Vitamin D in Multiple Sclerosis

  • Comprehensive MS Care

Why is this important to me?

Compelling evidence suggests that vitamin D is beneficial in MS. Vitamin D appears to reduce the risk of MS and modulate the immune system, and it may also protect the brain from damage.


What is the objective of this study?

The authors reviewed numerous studies investigating the relationship between vitamin D levels and MS.


Sun exposure, which is higher and more frequent if you live closer to the equator, increases vitamin D levels.

  • Populations who live furthest from the equator have a higher prevalence of MS.
  • Reduced sun exposure is linked to an increased risk of MS and may also increase the severity of the disease.


Vitamin D impacts the immune system in a way that is likely beneficial if you have MS. Vitamin D studies have shown to:

  • Reduce pro-inflammatory immune factors.
  • Prevent MS-like symptoms in an inflammation-mediated animal model of MS.
  • Reduce disease severity in certain animal model.
  • Reduce disability in this animal model.


Although researchers do not know the optimal level of vitamin D that you should aim for, the best amount of sun exposure or vitamin D supplementation, or the best time to increase exposure to vitamin D, studies have shown:

  • A vitamin D level ≥100 nmol/L is associated with a 50% reduced risk of MS compared to a level <75 nmol/L.
  • Taking a vitamin D supplement is associated with a reduced risk of developing MS.
  • Vitamin D levels during pregnancy reduce the risk of MS in female offspring, suggesting that very early exposure to vitamin D levels is beneficial.


Some studies have suggested that vitamin D may be helpful if you already have MS.

  • An increased level of vitamin D is associated with a decrease in the risk of a relapse.
  • If you already take a disease-modifying therapy such as interferon-beta or natalizumab (Tysabri®) for your MS, adding vitamin D may further reduce the risk of relapses.
  • Higher levels of vitamin D are associated with fewer, new MS brain lesions and less severe brain shrinkage.
  • If you have optic neuritis as an initial demyelinating event but have not converted to MS, vitamin D may delay a second clinical attack.
  • Additional clinical trials are underway to further investigate the role of vitamin D in improving MS.


Evidence to support the idea that vitamin D protects the nervous system if you have MS is sparse, but studies are underway.

  • Vitamin D may protect the nerve layer in the retina from thinning if you have optic neuritis.
  • Vitamin D may provide protection by reducing free radicals and impacting related molecules.


Vitamin D supplementation is easy, inexpensive, and generally well-tolerated, and is routinely recommended if you have MS or are at increased risk of developing the disease. Vitamin D is a potential therapy to be added to disease-modifying therapy for MS. Numerous clinical trials are being conducted to better understand the effects of the vitamin and its optimal use. Although beneficial effects on the immune system are fairly clear, potential neuroprotective effects require more study.


How did the authors study this issue?

The authors reviewed multiple clinical studies that investigated the impact of vitamin D on MS.

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Original Article

Vitamin D in Multiple Sclerosis and Central Nervous System Demyelinating Disease—A Review

Jodie M. Burton, MD, MSc, FRCPC, Fiona E. Costello, MD, FRCPC

Journal of Neuro-Ophthalmology

Background: The role of vitamin D as both a risk factor and a disease modifier in multiple sclerosis (MS) has a storied history with ongoing accumulation of supportive convergent evidence from animal data, clinical studies and trials, and biomarkers of disease.

Evidence Acquisition: A detailed review of the published literature ranging from in vivo immune studies to human clinical studies of epidemiology, physiology, immunology, clinical, and radiological markers was undertaken.

Results: There is compelling evidence that vitamin D is not only a risk factor for central nervous system (CNS) demyelinating disease (namely MS) but also seems to modify both the inflammatory and neurodegenerative elements of the disease, with large-scale treatment trials underway. The authors also address questions of interest that remain unanswered.

Conclusions: Vitamin D is an important contributor and modifiable risk factor in CNS demyelinating disease. Further work will determine whether it is also neuroprotective and if such benefits will apply to other inflammatory and degenerative neurological diseases.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disorder of the central nervous system (CNS) and the leading cause of nontraumatic neurological disability in young adults (1,2). In 85% of patients, MS is initially heralded by an inflammatory event known as a “clinically isolated syndrome” (CIS), followed by a relapsing course with periods of remission (2,3). After a median disease duration of 20 years, most MS patients transitioned into a secondary progressive phase of the disease (4). Approximately 15% of patients accumulate neurological disability with or without superimposed relapses from the onset of their condition (1,2). Although the realm of therapeutics has evolved dramatically (5,6), neuroprotective treatments remain elusive in MS. Recently, vitamin D has gained attention as a potential adjuvant therapy that seems to reduce MS risk and ameliorate disease severity. A potent immunomodulator, vitamin D, is now routinely recommended to individuals affected by or deemed to be at increased risk of MS (7). Numerous trials are underway to examine the potential benefits of “add-on” vitamin D to approved MS medications. Moreover, vitamin D has been proposed to have neuroprotective effects, a hypothesis, which has been supported by the reduced MS risk associated with sun exposure and the use of vitamin D supplements (8). In this review, we will discuss the epidemiology, immunology, and clinical effects of vitamin D on MS and other demyelinating disorders of the CNS.



