The Impact of Coconut Oil and Epigallocatechin Gallate on the Levels of IL-6, Anxiety and Disability in Multiple Sclerosis Patients.

BACKGROUND: Due to the inflammatory nature of multiple sclerosis (MS), interleukin 6 (IL-6) is high in blood levels, and it also increases the levels of anxiety related to functional disability. Epigallocatechin gallate (EGCG) decreases IL-6, which could be enhanced by the anti-inflammatory effect of high ketone bodies after administering coconut oil (both of which are an anxiolytic). Therefore, the aim of this study was to assess the impact of coconut oil and EGCG on the levels of IL-6, anxiety and functional disability in patients with MS. METHODS: A pilot study was conducted for four months with 51 MS patients who were randomly divided into an intervention group and a control group. The intervention group received 800 mg of EGCG and 60 mL of coconut oil, and the control group was prescribed a placebo. Both groups followed the same isocaloric Mediterranean diet. State and trait anxiety were determined before and after the study by means of the State-Trait Anxiety Inventory (STAI). In addition, IL-6 in serum was measured using the ELISA technique and functional capacity was determined with the Expanded Disability Status Scale (EDSS) and the body mass index (BMI). RESULTS: State anxiety and functional capacity decreased in the intervention group and IL-6 decreased in both groups. CONCLUSIONS: EGCG and coconut oil improve state anxiety and functional capacity. In addition, a decrease in IL-6 is observed in patients with MS, possibly due to the antioxidant capacity of the Mediterranean diet and its impact on improving BMI.

Lipoic Acid Stimulates cAMP Production in Healthy Control and Secondary Progressive MS Subjects.

Lipoic acid (LA) exhibits antioxidant and anti-inflammatory properties; supplementation reduces disease severity and T lymphocyte migration into the central nervous system in a murine model of multiple sclerosis (MS), and administration in secondary progressive MS (SPMS) subjects reduces brain atrophy compared to placebo. The mechanism of action (MOA) of LA's efficacy in suppression of MS pathology is incompletely understood. LA stimulates production of the immunomodulator cyclic AMP (cAMP) in vitro. To determine whether cAMP could be involved in the MOA of LA in vivo, we performed a clinical trial to examine whether LA stimulates cAMP production in healthy control and MS subjects, and whether there are differences in the bioavailability of LA between groups. We administered 1200 mg of oral LA to healthy control, relapsing remitting MS (RRMS) and SPMS subjects, and measured plasma LA and cAMP levels in peripheral blood mononuclear cells (PBMCs). There were no significant differences between the groups in pharmacokinetic (PK) parameters. Healthy and SPMS subjects had increased cAMP at 2 and 4 h post-LA treatment compared to baseline, while RRMS subjects showed decreases in cAMP. Additionally, plasma concentrations of prostaglandin E2 (PGE2, a known cAMP stimulator) were significantly lower in female RRMS subjects compared to female HC and SPMS subjects 4 h after LA ingestion. These data indicate that cAMP could be part of the MOA of LA in SPMS, and that there is a divergent response to LA in RRMS subjects that may have implications in the efficacy of immunomodulatory drugs. This clinical trial, "Defining the Anti-inflammatory Role of Lipoic Acid in Multiple Sclerosis," NCT00997438, is registered at https://clinicaltrials.gov/ct2/show/record/NCT00997438 .

High dose biotin as treatment for progressive multiple sclerosis.

BACKGROUND: Published data suggested high dose biotin improved patients with progressive MS. We wished to determine benefits and side effects of administering daily high dose biotin to patients with progressive multiple sclerosis in a large MS specialty clinic. METHODS: Forty-three patients with progressive multiple scleroses were prescribed pharmaceutical grade biotin as a single daily dose of 300mg/day. Brain MRIs were performed at baseline and after one year on biotin. Quantitative neurologic exams (EDSS) and blood work monitoring for biotin toxicity were performed at baseline and every three months thereafter. RESULTS: High dose biotin was safe, and well tolerated, with no evidence of toxicity on blood work and no new lesions on brain MRIs. None of the patients' EDSS scores improved. One-third of patients (38-43%) worsened, most often with increased lower extremity weakness, worsened balance, and more falling, with two patients worsening sufficiently to increase their EDSS scores by 0.5. Several worsened patients improved after stopping biotin. CONCLUSION: High dose biotin was safe and well tolerated, but of no demonstrable long-term benefit. More than one-third of patients worsened while on biotin, most likely due to their disease, but in some patients also possibly due to the inability of their injured central nervous systems to respond to the increased metabolic demands induced by biotin.

