Abstract:
Multiple sclerosis (MS) is a disease where the immune system attacks the nerve fibers and myelin sheath surrounding the fibers. Disruptions in the nervous system results in symptoms ranging from cognitive problems to vertigo. Currently, the antigen that causes MS is unknown, and diagnosis can be difficult. There are four forms of MS: clinically isolated syndrome, relapsing-remitting, primary progressive, and secondary progressive. Treatment options vary for MS, ranging from a large selection to medications, to alternative treatments such as vitamin D. Vitamin D is a fat soluble vitamin that plays a role in the immune function and inflammatory reduction. This review evaluates current research in the association between vitamin D and MS, ranging from how various calcidiol levels make an impact to how race plays a role in MS and vitamin D treatment. Future direction includes performing more research on the topic, making vitamin D supplements a common form of treatment for MS.
Introduction:
Multiple sclerosis (MS) is a disease that affects the body’s immune system, affecting more than 10,000 people each year. For patients diagnosed with MS, the immune system attacks nerve fibers and the myelin that surrounds them.1 When the nerve and/or myelin is damaged, the impulses that travel from the body to the brain and spinal cord are disrupted.1 Disruptions in the nervous system result in a variety of symptoms, ranging from fatigue and vertigo to cognitive changes, such as the ability to process new information.2 The exact antigen that causes immune cells to attack is currently unknown, giving MS the title of an immune mediated disease.1 Diagnosis of MS can be difficult, as there is no single result that can diagnose a patient with the disease. Currently to be diagnosed with multiple sclerosis (in addition to ruling out all other possible diseases) a patient must have damage in two different areas of the central nervous system and there must be evidence that this damage occurred at different periods of time. 3 There are currently four different types of MS established. Clinically isolated syndrome (CIS) is the beginning stages of MS, being defined as the first episode of inflammation and demyelination in the nervous system, lasting for at least twenty-four hours.4 CIS may lead into MS, but it may also lead to not meeting all forms of criteria to be considered the disease.4 Relapsing-remitting MS (RRMS) is the most common form of the disease, defined by attacks of new or increasing neurological symptoms (also called relapses) followed by periods of remission.4 Within RRMS, the disease can be characterized as active, not active, worsening, or not worsening.4 Primary progressive MS (PPMS) results from worsening symptoms, without relapses or remission.4 PPMS can also be further categorized as active, not active, with progression, or without progression.4 Lastly, secondary progressive MS (SPMS) follows a course of relapse and remission, but then will transition to a course to which there is worsening of neurological function.4
Vitamin D is a fat-soluble vitamin that can be obtained from sun exposure, supplements, and food.5 When obtained, the vitamin must undergo hydroxylation to be activated. First, the liver converts vitamin D to 25-hydoxyvitamin D (calcidiol).5 Secondly, the kidneys convert vitamin D into 1,25 dihydroxyvitamin D (calcitriol).5 One of the main mechanisms in vitamin D is to promote the absorption of calcium in the intestinal tract, in addition to maintaining proper serum calcium and phosphate levels for proper bone growth and remodeling.5 Other roles that vitamin D hold are cell growth modulation, inflammation reduction, neuromuscular and immune function.5 Based on vitamin D’s roles, vitamin D is now emerging as a potential treatment option for multiple sclerosis. This paper will explore the research behind vitamin D and its impact on the treatment of multiple sclerosis.
Body:
The link between vitamin D treatment and MS has been evaluated across many cultures, and will be reviewed in detail. Runia et. al. (2012) conducted a study about the association between calcidiol concentration levels and the course of MS during the relapsing and remitting periods. In addition, patients had to notify researchers when infection or relapses occurred.6 After measurements were collected, statistical analysis of calcidiol concentrations over time indicated a sinusoidal pattern. 6 In order to associate the calcidiol concentrations to the rate of relapses, patients were divided into one week intervals for 2.3 years.6 A Poisson regression model was used to assess the concentration of serum compared to the rate of relapses.6 Out of the 73 patients in the study, 9 dropped out before completion, and the remaining experienced 139 relapses during the period of study. 6 Serum concentrations were high in the summer and low in winter, which could be due the change of seasons and the lack of sun/going outside during the cooler months.6 In general, rates of exacerbation were found to decrease when levels of calcidiol serum were increased, a ratio of 2.0 to 1.4 in groups with low and medium levels of serum concentration.6 From low concentration levels to high concentration levels, the risk was two times higher compared in those with a low concentration.6 There are some strengths and weaknesses of this study. For the strengths, this study allowed for frequent measurements of serum levels, allowing for more accurate data measurements. Secondly, only 28 of the patients used interferon-B, a form of treatment for MS during some point of the study. Interferon-B has been suggested that it has a beneficial effect for vitamin D in MS patients.6 This study did not test nor find such relationship with patients. One main weakness was that many patients did not report how much sunshine they received throughout the study. Ultraviolet rays provide vitamin D to patients, and if some patients were outside more compared to others, this could have contributed to greater serum concentration levels. Another weakness to this study was the small size of the patients. With only 73 patients to begin with, and 9 dropped out before it was finished, leaving 64 Dutch Caucasian patients to examine.6 In order to have more accurate results, more patients should be selected from a wide variety of races.