For over a century, MS has been observed to follow a striking geographic pattern. Namely populations living increasing degrees of latitude in both northern and southern hemispheres have increased disease prevalence (9–14). Solar/ultraviolet radiation (UVR) has emerged as the most potent environmental factor, linked to latitude, which inversely correlates with MS prevalence rates (9,15,16) (Fig. 1). Specifically, the risk of MS to individuals who migrate from a “high-risk” MS geographic location to a “low-risk” is reduced (and vice versa) if such a move occurs at a relatively young age (18–22). Reduced UVR exposure has been linked with an increased risk of developing MS (22,23) and more severe disability (24). Specifically, a meta-analysis of 52 studies showed a highly significant association (P< 10−8) between MS prevalence and annual amount of UVR (24).

However, observations in Norway, where more northerly coastal fishing areas of the country have significantly lower rates of MS than the inland regions to the south (25,26), have challenged the north–south gradient-latitude UVR hypothesis. Furthermore, the epidemiological investigation of MS showed that subjects who reported high fatty fish intake had a lower odds ratio (OR) [0.82 (0.68–0.98)] for the presence of MS vs those with low intake, whereas lean fish intake had no such effect (27). The unifying hypothesis is that factors including UVR exposure and fatty fish intake ultimately reflect vitamin D intake and production; a conclusion that has been reached after a multitude of both large and small convergent studies (17).


Immune Mechanisms of Vitamin D

Immune regulation is the presumed mechanism by which vitamin D impacts CNS demyelinating disease, supported by the presence of vitamin D receptors on monocytes, activated T cells, and antigen-presenting cells (28–31) (Fig. 2). Activation of the vitamin D receptor is known to alter transcription, proliferation, and differentiation of immune cells (29,33,34). In addition, 1,25-hydroxyvitamin (OH)2D-stimulated B lymphocytes, macrophages, and dendritic cells produce 1α-hydroxylase, whereas 24-hydroxylase is expressed in the presence of 1,25(OH)2D in B lymphocytes and in resting activated monocytes and macrophages (35–37). Other immune effects of 1,25(OH)2D include a reduction in the expression of major histocompatibility complex Class 2 and costimulatory receptors by monocytes (in vitro) (38,39) and reduction in monocyte secretion of proinflammatory cytokines interleukin (IL)-6, IL-12, tumor necrosis factor alpha, and prostaglandin E2 (40–42). Vitamin D receptors also are found on T lymphocytes, which increase with application of 1,25(OH)2D (29), and this in turn, directly impacts T-cell proliferation and associated cytokines. Specifically, IL-2, IL-6, interferon gamma, and granulocyte–macrophage colony-stimulating factor production (proinflammatory effectors that are part of the proinflammatory Th1 “pathway”) are inhibited by 1,25(OH)2D in vitro. Similarly, 1,25(OH)2D promotes an increase in Th2 anti-inflammatory cytokines (43–48). In experimental allergic encephalomyelitis (EAE), the widely accepted model of MS, administration of 1,25(OH)2D before EAE induction has prevented the appearance of MS symptoms, whereas administration after EAE induction has led to disease amelioration, with reduced disability and increased survival time (36,49–52). Studies have shown that the absence of vitamin D receptors negates these effects (31,53). Gender may influence the effect of vitamin D supplementation on EAE outcomes. When EAE animals were supplemented with vitamin D3, the precursor of 1,25(OH)2D, only female mice with functioning ovaries had beneficial neurological outcomes (54,55).

Does Vitamin D Supplementation Impact Multiple Sclerosis Risk and Prevalence?