A low vitamin D status at diagnosis is associated with an early conversion to secondary progressive multiple sclerosis.

Low circulating 25-hydroxyvitamin D (25(OH)D) levels have been associated with an increased risk of relapses in relapsing remitting multiple sclerosis (RRMS), but an association with disability progression is uncertain. Lower 25(OH)D levels are found in secondary progressive MS (SPMS) when compared to RRMS. We hypothesized that a poor vitamin D status in RRMS is associated with an increased risk of conversion to SPMS. In a retrospective longitudinal study we measured 25(OH)D levels at the start of a 3-year follow-up, and analyzed whether these levels predict the risk of RRMS to SPMS conversion. In 338 RRMS patients, vitamin D status did not predict the 3-year risk of conversion to SPMS (n=51; OR 0.970; p=0.65). However, in diagnostic blood samples of SPMS patients with a relatively short RRMS duration (n=19) 25(OH)D levels were significantly lower (38nmol/L; Q1-Q3: 24-50) than in diagnostic samples of matched RRMS patients with no progression to SPMS ((n=38; 55nmol/L; Q1-Q3: 40-70) (p<0.01). These data indicate an association between a low vitamin D status at the start of RRMS and the early conversion to SPMS. Therefore, time to SPMS conversion is of interest as clinical measure in (follow-up of) clinical vitamin D supplementation studies.

Short-term, high-dose glucocorticoid treatment does not contribute to reduced bone mineral density in patients with multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) are at increased risk of reduced bone mineral density (BMD). A contributing factor might be treatment with high-dose glucocorticoids (GCs). OBJECTIVES: The objective of this paper is to assess bone mass in patients with MS and evaluate the importance of short-term, high-dose GC treatment and other risk factors that affect BMD in patients with MS. METHODS: A total of 260 patients with MS received short-term high-dose GC treatment and had their BMD measured by dual x-ray absorptiometry. BMD was compared to a healthy age-matched reference population (Z-scores). Data regarding GCs, age, body mass index (BMI), serum 25(OH)D, disease duration and severity were collected retrospectively and analysed in a multiple linear regression analysis to evaluate the association between each risk factor and BMD. RESULTS: Osteopenia was present in 38% and osteoporosis in 7% of the study population. Mean Z-score was significantly below zero, indicating a decreased BMD in our MS patients. Multiple linear regression analysis showed no significant association between GCs and BMD. In contrast, age, BMI and disease severity were independently associated with both lumbar and femoral BMD. CONCLUSION: Reduced BMD was prevalent in patients with MS. GC treatment appears not to be the primary underlying cause of secondary osteoporosis in MS patients.

Vitamin D is associated with degree of disability in patients with fully ambulatory relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Vitamin D deficiency is a recognized risk factor for multiple sclerosis (MS) and is associated with increased disease activity. It has also been proposed that the lower the vitamin D levels are, the higher is the handicap. METHODS: To refine the links between vitamin D insufficiency and disability in MS patients, a retrospective cohort analysis was performed including 181 patients prospectively followed without previous vitamin D supplementation, and age, gender, age at MS onset, MS type, MS activity, Expanded Disability Status Scale (EDSS) were analysed in correlation with plasma vitamin D levels. RESULTS: Vitamin D levels were significantly higher in relapsing-remitting MS than in progressive forms of MS in multivariate analyses adjusted for age, ethnicity, gender, disease duration and season (P = 0.0487). Overall, there was a negative correlation between vitamin D level and EDSS score (P = 0.0001, r = -0.33). In relapsing-remitting MS, vitamin D levels were only correlated with disability scores for EDSS < 4 (P = 0.0012). Patients with >20 ng/ml of vitamin D were 2.78 times more likely to have an EDSS < 4 (P = 0.0011, 95% confidence interval 1.49-5.00). CONCLUSION: Data support previous work suggesting that vitamin D deficiency is associated with higher risk of disability in MS. Vitamin D levels also correlated with the degree of disability in fully ambulatory patients with relapsing-remitting MS. These additional results support the pertinence of randomized controlled trials analysing the interest of an early vitamin D supplementation in MS patients to influence evolution of disability.

Long-term effects of whole body cryostimulation on uric acid concentration in plasma of secondary progressive multiple sclerosis patients.

