Vitamin D in neurologic disorders …

Douglas J Lanska MD MS MSPH

Neuroimmunology

Updated 05.22.2024
Released 09.24.2012
Expires For CME 05.22.2027

Vitamin D in neurologic disorders

Author: Douglas J Lanska MD MS MSPH

See Contributor Disclosures

Vitamin D in neurologic disorders

In This Article

Quick Link

Introduction

Overview

Vitamin D status has been associated with a variety of neurologic disorders, including multiple sclerosis, cognitive impairment, Parkinson disease, and stroke, among others. This article describes the role of vitamin D in the healthy brain as well as the mechanisms by which vitamin D may provide immune modulation and neuroprotection in the diseased brain. The current evidence regarding the impact of vitamin D on the development and treatment of other neurologic diseases is described, with an emphasis on multiple sclerosis.

Key points

	• Vitamin D status is associated with the incidence and prevalence of a variety of neuromuscular and neurologic disorders, including osteomalacic myopathy and multiple sclerosis.
	• Vitamin D status also influences the risk of adverse outcomes in patients with neurologic diseases who are prone to fall, including the risk of hip and spinal compression fractures and other fragility fractures.
	• Vitamin D receptors are found throughout the CNS. Receptor-mediated benefits for reducing CNS damage include anti-immune activation and neuroprotection.
	• Supplementation with vitamin D may improve outcome in select neuroimmune and neurodegenerative neurologic disorders, but available studies to date have not provided convincing evidence that vitamin D treatment improves either the frequency of relapses, measures of disability, or measures of disease activity on MRI in patients with multiple sclerosis.

Historical note and terminology

The discovery of vitamin D (the “sunshine vitamin”) began with Scottish physician Theobald Palm’s observation in the 1890s that rickets primarily affected children in the industrial cities of Europe, whereas those in more sun-exposed areas of Southeast Asia and Japan were unaffected (34; 21). A leading hypothesis at the time was that affected children in Europe had succumbed to an infectious source that caused bone deformities and fractures, yet despite the rampant infections Palm encountered on his Asian travels, those children were not affected by rickets. He surmised that a lack of sunlight exposure was the causative factor, and this was confirmed shortly thereafter by observational studies showing that children who had moved from low-light industrial areas to higher elevations or the countryside subsequently had improved bone health. In 1918, American biochemist Elmer McCollum (1879-1967) identified vitamin D as the crucial nutrient in cod liver oil, which was used at that time to prevent or cure rickets (96; 56; 29). When combined with Palm’s earlier observations about rickets, the connection between vitamin D and sunlight became clear. Vitamin D was quickly supplemented in diets globally, and nutritional rickets was essentially eradicated.

Vitamin D is a hormone, and many authors describe it as vitamin D hormone. It is a vitamin only under certain environmental conditions of inadequate exposure to ultraviolet light. Vitamin D plays an essential role in regulating calcium and phosphate homeostasis, but it also has broader roles that include roles in neural development and neurotrophic signaling.

Vitamin D has been suggested as a causal or disease-modifying factor in a wide variety of neurologic, neuropsychiatric, and neuromuscular conditions, including multiple sclerosis, dementia, stroke, migraine, sudden sensorineural hearing loss, attention-deficit/hyperactivity disorder, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), post-herpetic neuralgia, and osteomalacic myopathy. Further study revealed a strong association between low vitamin D levels and increased multiple sclerosis rates, and this stimulated extensive research efforts to define the immune and genetic mechanisms by which vitamin D may influence the disease. Vitamin D status also influences the risk of adverse outcomes in patients with neurologic diseases who are prone to fall, including the risk of hip and stroke spinal compression fractures and other fragility fractures.

This review is focused on major neurologic disorders of the central nervous system, particularly multiple sclerosis, dementia or Alzheimer disease, Parkinson disease, and stroke. The plethora of other associations is outside the scope of this review. Most of the identified associations are based on low-quality evidence from cross-sectional studies, without sufficient attention to potential biases and confounders, and most fail to adequately consider the possibility that behavioral changes associated with disease may result in low vitamin D levels (eg, due to less activity and sun exposure). One exception with significant biological plausibility is the association of low 25(OH)D levels with benign paroxysmal positioning vertigo (49; 57; 24), but an assessment of this issue is outside of the scope of this article.