It is not currently known what serum 25(OH)D level the “average” person should aim to attain, or what the amount of UVR exposure and/or vitamin D supplementation is required to achieve this. Normal 25(OH)D values measure between 50 and 80 nmol/L (57), albeit this is somewhat controversial (57,58). To reach a value of ≥75 nmol/L, the average adult requires 1,500 to 2,000 IU/d of supplemental vitamin D, whereas a child requires at least 1,000 IU/d (59). There is evidence to suggest that the degree of vitamin D deficiency impacts MS risk. In a prospectively designed nested case–control study of American serviceman (60), 25(OH)D levels at enlistment among those who later developed MS showed a striking risk threshold: healthy, non-Hispanic whites with an entry serum 25(OH)D level of ≥100 nmol/L had a 50% reduced risk of developing MS vs those with levels below 75 nmol/L (61). There was a decreased risk of MS (OR = 0.38, 0.19–0.75) in whites with serum 25(OH)D in the highest quintile (99.1–152.9 nmol/L) vs those in the lowest quintile (less than or equal to 63.3 nmol/L). In the Nurses' Health Study and Nurses' Health Study II, Munger et al (61) found parallels in dietary vitamin D intake and MS risk. The pooled age-adjusted relative risk comparing women in the highest quintile of total vitamin D intake at baseline with those in the lowest was 0.67 (0.40–1.12). Intake of vitamin D from supplements was also inversely associated with the risk of MS; the relative risk comparing women with intake of greater than or equal to 400 IU/d with women with no vitamin D supplementation was 0.59 (0.38–0.91). A review of cases with MS that came out of the Nurses' Health Study also revealed that predicted 25(OH)D levels in the mothers of incident and prevalent MS cases were inversely associated with MS risk in their daughters (40% lower when comparing the highest to lower quintile [mean intake 350 and 65 IU/d, respectively]) (61). The impact of vitamin D and future risk of MS among CIS patients was addressed by Martinelli and colleagues (62). Cox proportional hazard modeling revealed that hazard ratios of converting to MS for very low (<10th percentile) and low (<25th percentile) 25(OH)D levels were 3.11 (1.25–7.71) and 1.89 (0.96–3.70), respectively. Thus, those in the lowest vitamin D serum level groups had the greatest risk. In a separate analysis of men and women, at 25(OH)D levels measuring <25th percentile, there was a relatively greater increase in the risk for MS in women (63). Vitamin D level and exposure in early life may be associated with future development of MS. Mirzaei et al (62) found that vitamin D levels and ingestion during pregnancy affected the risk of MS in female offspring when evaluating the Nurses' Health Study. A study of UVR and MS in Newfoundland showed that UVR/vitamin D status at a period as early as in utero might contribute to future MS risk (20).


Is There Evidence That Vitamin D Treats the Inflammatory Manifestations of Multiple Sclerosis?


Observational studies have shown a relationship between vitamin D, sun exposure, and relapse events. In an Australian longitudinal study (64), 145 relapsing-remitting multiple sclerosis (RRMS) patients were followed for more than 2 years with serial 25(OH)D measurements performed every 6 months. The authors found that for every 10 nmol/L increase in serum 25(OH)D, there was a 9% reduction in relapse risk and that with serum levels of 25(OH)D of roughly 100 nmol/L, there was more than an 80% reduction in the hazard rate of relapse. Mowry et al (65) prospectively followed patients with pediatric onset MS and CIS. Among 110 patients, for every 25 nmol/L increase in adjusted 25(OH)D level, there was a 34% decrease in the rate of subsequent relapse events (65). In an observational study, 156 patients were evaluated with respect to 25(OH)D and relapse rate before and after initiation of disease modifying medications (DMTs) for MS (66). In 76 patients, DMT was started before vitamin D supplementation by 4.2 years (±2.7 years), whereas both treatments were started simultaneously in 80 patients (67). With supplementation, the 25(OH)D level increased from 49 ± 22 nmol/L to 110 ± 26 nmol/L on average. Pooling of data showed a strong impact of the addition of vitamin D on relapse rate: every 10 nmol increase in 25(OH)D level was associated with a reduction in the relapse incidence rate of 13.7%, although there seemed to be no added benefit above a 25(OH)D of 110 nmol/L. In related work, Scott et al (67) showed that among 118 patients using natalizumab, 45 were vitamin D deficient. Sixteen of 26 patients with MS-related relapses in the year before vitamin D testing, and 12 of 17 with relapses after testing were noted among the vitamin D–deficient patients. Patients who were vitamin D sufficient had significantly fewer relapses pretesting and posttesting (67). Notably, studies that have shown that 25(OH)D levels are reduced during relapses as compared with periods of remission (68,69) need to be viewed with caution because it is not possible to determine whether sun-avoidant behavior at the time of relapse is a contributing factor.


Early trials of vitamin D supplementation for MS were methodologically flawed either by design or agent choice (70,71), but in more recent years, a small number of more appropriately designed vitamin D treatment trials have been completed. James et al (72) performed a meta-analysis of interventional trials studying the impact of vitamin D on MS relapses, finding a total of 5 studies acceptable for inclusion. Three studies used vitamin D3, 1 used vitamin D2, and 1 used calcitriol. Overall, an impact on relapse events was not found, although the small sample size and heterogeneity of study design and treatment regimen were likely contributors. However, some trials did show a trend toward fewer relapse events in the high-dose vitamin D trial with an OR = 0.31 (0.08–1.21) (73). Using data obtained from the SENTINEL natalizumab trial (in which patients received intramuscular interferon beta-1 alpha with or without natalizumab), Ascherio et al (74) evaluated evidence of MS disability and progression. Serum 25(OH)D values were measured at baseline and 6, 12, and 24 months. A 50-nmol/L increment in mean serum 25(OH)D levels in the first 12 months predicted a 57% lower rate of new active lesions (P < 0.001), 57% lower relapse rate (P = 0.03), 25% lower annual increase in T2 lesion volume (P < 0.001), and 0.41% lower annual loss in brain volume (P = 0.07) between months 12 and 60. Likewise, Ascherio et al (74) studied patients with respect to 25(OH)D measures and MS outcomes within the BENEFIT (The Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment) trial, which was designed to assess the impact of interferon beta-1 beta in delaying conversion of CIS to MS. Overall, the relapse rate decreased by 27% for a 50-nmol/L increment in 25(OH)D, but this value did not reach statistical significance. Changes in disability were also found between the groups above or below a 25(OH)D of 50 nmol/L, but this value was not clinically significant (74). Currently, several large-scale, DMT add-on trials of relatively high-dose vitamin D are underway, including a trial of glatiramer acetate ± 5,000 IU/d or 600 IU/d of vitamin D3 (75), the SOLAR trial of interferon beta-1 alpha subcutaneous ± 14,000 IU/d of vitamin D (77), and the CHOLINE trial, also of interferon beta-1 alpha subcutaneous ±twice monthly infusions of 100,000 IU of vitamin D3 (77).