As mentioned before, interferon-B (IFN-B) has been used as a form of treatment for MS. IFN-B is a cytokine that balances the expression of pro and anti inflammatory agents in the brain, resulting in the reduction of inflammatory cells in the blood brain barrier.7 In addition, when IFN-B has been found to reduce serum cholesterol while raising the circulating levels of calcidiol. In a study performed by Stewart et. al. (2012), the use of IFN-B medication was used to evaluate the relapse risk of MS patients by the interaction of vitamin D levels.7 Serum 25-hydroxyvitamin D (calcidiol) levels were measured along with assessment of factors, including IFN-B treatment biannually.7 After evaluation for three years, subjects using IFN-B were found to have higher calcidiol levels than subjects who did not.7 In addition, patients who had levels of calcidiol at or above 50 nmol/L were associated with a lessened relapse risk when treated with IFN-B.7 If patients had calcidiol levels lower than 50 nmol/L and were treated with IFN-B, they developed a higher risk of relapse.7 Experimenters suggested that IFN-B may be acting on cytochrome p450 expression, which vitamin D metabolism is included in.7 A strength present in this study were that experimenters evaluated all factors of patients that may have some affect on calcidiol levels, such as smoking and time spent outdoors. In addition the study was fairly large, using 178 patients of variety of lifestyles. A weakness to this study was that although the patients had different lifestyle choices, they all came from the same cohort in southern Tasmania.
In-vitro studies have found that calcidiol converts CD4 T-cells and MHC class II molecules to obtain more anti-inflammatory properties.8 A review done by Jahromi et. al. in 2016 examined the current relationship between vitamin D and MS was studied, with a focus on the immune properties that vitamin D exhibits In relation to the disease. One study mentioned in the review was regarding mice with an animal form of MS-experimental autoimmune encephalomyelitis (EAE).8 When treated with vitamin D, inflammatory cells apoptosis occurred, immune cell infiltration was suppressed and proinflammatory cytokine secretion was inhibited.8 Additional studies highlighted on that the protective role vitamin D plays may be influenced by it’s interaction with factors such as inflammatory and anti-inflammatory cytokines.8 Low levels of cytosine IFN-y may inhibit vitamin D in the treatment of demyelinating disease, thus increasing the risk of MS relapse.8 Human clinical trials were also evaluated in this review. It was found in two different studies that low levels of vitamin D could aggravate MS, and that vitamin D levels are reduced once MS symptoms begin to occur.8 In clinical trials with MS patients, it was found that patients treated with 10, 400 IU vitamin D/day decreased the production of CD4+ T cells in patients.8 After review, authors suggested that serum calcidiol levels should be between 30 and 100 ng/ml, with less than 10 ng/ml being considered a deficiency.8 When treating patients with MS, 40 ng/ml of vitamin D should be prescribed.8 This review provided an overview of various studies related to MS and vitamin D treatment. A strength to this study was that they provided evidence of treatment improvement from animals and humans at the cellular level. Many researches test solely on animals, but clinical trials must be performed in order to get realistic human results. In addition, this review answered current questions that someone struggling with MS may have, such as how much vitamin D they should be taking and how often their calcidiol serum levels should be tested.