Description

	• The synthesis of vitamin D in the body involves several steps across different organs and involves different enzymes and carrier molecules.
	• Endogenous vitamin D is synthesized in the epidermis and dermis.
	• 7-dehydrocholesterol absorbs ultraviolet B (UVB) radiation, leading to the formation of previtamin D.
	• Previtamin D isomerizes to vitamin D3 and then enters the circulation attached to vitamin D–binding protein.
	• Exogenous vitamin D constitutes a much smaller proportion of total body vitamin D and comes from dietary and supplement sources such as vitamin D3 (cholecalciferol) from animal sources and vitamin D2 (ergocalciferol) plant and fungal sources.
	• Forms of exogenous vitamin D are also bound to vitamin D–binding protein and then, along with the endogenous forms, are hydrolyzed in the liver into calcidiol, ie, 25-hydroxy vitamin D [25(OH)D].
	• Serum total 25(OH)D is the most accurate measurement of body vitamin D concentrations because it accounts for dietary and endogenous sources and has a longer half-life than other forms.
	• 25(OH)D is transported to the proximal tubule of the kidney where it is further hydrolyzed into the active form, 1,25(OH)2D (calcitriol), although cells in many other sites, including in the CNS, are capable of similarly hydrolyzing calcidiol into active calcitriol.
	• 1,25(OH)2D exerts its actions through vitamin D receptors found on cells throughout the body.
	• Vitamin D insufficiency/deficiency is associated with the following: (1) reduced sunlight exposure and intensity; (2) malabsorption or protein-wasting syndromes; (3) enzyme-inducing antiepileptic medications; (4) disorders associated with higher vitamin D metabolism (sarcoidosis, tuberculosis, primary hyperparathyroidism); and (5) mutations in the genes involved in vitamin D synthesis and breakdown.

Synthesis. Vitamin D synthesis in the body involves several steps across different organs and involves different enzymes and carrier molecules.

Vitamin D synthesis in humans

Synthesis of vitamin D in humans. Source: OpenStax College (2013). (Courtesy of Wikimedia Commons. Creative Commons Attribution 3.0 Unported.)
Graphical description of vitamin D synthesis in humans

Legend: CYP24A1 = cytochrome P450 2741, commonly known as 1,25-dihydroxyvitamin D3 24-hydroxylase; CYP27A1 = cytochrome P450 27A1, commonly known as sterol 27-hydroxylase; CYP27B1 = cytochrome P450 27B1, commonly known as 25-hydro...

Endogenous vitamin D is synthesized in the epidermis and dermis. 7-dehydrocholesterol absorbs ultraviolet B (UVB) radiation, leading to the formation of previtamin D.

7-dehydrocholesterol conversion to previtamin D

Conversion of 7-dehydrocholesterol to previtamin D by ultraviolet B radiation in the epidermis and dermis Source: NEUROtiker (2009). (Courtesy of Wikimedia Commons. Public domain.)

Previtamin D isomerizes to vitamin D3 and then enters the circulation attached to vitamin D-binding protein.

Previtamin D conversion to vitamin D3

Conversion of previtamin D to vitamin D3 (cholecalciferol) by isomerization

Exogenous vitamin D constitutes a much smaller proportion of total body vitamin D and comes from dietary and supplement sources as vitamin D3 (cholecalciferol) from animal sources, and as vitamin D2 (ergocalciferol) plant and fungal sources.

Vitamin D3 (cholecalciferol)

Source: Calvero (2007). (Courtesy of Wikimedia Commons. Public domain.)
Vitamin D2 (ergocalciferol)

Source: Calvero (2007). (Courtesy of Wikimedia Commons. Public domain.)

These forms are similarly bound to vitamin D-binding protein and then, along with the endogenous forms, they are hydrolyzed in the liver into 25(OH)D (calcidiol).

Cholecalciferol enzymatic conversion to calcidiol

Enzymatic conversion of cholecalciferol to calcidiol by cholecalciferol 25-hydroxylase, a step in the biosynthesis of the active form of vitamin D3. Source: Robert Allen (2010). (Courtesy of Wikimedia Commons. Public domain.)
25-hydroxy-vitamin D (Calcidiol)

Source: NEUROtiker (2007). (Courtesy of Wikimedia Commons. Public domain.)