Magnetic Resonance Imaging

In 2000, Auer et al (78) reported a striking, near sinusoidal annual variation in the number of active magnetic resonance imaging (MRI) lesions in 53 MS patients, positioning a variety of potential explanations including infectious agents and/or UV exposure. Embry et al (79) argued that vitamin D status could explain these observations because 25(OH)D also shows a near sinusoidal annual fluctuation at higher latitudes. These investigators evaluated the published monthly 25(OH)D levels in 415 people in tandem with the data from Auer and found that third-order polynomial curves fit both the 25(OH)D and lesion data significantly. When the 25(OH)D data were lagged by 2 months, there was a close correspondence between the 2 curves with high levels of 25(OH)D correlating with low levels of lesion activity and vice versa. A randomized placebo add-on trial in Finland compared MRI outcomes in 2 groups of patients using interferon beta-1 alpha: one group received 20,000 IU/d of vitamin D3, whereas the second group took placebo more than 12 months (80). Although the primary outcome of T2 lesion burden of disease did not differ between groups, secondary outcomes of total number of T1 gadolinium-enhancing lesions showed a greater degree of decrease in the vitamin D group (P = 0.004). Mowry et al (81) evaluated the relationship between MRI lesion activity and 25(OH)D levels in patients with CIS or RRMS. Annual 25(OH)D levels were evaluated for an association with subsequent new T2-weighted and gadolinium-enhancing T1-weighted lesions on brain MRI, clinical relapses, and disability. A total of 2,362 MRI scans were acquired from 469 subjects. In multivariate analyses, each 25 nmol/L 25(OH)D level was associated with a 15% lower risk of a new T2 lesion (incidence rate ratio = 0.85, P = 0.004) and a 32% lower risk of a gadolinium-enhancing lesion (incidence rate ratio, P = 0.002) (82). In the aforementioned BENEFIT trial (74), the relative decrease in T2 lesion volume for a 50-nmol/L increase in 25(OH)D was 20% per year (P < 0.001). The same 25(OH)D increase was associated with a 0.27% lower rate of brain loss/atrophy in all patients, and the overall 25(OH)D-associated annual difference in brain volume loss for a 50-nmol/L increase in 25(OH)D was 0.41%.


Vitamin D, Demyelinating Disease, and the Visual System

Interrogating the Afferent Visual Pathway Model of Multiple Sclerosis to the Impact of Vitamin D on Central Nervous System Demyelination

As a putative model of MS, the afferent visual pathway (AVP) model, with optic neuritis (ON) as its relapse “prototype,” offers several potential advantages (82). The AVP allows for precise localization and, in the setting of acute ON, provides objective evidence of a symptomatic lesion involving optic nerve, which can be anatomically localized in the CNS. Additionally, the AVP is a functionally eloquent CNS system, and deficits therein can be captured with reproducible measures of visual function including high- and low-contrast visual acuity, automated perimetry, and color vision testing. Furthermore, optical coherence tomography (OCT) provides structural measures of neuronal and axonal integrity in the AVP. By pairing OCT measures with quantitative visual outcomes, it is feasible to devise a structural–functional paradigm to elucidate the temporal evolution and relative contributions of inflammation, axonal loss, neuronal damage, and cortical compensation to post-ON recovery. The AVP model can be used to monitor tissue specific factors that underlie injury and repair in the CNS of MS patients.


Does Vitamin D Have an Impact in Patients With Optic Neuritis?

Clinical studies suggest that the administration of vitamin D3 supplements to ON patients with low serum vitamin 25(OH)D levels may delay the onset of a second clinical attack and the subsequent conversion to MS. Malik et al (84) studied adult (n = 253) and pediatric (n = 38) patients presenting with an ON first demyelinating event. Men (adjusted OR = 2.28, P = 0.03) and ON patients with severe attacks (adjusted OR = 5.24, P < 0.001) had poorer recovery post-ON. Recovery was significantly better in the pediatric vs adult group. Season-adjusted vitamin D level was associated with ON attack severity (OR for 10-U increase in vitamin D level = 0.47; 95% confidence interval, 0.32–0.68; P < 0.001), but not recovery.


