalent biweekly intake in 2nd and 3rd trimesters; stopping supplementation if 25(OH)D serum level exceeds 100 ng/ml. Although the results of high power studies are not available, correcting vitamin D status seems plausible in all MS and CIS patients. Maintaining the serum 25(OH)D level between 40 and 100 ng/ml is not known to exert adverse effect. More ever, it might be associated with lower disease activity.

Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study.

Despite updating knowledge and a growing number of medications for multiple sclerosis (MS), no definite treatment is available yet for patients suffering from progressive forms of the disease. Autologous bone marrow derived mesenchymal stem cell (BM-MSC) transplantation is a promising method proposed as a therapy for MS. Although the safety of these cells has been confirmed in hematological, cardiac and inflammatory diseases, its efficacy in MS treatment is still under study. Patients with progressive MS (expanded disability status scale score: 4.0 -6.50) unresponsive to conventional treatments were recruited for this study. Twenty-five patients [f/m: 19/6, mean age: 34.7±7] received a single intrathecal injection of ex-vivo expanded MSCs (mean dose: 29.5×10(6) cells). We observed their therapeutic response for 12 months. Associated short-term adverse events of injection consisted of transient low-grade fever, nausea /vomiting, weakness in the lower limbs and headache. No major delayed adverse effect was reported. 3 patients left the study for personal reasons. The mean (SD) expanded disability status scale (EDSS) score of 22 patients changed from 6.1 (0.6) to 6.3 (0.4). Clinical course of the disease (measured by EDSS) improved in 4, deteriorated in 6 and had no change in 12 patients. In MRI evaluation, 15 patients showed no change, whereas 6 patients showed new T2 or gadolinium enhanced lesions (1 lost to follow-up). It seems that MSC therapy can improve/stabilize the course of the disease in progressive MS in the first year after injection with no serious adverse effects. Repeating the study with a larger sample size, booster injections and longer follow-up using a controlled study design is advised.

Antigliadin antibody in sporadic adult ataxia.

BACKGROUND: The most common neurologic manifestation of gluten sensitivity is ataxia, which accounts for up to 40% of idiopathic sporadic ataxia. Timing of diagnosis of gluten ataxia is vital as it is one of the very few treatable causes of sporadic ataxia and causes irreversible loss of Purkinje cells. Antigliadin antibody (AGA) of the IgG type is the best marker for neurological manifestations of gluten sensitivity. This study was conducted to measure the prevalence of gluten ataxia in a group of Iranian patients with idiopathic ataxia. METHODS: For 30 patients with idiopathic cerebellar ataxia, a questionnaire about clinical and demographic data was completed. Serum AGA (IgA and IgG) and antiendomysial antibody (AEA) were assessed. Gluten ataxic patients underwent duodenal biopsy. Magnetic resonance imaging was done for all patients to see if cerebellar atrophy is present. RESULTS: Only 2 patients had a positive IgG AGA (6.7%) who both had a positive AEA while none of them showed changes of celiac disease in their duodenal biopsies. Only presence of gastrointestinal symptoms and pursuit eye movement disorders were higher in patients with gluten ataxia. CONCLUSION: Prevalence of gluten ataxia in Iranian patients with idiopathic ataxia seems to be lower than most of other regions. This could be explained by small sample size, differences in genetics and nutritional habits and also effect of serologic tests in clinical versus research setting. Further researches with larger sample size are recommended.

Gastrointestinal adverse effects of antiepileptic drugs in intractable epileptic patients.

Gastrointestinal (GI) discomforts are among the most common side effects of antiepileptic drugs (AEDs) that might lead to discontinuation or irregular consumption of the drugs. This study was conducted to evaluate the frequency of GI side effects of different AEDs in intractable epileptic patients treated with single or multiple drugs. GI discomfort of 100 epileptic patients (aged 35-76 years) treated with one or multiple AEDs was assessed. Seventy six patients (76%) were treated with two or more AEDs, and 24 (24%) were on monotherapy. The most common prescribed drug for monotherapy was carbamazepine and the most frequent combination was phenytoin and carbamazepine. Patients were suffering from different GI side effects including heartburn (34.6%), nausea (33.7%), constipation (26%), vomiting (22.1%), diarrhea (21.2%) and dysphagia (19.2%). Nausea and vomiting were significantly higher in patients receiving monotherapy with carbamazepine and valproic acid, respectively. When phenytoin, gabapentine, or valproic acid was added to the other AEDs, the risk of the occurrence of diarrhea, dysphagia, or heartburn was significantly increased, respectively. Addition of gabapentine to the other AEDs in multiple drug therapy was accompanied with the highest frequency of GI complications. This study indicated that GI side effects, which can affect drug absorption and utilization, were common in intractable epileptic patients with long-term AEDs treatment. This may influence the efficacy of the therapy with AEDs and enhance the probability of further attacks.

Simvastatin treatment in patients with relapsing-remitting multiple sclerosis receiving interferon beta 1a: a double-blind randomized controlled trial.

OBJECTIVES: This study was conducted to evaluate the effect of simvastatin (40 mg/day) as an adjuvant therapy to interferon beta (IFNb 1a, 30 microg once weekly) in relapsing-remitting multiple sclerosis patients, compared with placebo. METHODS: We enrolled 85 patients with relapsing-remitting multiple sclerosis (71% female) who were already receiving IFNb 1a (Avonex), with Expanded Disability Status Scale score of less than 5.0. The patients were assigned (in random and double-blinded fashion) into the two groups of simvastatin and placebo. All patients continued to receive their current IFNb treatment. The outcome measures were total relapse rate, Expanded Disability Status Scale score, and the number of gadolinium-enhanced (Gd+) and new T2 lesions in magnetic resonance imaging after a 1-year follow-up. We used Mann-Whitney and one-way multivariate analysis of variances to analyze the data. RESULTS: Four patients in the placebo and two in the simvastatin group prematurely withdrew from the study due to experiencing two attacks. The total attack number in the simvastatin group was significantly lower than placebo group (moderate effect size r = 0.29) (p = 0.01). The final Expanded Disability Status Scale scores were lower in the simvastatin group (1.01 +/- 1.40, mean +/- SD) than in the placebo group (1.73 +/- 1.49, mean +/- SD), but this difference was not significant after controlling the baseline Expanded Disability Status Scale score (p = 0.07). In the simvastatin group, the mean +/- SD of gadolinium-enhanced and new T2 lesions were 0.66 +/- 1.18 and 3.39 +/- 3.55, respectively, (compared with 0.74 +/- 1.21 and 3.39 +/- 3.55 in the placebo group). Although there was a decreasing trend in lesions on magnetic resonance imaging, this difference was not statistically significant (p = 0.62). The combination therapy was safe and well tolerated, and no serious adverse effect was noted. CONCLUSION: Our study supports the safety and efficacy of simvastatin as an add-on therapy to INFb 1a in patients with relapsing-remitting multiple sclerosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00668343. This interventional study provides Class I evidence stating that adding simvastatin 40 mg/day to IFNb 1a 30 microg a week in patients with relapsing-remitting multiple sclerosis may reduce the relapse rate (moderate effect size r = 0.29) (p = 0.01) compared with treatment with IFNb 1a alone.