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Show Vitamin D in Multiple Sclerosis and Central Nervous System Demyelinating Disease-A Review Jodie M. Burton, MD, MSc, FRCPC, Fiona E. Costello, MD, FRCPC 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) demye-linating 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 un-answered. 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 degener-ative neurological diseases. Journal of Neuro-Ophthalmology 2015;35:194-200 doi: 10.1097/WNO.0000000000000256 © 2015 by North American Neuro-Ophthalmology Society Multiple sclerosis (MS) is an inflammatory and neu-rodegenerative disorder of the central nervous sys-tem (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 dis-ease (4). Approximately 15% of patients accumulate neu-rological disability with or without superimposed relapses from the onset of their condition (1,2). Although the realm of therapeutics has evolved dramatically (5,6), neu-roprotective treatments remain elusive in MS. Recently, vitamin D has gained attention as a potential adjuvant therapy that seems to reduce MS risk and ameliorate dis-ease 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 ef-fects, 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. EPIDEMIOLOGICAL EVIDENCE SUPPORTING A ROLE FOR VITAMIN D IN MULTIPLE SCLEROSIS 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 individ-uals who migrate from a "high-risk" MS geographic loca-tion 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 Departments of Clinical Neurosciences and Community Health Sci-ences (JMB), University of Calgary, Calgary, Alberta, Canada; and Departments of Clinical Neurosciences and Surgery (FEC), Univer-sity of Calgary, Calgary, Alberta, Canada. The authors report no conflicts of interest. Address correspondence to Jodie M. Burton, MD, MSc, FRCPC, De-partments of Clinical Neurosciences and Community Health Scien-ces, University of Calgary, HSC Room 1007c, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; E-mail: jodie.burton@ albertahealthservices.ca 194 Burton and Costello: J Neuro-Ophthalmol 2015; 35: 194-200 State-of-the-Art Review Section Editors: Valérie Biousse, MD Steven Galetta, MD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. developing MS (22,23) and more severe disability (24). Specifically, a meta-analysis of 52 studies showed a highly significant association (P , 1028) 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 epi-demiological 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 includ-ing 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 1a-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 histo-compatibility complex Class 2 and costimulatory receptors by monocytes (in vitro) (38,39) and reduction in mono-cyte 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 lym-phocytes, 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 pro-motes 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 recep-tors negates these effects (31,53). Gender may influence the effect of vitamin D supplementation on EAE out-comes. When EAE animals were supplemented with vita-min D3, the precursor of 1,25(OH)2D, only female mice with functioning ovaries had beneficial neurological out-comes (54,55). Vitamin D and Central Nervous System Demyelinating Diseases: Key Questions 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 devel-oped 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 supple-ments 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 FIG. 1. Geographic pattern of multiple sclerosis prevalence and latitude and ultraviolet exposure worldwide [modified from reference (17)]. Burton and Costello: J Neuro-Ophthalmol 2015; 35: 194-200 195 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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 compar-ing 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 anal-ysis 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 expo-sure 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? Relapses Observational studies have shown a relationship between vitamin D, sun exposure, and relapse events. In an Australian longitudinal study (64), 145 relapsing-remitting multiple scle-rosis (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 pa-tients 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 FIG. 2. Vitamin D and immune effectors involved in multiple sclerosis [modified from reference (32)]. 196 Burton and Costello: J Neuro-Ophthalmol 2015; 35: 194-200 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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 inclu-sion. 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 base-line and 6, 12, and 24 months. A 50-nmol/L increment in mean serum 25(OH)D levels in the first 12 months pre-dicted 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 de-signed to assess the impact of interferon beta-1 beta in delay-ing 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 vita-min 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 vari-ety 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 activ-ity 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 (inci-dence 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 "pro-totype," 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 elo-quent 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 neuro-nal and axonal integrity in the AVP. By pairing OCT Burton and Costello: J Neuro-Ophthalmol 2015; 35: 194-200 197 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. measures with quantitative visual outcomes, it is feasible to devise a structural-functional paradigm to elucidate the temporal evolution and relative contributions of inflamma-tion, axonal loss, neuronal damage, and cortical compensa-tion 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 neuro-protective 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 neu-romyelitis optica spectrum disorders (NMOSD) is sparse. Kimbrough et al (85) have shown that along with vitamin D deficiency, other features associated with eventual diag-nosis of NMOSD included longitudinal extensive trans-verse 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 signif-icantly 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 concen-trations of calcitriol protect neurons from the effects of free radical species such as superoxide and hydrogen peroxide. Furthermore, calcitriol reduces nitrous oxide levels by in-hibiting the expression of inducible nitric oxide synthase in the spinal cord and brain and induce neurotrophins (88). In clinical studies of demyelination, evidence of neuro-protection would typically include long-term clinical mon-itoring 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). CONCLUSIONS 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. 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