The authors are currently evaluating the potential neuroprotective effects of vitamin D status on ON recovery, finding that vitamin D sufficiency (25(OH)D ≥ 80 nmol/L) at ON onset is associated with less thinning on OCT measures of intereye retinal nerve fiber layer thickness and ganglion cell layer (GCL) values at 6 months (84). Evidence linking vitamin D with disease outcomes in neuromyelitis optica spectrum disorders (NMOSD) is sparse. Kimbrough et al (85) have shown that along with vitamin D deficiency, other features associated with eventual diagnosis of NMOSD included longitudinal extensive transverse myelitis at onset, female gender, African American race, elevated IgG index, an antinuclear antibody titer of 1:160, and antibodies to Ro/SS-A antigen. Similarly, Mealy et al (86) showed that vitamin D levels were significantly lower in patients who developed recurrent spinal cord disease, adjusting for season, age, sex, and race. In this study, vitamin D insufficiency was also been linked to disability in NMOSD patients.


Vitamin D and Demyelinating Disease: Unanswered Questions

Is Vitamin D Neuroprotective?

Although the evidence to support an anti-inflammatory role for vitamin D in demyelinating disease is widely accepted, proof of a neuroprotective effect remains elusive. Animal studies have shown at least 2 novel actions of relatively low concentrations of 1,25(OH)2D on neurons, including a direct neuroprotective action against excitotoxic insults and a decrease in both L-type voltage sensitive calcium channels activity and mRNA levels of the corresponding pore-forming subunits of the L-type channel (87). Other mechanisms of vitamin D–associated reduction of calcium levels in the CNS involve stimulation of calcium-binding proteins (parvalbumin and calbindins) and the inhibition of brain gamma glutamyl transpeptidase. Nanomolar concentrations of calcitriol protect neurons from the effects of free radical species such as superoxide and hydrogen peroxide. Furthermore, calcitriol reduces nitrous oxide levels by inhibiting the expression of inducible nitric oxide synthase in the spinal cord and brain and induce neurotrophins (88).


In clinical studies of demyelination, evidence of neuroprotection would typically include long-term clinical monitoring and MRI metrics including brain atrophy measures. Using the AVP model, it has been shown that GCL thinning representing neuronal loss post-ON is worse among patients with a serum 25(OH)D <80 nmol/L (84).



There is mounting evidence physiological, experimental, epidemiological, genetic, and immunological arguments supporting a role of hypovitaminosis D in the risk of MS. From a practical standpoint, vitamin D supplementation is relatively simple, inexpensive, and well tolerated. The wealth of evidence in clinical research suggests that vitamin D supplementation is beneficial in early and relapsing–remitting phases of MS. The potential role for vitamin D in promoting neuroprotection and repair in CNS inflammatory disorders awaits further study.



1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502–1517.

2. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. NEJM. 2000;343:938–952.

3. Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part 1: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol. 2005;4:281–288.

4. Tremlett H, Zhao Y, Devonshire V. Natural history of secondaryprogressive multiple sclerosis. Mult Scler. 2008;14:314–324.

5. Burton JM, Costello F. Novel agents and emerging treatment strategies in multiple sclerosis. Clin Med Rev Ther. 2011;3. doi: 10.4137/CMRT.S2895.

6. Ontaneda D, Di Capua D. Benefits versus risks of latest therapies in multiple sclerosis: a perspective review. Ther Adv Drug Saf. 2012;3:291–303.

7. Hanwell HEC, Banwell B. Assessment of evidence for a protective role of vitamin D in multiple sclerosis. Biochim Biophys Acta. 2011;1812:202–212.

8. Smolders J, Damoiseaux J, Menheere P, Hupperts R. Vitamin D as an immune modulator in multiple sclerosis, a review. J Neuroimmunol. 2008;194:7–17.

9. Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatr Scand Suppl. 1960;147:132–147.

10. Ulett G. Geographic distribution of multiple sclerosis. Dis Nerv Syst. 1948;9:342–346.

11. Limburg CC. Geographic distribution of multiple sclerosis and its estimated prevalence in the United States. Res Publ Assoc Res Nerv Dis. 1950;28:15–24. 

12. Kurland LT. The frequency and geographic distribution of multiple sclerosis as indicated by mortality statistics and morbidity surveys in the United States and Canada. Am J Hyg. 1952;55:457–476.

13. Vukusic S, Van Bokstael V, Gosselin S, Confavreux C. Regional variations of multiple sclerosis prevalence in French farmers. J Neurol Neurosurg Psychiatry. 2007;78:707–709.