Cognitive impairment is one of the most common symptoms of MS, affecting up to 65% of patients.9 Memory (verbal and non-verbal) and information processing speed are two cognitive functions that can be impaired greatly with the diagnosis of MS. Darwish et. al. completed a study in 2017 that examined the use of vitamin D on the improvement of cognition on MS patients.9 The Montreal Cognitive Assessment (MoCA), Stroop, Symbol Digit Modalities (SDMT), and Brief Visuospatial Memory Test (BVMT-R) test were all performed as baselines in this study.9 Vitamin D3 replacement was provided for three months, followed by retesting of cognition with the same baselines as before. When comparing patients with deficient and sufficient levels of vitamin D, patients with lower levels increased in vitamin D serum concentration and increased in cognitive performances in the MoCA and BVMT-R tests (testing general memory including long term and visuospatial memory).9 In Stroop and SDMT, changes were not a prevalent. It was suggested that this occurred because SDMT results change over a long duration of time (5-10 years) compared to the other two tests that showed improvements.9 The study suggested that delayed recall showed that the effect of vitamin D having a more important role in long-term and demanding memory.9 One strength to this study was the variety of patients, ranging from 24 to 58 years old with 40 males and 48 females. Compared to other studies, they did not only test the increase of calcidiol levels, but actually evaluated how these increased levels can help improve symptoms that MS patients experience. One weakness to this study was the short time frame. Three months did not allow for a complete and accurate evaluation for the Stroop and SDMT tests, which need a longer development period. Another weakness was that patients did not fill out a lifestyle diary that was needed to take other factors of cognitive improvement into consideration, such as diet and sun exposure.
In many studies, patients with MS are seen as a collective whole, with only lifestyles taken into consideration, not the race or ethnicity of the patient. Langer-Gould et. al. (2018) examined the beneficial effect of vitamin D and/or sun exposure for MS risk across blacks, Hispanics, and whites.10 In this study, it was stated that blacks and Hispanics typically have lower levels of calcidiol compared to whites, but less cases of MS in the two races.10 This vitamin D hypothesis originated on the observation that MS prevalence increases as you move farther away from the equator (where more white people live), thus low ultraviolet radiation means a lower source of vitamin D, and a higher chance of MS.10 This hypothesis is challenged due to blacks and Hispanics having lower vitamin D levels compared to whites even when they have the same amount of UV exposure.10 This study evaluated the life time sun exposure of MS patients from black, white, and Hispanic descent.10 It was determined that there is a high association with lifetime sun exposure and MS risk across racial/ethnic groups.10 Sun exposure provides a protective effect through a immunomodulatory mechanism.10 When using vitamin D as a treatment option, it was found that white MS patients show improvement, while blacks and Hispanics do not.10 This may be due to MS patients producing a bias due to disability and not going outside, thus not receiving vitamin D from sunlight, creating a false positive result.10 It was concluded that sun exports serves as protection for MS, but serum calcidiol levels do not increase in darker skin toned individuals.10 Results suggested that sun light exposure may be more beneficial than vitamin D medication for reducing the risk of MS, particularly in blacks and Hispanics.10 A strength to this study was the very large sample size. Over 1,000 patients were evaluated in this study, with whites being the most populated group (520 patients) and blacks being the lowest represented (247 patients).10 In addition, this study took into account of various other factors that may occur across patients, such as lifestyle choices such as smoking, age, and BMI. A weakness to this study was that the researchers could not exactly explain why serum concentration levels were lower in Hispanics and blacks compare to whites. They suggested that calcidiol concentration may not be a good measurement of the immune system regulation for MS, but did not expand further upon that.10
Conclusion:
When deciding upon topics, I decided to chose multiple sclerosis due to the large effect that it has on 2.3 million people across the world. Although it is considered a rare disease, it makes a impact on many due to it being quite debilitating to those who are diagnosed. By researching this disease, I was able to discover that the exact cause for MS is still not found. I think it is important to continue upon research of MS, in hope of finding the exact antigen that causes this crippling disease. Vitamin D is seen as an alternative medicine form of MS currently, and in the future, direction towards more research of using calcidiol medication in the form of treatment should be done in order to further strengthen the association that the vitamin has on the improvement of MS.
References
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4. Types of MS. (n.d.). Retrieved February 28, 2018, from https://www.nationalmssociety.org/ What-is-MS/Types-of-MS
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7. Stewart, N., Simpson, S., Van Der Mei, I., Ponsonby, A., Blizzard, L., Dwyer, T., . . . Taylor, B. V. (2012). Interferon- and serum 25-hydroxyvitamin D interact to modulate relapse risk in MS. Neurology, 79(3), 254-260.
8. Jahromi, S., Sahraian, M., Togha, M., Sedighi, B., Shayegannejad, V., Nickseresht, A., . . . Alaie, S. (2016). Iranian consensus on use of vitamin D in patients with multiple sclerosis. BMC Neurology, 16(1).
9. Darwish, H., Haddad, R., Osman, S., Ghassan, S., Yamout, B., Tamim, H., & Khoury, S. (2017). Effect of Vitamin D Replacement on Cognition in Multiple Sclerosis Patients. Scientific Reports, 7, 459.
10. Langer-Gould, A., Lucas, R., Xiang, A., Chen, L., Wu, J., Gonzalez, E., . . . Ba