BACKGROUND: Uric acid (UA) has been suggested to be a marker of multiple sclerosis (MS) activity. Whole body cryostimulation (WBCT) is a new form of additional treatment and becoming popular in medicine. OBJECTIVES: The aims of this study were to determine the long-term effects of WBCT on the level of plasma UA in selected group of MS patients only with secondary progressive (SPMS) clinical form and verify results with functional state of patients assessed by expanded disability status scale (EDSS). MATERIALS AND METHODS: SPMS patients (n = 22) and healthy controls (n = 22) participated in 10 3-min-long exposures of WBCT (one exposure per day). Results were collected before the WBCT treatment and after completion the WBCT series as well as one and three months later. RESULTS: WBCT increased UA concentration in plasma of SPMS patients not only directly after 10 exposures (p < 0.0001) but also one (p < 0.0001) and three (p < 0.005) months later. Furthermore, WBCT causes positive changes in EDSS scale both directly after WBCT (7% lower) and maintain this level 1 month later as well as 3 month later (5% lower). CONCLUSIONS: WBCT may be used as adjuvant therapy via increase UA blood level; it improves functional status of SPMS patients.

Homocysteine, vitamin B12 and folate levels in Iranian patients with Multiple Sclerosis: a case control study.

BACKGROUND: Recently, homocysteine (Hcy), folate, and vitamin B12 have been proposed to have several roles on MS pathogenesis. OBJECTIVE: We performed this study to determine the role of serum levels of Hcy, vitamin B12, and folate in patients with relapsing remitting MS (RRMS) and compared them with healthy controls. METHODS: We recruited 75 RRMS patients and 75 subjects as controls with the same age and sex. Homocysteine was measured using fluorimetric high-performance liquid chromatography. Plasma folate and vitamin B12 levels were measured through ion-capture method. RESULTS: Mean plasma levels of vitamin B12, folate, and Hcy in cases were 342.64 ± 210.66 pg/ml, 9.74 ± 4.77 ng/ml, and 22.73 ± 11.63 µM/L, respectively, which showed significant difference in comparison with the controls. In addition, there were significant correlations between mean serum Hcy levels and duration of disease (r=0.2, p=0.05) and treatment with interferon (r=0.21, p=0.01). In cases, Hcy level was higher among those on ß interferon (24.56 ± 11.87 vs. 19.71 ± 10.75, p=0.01). CONCLUSIONS: We concluded that serum levels of vitamin B12 and folate decreased in RRMS patients, but Hcy levels increased significantly. It seems necessary to conduct prospective trials to determine whether the treatment with supplements and correct biomarker levels in the early stage of the disease can change the course of the disease. We recommend regular checking of the serum level of Hcy in patients who use disease-modifying drugs.

Melatonin reduces oxidative stress in the erythrocytes of multiple sclerosis patients with secondary progressive clinical course.

Oxidative stress plays a major role in multiple sclerosis (MS). Melatonin is a potent neuroprotectant. The aims of this study were to determine the actions of melatonin in the reduction of oxidative stress in MS. Therefore, we estimated lipid peroxidation and activities of main antioxidative enzymes in the red blood cells (RBCs) from selective group of MS patients only with secondary progressive (SPMS) clinical form and verified results with functional state. The sixteen (n=16) SPMS patients were supplemented with melatonin (10 mg daily/30 days). Age matched healthy subjects were used as a control (n=13). We determined the level of lipid peroxidation by malondialdehyde (MDA) and activities of main antioxidative enzymes: superoxide dismutase (SOD), catalase (CAT) and glutathione peroxide (GPx) in RBCs of SPMS patients. Melatonin caused statistically significant increase of SOD, GPx (p<0.0001 and p=0.004065, respectively) and decrease of MDA in erythrocytes of SPMS patients (p=0.00019). Correlation analysis of Spearman showed positive correlation between SOD and (expanded disability status scale) EDSS scale both before (r=0.64, p=0.00756) and after (r=0.634, p=0.00834) melatonin treatment. These results demonstrate that supplementation with melatonin SPMS patients should be taken into account, especially in progressive form of MS.

Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis.