14. McLeod JG, Hammon SR, Hallpike JF. Epidemiology of multiple sclerosis in Australia. With NSW and SA survey results. Med J Aust. 1994;160:117–122.

15. Geiger R. The Climate Near the Ground. Cambridge, MA: Harvard University Press, 1965. pp. 442–446.

16. Kurtzke JF. On the fine structure of the distribution of multiple sclerosis. Acta Neurol Scand. 1967;43:257–282.

17. Pierrot-Deseilligny C, Souberbielle JC. Is hypovitaminosis D one of the environmental risk factors for multiple sclerosis? Brain. 2010;133:1869–1888.

18. Hammond SR, English DR, McLeod JG. The age-range risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain. 2000;123:968–974.

19. Kurtzke JF, Beebe JW, Norman JE. Epidemiology of multiple sclerosis in US veterans: III: migration and the risk of MS. Neurology. 1985;35:672–678.

20. Sloka JS, Pryse-Phillips WE, Stefanelli M. The relation of ultraviolet radiation and multiple sclerosis in Newfoundland. Can J Neurol Sci. 2008;35:69–74.

21. Staples J, Ponsonby AL, Lim L. Low maternal exposure to ultraviolet radiation in pregnancy, month of birth, and risk of multiple sclerosis in offspring: longitudinal analysis. BMJ. 2010;340:c1640.

22. Bjornevik K, Riise T, Casetta I, Drulovic J, Granieru E, Holmoy T, Kampman MT, Landtblom AM, Lauer K, Lossius A, Magalhaes S, Myhr KM, Pekmezovic T, Wesnes K, Wolfson C, Pugliatti M. Sun exposure and multiple sclerosis risk in Norway and Italy: the EnvIMS study. Mult Scler. 2014;20:1042–1049.

23. Islam T, Gauderman WJ, Cozen W, Mack TM. Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology. 2007;69:381–388.

24. Sloka S, Silva C, Pryse-Phillips J, Metz S, Patten S, Yong VW. Environmental risks for multiple sclerosis: quantitative analyses and biological mechanisms. Mult Scler. 2009;15 (suppl 2):S158.

25. Swank RL, Lerstad O, Strøm A, Backer J. Multiple sclerosis in rural Norway: Its geographic and occupational incidence in relation to nutrition. N Engl J Med. 1952;246:721.

26. Kampman MT, Brustard M. Vitamin D: a candidate for the environmental effect in multiple sclerosis—observations from Norway. Neuroepidemiology. 2008;30:140–146.

27. Bäärnhielm M, Olsson T, Alfredsson L. Fatty fish intake is associated with decreased occurrence of multiple sclerosis. Mult Scler. 2014;20:726–732.

28. Bhalla AK, Amento EP, Clemens TL, Holick MF, Krane SM. Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab. 1983;57:1308–1310.

29. Vedman CM, Cantorna MT, DeLuca HF. Expression of 1,25- dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys. 2000;374:334–338.

30. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25- dihydroxyvitamin D3 receptors in human leukocytes. Science. 1983;221:1181–1183.

31. Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J. 2001;15:2579–2585.

32. Cadden MH, Koven NS, Ross MK. Neuroprotective effects of vitamin D in multiple sclerosis. Neurosci Med. 2011;2:198–207.

33. Dong X, Lutz W, Schroeder TM, Bachman LA, Westendorf JJ, Kumar R, Griffin MD. Regulation of relB in dendritic cells by means of modulated association of vitamin D receptor and histone deacetylase 3 with the promoter. Proc Natl Acad Sci U S A. 2005;102:16007–16012.

34. Muthian G, Raikwar JP, Rajasingh J, Bright JJ. 1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/ IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis. Neurosci Res. 2006;83:1299–1309.

35. Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effect of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol. 2007;179:1634–1647.

36. Overbergh L, Decallonne B, Valckx D, Verstuyf A, Depovere J, Laureys J, Rutgeerts O, Saint-Arnaud R, Bouillon R, Mathieu C. Identification and immune regulation of 25-hydroxyvitamin D-1- alphahydroxylase in murine macrophages. Clin Exp Immunol. 2000;120:139–146.

37. Chen KS, DeLuca HF. Cloning of the human 1 alpha, 25- dihydroxyvitamin D-3 24-hydroxylase gene promoter and identification of two vitamin D-responsive elements. Biochim Biophys Acta. 1995;1263:1–9.

38. Rigby WF, Waugh M, Graziano RF. Regulation of human monocyte HLA-DR and CD4 antigen expression, and antigen presentation by 1, 25-dihydroxyvitamin D3. Blood. 1990;76:189–197.

39. Xu H, Soruri A, Gieseler RK, Peters JH. 1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class-II antigen expression, accessory activity, and phagocytosis of human monocytes. Scand J Immunol. 1993;38:535–540.

40. D’Ambrosio D, Cippitelli M, Cocciolo MG, Mazzeo D, Di Lucia P, Lang R, Sinigaglia F, Panina-Bordignon P. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NFkappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest. 1998;101:252–262.

41. Muller K, Haahr PM, Diamant M, Rieneck K, Kharazmi A, Bendtzen K. 1,25-Dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the posttranscriptional level. Cytokine. 1992;4:506–512.

42. Zarrabeitia MT, Riancho JA, Amado JA, Olmos JM, GonzalezMacias J. Effect of calcitriol on the secretion of prostaglandin E2, interleukin 1, and tumor necrosis factor alpha by human monocytes. Bone. 1992;13:185–189.

43. Muller K, Diamant M, Bendtzen K. Inhibition of production and function of interleukin-6 by 1,25-dihydroxyvitamin D3. Immunol Lett. 1991;28:115–120.

44. Bhalla AK, Amento EP, Krane SM. Differential effects of 1,25- dihydroxyvitamin D3 on human lymphocytes and monocyte/ macrophages: inhibition of interleukin-2 and augmentation of interleukin-1 production. Cell Immunol. 1986;98:311–322.

45. Muller K, Odum N, Bendtzen K. 1,25-dihydroxyvitamin D3 selectively reduces interleukin-2 levels and proliferation of human T cell lines in vitro. Immunol Lett. 1993;35:177–182.

46. Reichel H, Koeffler HP, Tobler A, Norman AW. 1 alpha, 25- dihydroxyvitamin D3 inhibits gamma-interferon synthesis by normal human peripheral blood lymphocytes. Proc Natl Acad Sci U S A. 1987;84:3385–3389.

47. Rigby WF, Stacy T, Fanger MW. Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J Clin Invest. 1984;74:1451–1455.

48. Towers TL, Freedman LP. Granulocyte-macrophage colonystimulating factor gene transcription is directly repressed by the vitamin D3 receptor. Implications for allosteric influences on nuclear receptor structure and function by a DNA element. J Biol Chem. 1998;273:10338–10348.

49. Cantorna MT, Hayes CE, DeLuca HF. 1,25-dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc Natl Acad Sci U S A. 1996;93:7861–7864.

50. Lemire JM, Archer DC. 1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J Clin Invest. 1991;87:1103–1107.

51. Van Etten E, Branisteanu DD, Overbergh L, Bouillon R, Verstuyf A, Mathieu C. Combination of a 1,25-dihydroxyvitamin D3 analog and a bisphosphonate prevents experimental autoimmune encephalomyelitis and preserves bone. Bone. 2003;32:397–404.

52. Nashold FE, Hoag KA, Goverman J, Hayes CE. Rag-1- dependent cells are necessary for 1,25-dihydroxyvitamin D(3) prevention of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2001;119:16–29.

53. Meehan TF, DeLuca HF. The vitamin D receptor is necessary for 1alpha, 25-dihydroxyvitamin D(3) to suppress experimental autoimmune encephalomyelitis in mice. Arch Biochem Biophys. 2002;408:200–204.

54. Spach KM, Hayes CE. Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. J Immunol. 2005;175:4119–4126.

55. Cantorna MT, Humpal-Winter J, DeLuca HF. Dietary calcium is a major factor in 1,25-dihydroxycholecalciferol suppression of experimental autoimmune encephalomyelitis in mice. J Nutr. 1999;129:1966–1971.

56. Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int. 2005;16:713–716.

57. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Cliton SK. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96:53–58.

58. Vieth R. Why the optimal requirement for vitamin D3 is probably much higher than what is officially recommended for adults. J Steroid Biochem Mol Biol. 2004;89–90:575–579.

59. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad H, Weaver CM. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96:1911–1930.

60. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296:2832–2838.

61. Munger KL, Zhang SM, O’Reilly E, Hernan MA, Olek MJ, Willett WC, Ascherio A. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62:60–65.

62. Mirzaei F, Michels KB, Munger K, O’Reilly E, Chitnis T, Forman MR, Giovannucci E, Rosner B, Ascherio A. Gestational vitamin D and the risk of multiple sclerosis in offspring. Ann Neurol. 2011;70:30–40.

63. Martinelli V, Dalla Costa G, Colombo B, Dalla Libera D, Rubinacci A, Filippi M, Furlan R, Comi G. Vitamin D levels and risk of multiple sclerosis in patients with clinically isolated syndromes. Mult Scler. 2014;20:147–155.

64. Simpson S Jr, Taylor B, Blizzard L, Ponsonby AL, Pittas F, Tremlett H, Dwyer T, Gies P, van der Mei I. Higher 25- hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol. 2010;2:193–203.

65. Mowry EM, Krupp LB, Milazzo M, Chabas D, Strober JB, Belman AL, McDonald JC, Oksenberg JR, Bacchetti P, Waubant E. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol. 2010;67:618– 624.