PURPOSE: To assess the relationships of sun exposure history, supplementation and environmental factors to vitamin D levels in multiple sclerosis (MS) patients and to evaluate the associations between sun exposure and MRI measures. METHODS: This study included 264 MS patients (mean age 46.9±10 years, disease duration 14.6±10 years; 67.8% relapsing-remitting, 28% secondary progressive and 4.2% primary progressive MS) and 69 healthy controls. Subjects underwent neurological and 3 T MRI examinations, provided blood samples and answered questions to a structured questionnaire. Information on race, skin and eye colour, supplement use, body mass index (BMI) and sun exposure was obtained by questionnaire. The vitamin D metabolites (25-hydroxy vitamin D3, 1, 25-dihydroxy vitamin D3 and 24, 25-dihydroxy vitamin D3) were measured using mass spectrometry. RESULTS: Multivitamin supplementation (partial correlation r(p)=0.29, p<0.001), BMI (r(p)=-0.24, p=0.001), summer sun exposure (r(p)=0.22, p=0.002) and darker eye colour (r(p)=-0.18, p=0.015) had the strongest associations with vitamin D metabolite levels in the MS group. Increased summer sun exposure was associated with increased grey matter volume (GMV, r(p)=0.16, p=0.019) and whole brain volume (WBV, r(p)=0.20, p=0.004) after correcting for Extended Disability Status Scale in the MS group. Inclusion of 25-hydroxy vitamin D3 levels did not substantially affect the positive associations of sun exposure with WBV (r(p)=0.18, p=0.003) and GMV (r(p)=0.14, p=0.026) in the MS group. CONCLUSIONS: Sun exposure may have direct effects on MRI measures of neurodegeneration in MS, independently of vitamin D.

Immunomodulatory effects of Vitamin D in multiple sclerosis.

Although Vitamin D is best known as a modulator of calcium homeostasis, it also has immune modulating potential. A protective effect of Vitamin D on multiple sclerosis is supported by the reduced risk associated with sun exposure and use of Vitamin D supplements. Moreover, high circulating levels of Vitamin D have been associated with lower risk of multiple sclerosis. In this study, we measured 1,25 (OH)(2) Vitamin D and 25 (OH) Vitamin D levels in multiple sclerosis patients separated into different clinical subgroups according to disease status. In addition, direct effects of 1,25 (OH)(2) Vitamin D on ex vivo CD4+ T cells and myelin-peptide specific T cell lines were investigated to gain more insight into putative regulatory mechanisms in the disease pathogenesis. One hundred and thirty-two Hispanic patients with clinically definite multiple sclerosis were studied, 58 with relapsing remitting multiple sclerosis during remission, 34 during relapse and 40 primary progressive multiple sclerosis cases. Sixty healthy individuals matched with respect to place of residence, race/ethnicity, age and gender served as controls. Levels of 25(OH)D(3) and 1,25(OH)(2)D(3), measured by ELISA were significantly lower in relapsing-remitting patients than in controls. In addition, levels in patients suffering relapse were lower than during remissions. In contrast, primary progressive patients showed similar values to controls. Proliferation of both freshly isolated CD4+ T cells and MBP-specific T cells was significantly inhibited by 1,25(OH)(2)D(3). Moreover, activated Vitamin D enhanced the development of IL-10 producing cells, and reduced the number of IL-6 and IL-17 secreting cells. Notably, Vitamin D receptor expression was induced by 1,25(OH)(2)D(3) in both activated and resting cells. Interestingly, T cells were able to metabolize 25(OH)D(3) into biologically active 1,25(OH)(2)D(3), since T cells express alpha1-hydroxylase constitutively. Finally, 1,25(OH)(2)D(3) also increased the expression and biological activity of indoleamine 2,3-dioxygenase, mediating significant increase in the number of CD4+CD25+ T regulatory cells. Collectively, these data suggest that 1,25(OH)(2)D(3) plays an important role in T cell homeostasis during the course of multiple sclerosis, thus making correction of its deficiency may be useful during treatment of the disease.

Erythrocyte membrane fatty acids in benign and progressive forms of multiple sclerosis.

BACKGROUND: There is no good explanation why a proportion of patients with multiple sclerosis (MS) have a relatively benign form of the disease. An imbalance between saturated and unsaturated fatty acids (FA) might influence the disease course of MS. AIM: To assess whether the erythrocyte membrane fatty acid composition, which is a biological marker of long term dietary FA consumption, is different between patients with benign and progressive MS. METHODS: The erythrocyte membrane FA composition was measured by gas chromatography in 23 healthy controls, 27 patients with benign MS, 32 patients with secondary progressive MS and 23 patients with primary progressive MS. None of the patients was following a special diet. RESULTS: No significant differences in levels of saturated and unsaturated FA or in omega-3- and omega-6-polyunsaturated FA were found between controls and patients with the different subtypes of MS. CONCLUSION: Our data suggest that factors other than dietary fatty acid consumption are responsible for the different disease courses of MS.