66. Pierrot-Deseilligny C, Rivaud-Péchoux S, Clerson P, de Paz R, Souberbielle JC. Relationship between 25-OH-D serum level and relapse rate in multiple sclerosis patients before and after vitamin D supplementation. Ther Adv Neurol Disord. 2012;4:187–198.

67. Scott TF, Hackett CT, Dworek DC, Schramke CJ. Low vitamin D level is associated with higher relapse rate in natalizumab treated MS patients. J Neurol Sci. 2013;330:27–31.

68. Tremlett H, van der Mei IA, Pittas F, Blizzard L, Paley G, Mesaros D, Woodbaker R, Nunez M, Dwyer T, Taylor BV, Ponsonby AL. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31:271–279.

69. Soilu-Hanninen M, Airas L, Mononen I, Heikkila A, Viljanen M, Hanninen A. 25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosis. Mult Scler. 2005;11:266–271.

70. Goldberg P, Fleming MC, Picard EH. Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Med Hypotheses. 1986;21:193–200.

71. Wingerchuk DM, Lesaux J, Rice GP, Kremenchutzky M, Ebers GC. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76:1294–1296.

72. James E, Dobson R, Kuhle J, Baker D, Giovannoni G, Ramagopalan SV. The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis. Mult Scler. 2013;19:1571–1579.

73. Burton JM, Kimball S, Vieth R, Bar-Or A, Dosch HM, Cheung R, Gagne D, D’Souza C, Ursell M, O’Connor P. A phase I/II doseescalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010;74:1852–1859.

74. Ascherio A, Munger KL, White R, Köchert K, Simon KC, Polman CH, Freedman MS, Hartung HP, Miller DH, Montalbán X, Edan G, Barkhof F, Pleimes D, Radü EW, Sandbrink R, Kappos L, Pohl C. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol. 2014;71:306–314.

75. Mowry E. Johns Hopkins University. Vitamin D Supplementation in Multiple Sclerosis. Available at: NCT01490502. Accessed on February 25, 2015.

76. Merck KGaA. Supplementation of VigantOL Oil Versus Placebo as Add-on in Patients with Relapsing Remitting Multiple Sclerosis Receiving Rebif Treatment (SOLAR). Available at: Accessed on February 25, 2015.

77. Merck KGaA, Merk Serono S.A.S., France. A Multicentre Study of the Efficacy and Safety of Supplementary Treatment with Cholecalciferol in Patients with Relapsing Multiple Sclerosis Treated with Subcutaneous Interferon Beta-1a 44 ug 3 Times Weekly (CHOLINE). Available at: http://clinicaltrials. gov/show/NCT01198132. Accessed on February 25, 2015.

78. Auer DP, Schumann EM, Kumpfel T, Gössl C, Trenkwalder C. Seasonal fluctuations of gadolinium- enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol. 2000;47:276–277.

79. Embry A, Snowdon L, Vieth R. Vitamin D and seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol. 2000;48:271–272.

80. Soilu-Hanninen M, Aivo J, Lindstrom BM, Elovaara I, Sumelahti ML, Farkkila M, Tienari P, Atula S, Sarasoja T, Herrala L, Keskinarkaus I, Kruger J, Kallio T, Rocca MA, Filippi M. A randomized, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon b-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83:565–571.

81. Mowry EM, Waubant E, McCulloch CE, Okuda DT, Evangelista AA, Lincoln RR, Gourraud PA, Brenneman D, Owen MC, Qualley P, Bucci M, Hauser SL, Pelletier D. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72:234–240.

82. Costello F. The afferent visual pathway: designing a structuralfunctional paradigm of multiple sclerosis. ISRN Neurol. 2013;2013:134858.

83. Malik MT, Healy BC, Benson LA, Kivisakk P, Musallam A, Weiner HL, Chitnis T. Factors associated with recovery from acute optic neuritis in patients with multiple sclerosis. Neurology. 2014;82:2173–2179.

84. Burton JM, Trufyn J, Tung C, Eliasziw M, Costello F. The role of vitamin D and gender in optic neuritis recovery. Paper presented at: the 2014 Joint ACTRIMS-ECTRIMS Meeting; September 10–13, 2014; Boston, MA.

85. Kimbrough DJ, Mealy MA, Simpson A, Levy M. Predictors of recurrence following an initial episode of transverse myelitis. Neurol Neuroimmunol Neuroinflamm. 2014;1:e4.

86. Mealey MA, Newsome S, Greenberg BM. Low serum vitamin D levels and recurrent inflammatory spinal cord disease. Neuroepidemiology. 2011;37:52–57.

87. Brewer LD, Thibault V, Chen KC, Langub MC, Landfield PW, Porter NM. Vitamin D hormone confers neuroprotection in parallel with downregulation of L-type calcium channel expression in hippocampal neurons. J Neurosci. 2001;21:98– 108.

88. Kalueff AV, Eremin KO, Tuohimaa P. Mechanisms of neuroprotective action of vitamin D3. Biochemistry (Mosc). 2004;69:738–741.

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