This is the major circulating form of vitamin D, and serum total 25(OH)D is the most accurate measurement of body vitamin D concentrations, as it accounts for dietary and endogenous sources and has a longer half-life than other forms. 25(OH)D is transported to the proximal tubule of the kidney, where it is further hydrolyzed into the active form, 1,25(OH)2D (calcitriol), although cells in many other sites, including in the CNS, are capable of similarly hydrolyzing calcidiol into active calcitriol.

Calcidiol conversion to calcitriol

Enzymatic conversion of calcidiol to calcitriol by 25-hydroxyvitamin D3 1-alpha-hydroxylase. Source: Robert Allen (2010). (Courtesy of Wikimedia Commons. Public domain.)
1,25-dihydroxy-vitamin D (calcitriol)

(Courtesy of Wikimedia Commons. Public domain.)

Regulation. Prolonged sun exposure leads to an increase in skin melanocytes. Melanin competes with dehydrocholesterol for absorption of UVB rays, effectively leading to a negative feedback mechanism to regulate vitamin D production. Additionally, parathyroid hormone (PTH) can stimulate production of 1,25(OH)2D through increased hydroxylation in the kidney. 1,25(OH)2D decreases its own production by a blockade of PTH release.

Neurophysiology. 1,25(OH)2D exerts its actions through vitamin D receptors found on cells throughout the body. Those pertinent to neurologic disorders include CNS cells (neurons, astrocytes, and oligodendrocytes), microglia, and activated monocytes and B and T cells, in addition to sites throughout the musculoskeletal system (15; 83).

Proposed mechanisms of vitamin D deficiency in skeletal muscle atrophy

Deficiency leads to raised muscle protein breakdown via the ubiquitin-proteasomal pathway (UPP) and autophagy and upregulation of AMPK and members of the renin-angiotensin system. Whilst unclear, low vitamin D states may lead t...

The path by which vitamin D traverses the blood-brain barrier is uncertain, but both vitamin D receptors and the enzyme responsible for hydroxylation of vitamin D into its active form are present throughout neurons and glial cells, indicating that this is a well-regulated CNS mechanism (37). In vitro studies suggest vitamin D plays a role in both neural development and neurotrophic signaling. Additionally, vitamin D has neuroprotective effects in vitro in moderating neuronal damage from hyperexcitability in the presence of glutamate (74).

The neuroprotective effects of vitamin D may stem from a variety of mechanisms (83).

Vitamin D3 binding sites and signaling pathways

1,25(OH)2D3--active form of vitamin D3; CAMK2g--g subunit of calcium/calmodulin-dependent protein kinase 2; CAV-1--caveolin-1; L-VGCC--L-type voltage-gated calcium channel; MAPK--mitogen-activated protein kinase; PDIA3--protein...
Pathogenic mechanisms of neurodegenerative diseases and neuroprotective effects of different forms of vitamin D3 in experimental models of Alzheimer a...

Ab--amyloid b; BDNF--brain-derived neurotrophic factor; DA--dopamine; DAT--dopamine transporter; DOPAC--3,4-dihydroxyphenylacetic acid; GDNF--glial-derived neurotrophic factor; HVA--homovanillic acid; NGF--nerve growth factor; ...

Several studies have demonstrated that addition of 1,25(OH)2D3 to cell cultures causes either a reduction in levels of reactive oxygen species (ROS) or a mitigation of ROS toxicity. Vitamin D supplementation can additionally lead to localized elevations in nerve growth factors (neurotrophin 3 and growth-associated protein-3) (55), downregulation of voltage-sensitive calcium channels, and upregulation of calcium-binding proteins, thus, reducing the potential for damage from free calcium (140).

CNS immune functions. The modulatory role of vitamin D on the neurologic immune response is complex and multidimensional, based largely on studies with the experimental autoimmune encephalomyelitis (EAE) mouse model (113).

Effects of vitamin D on immune cells

(Source: Plantone D, Primiano G, Manco C, Locci S, Servidei S, De Stefano N. Vitamin D in neurological diseases. Int J Mol Sci 2022;24[1]:87. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Supplementation of vitamin D in mice prior to EAE induction prevents the EAE phenotype, and supplementation of vitamin D after EAE induction and disease onset prevents further progression (19). The mechanisms by which vitamin D can prevent or suppress EAE rely on inhibition of pathogenic CD4+ T cells (94) and a subsequent decline in CD4+ cell response to antigen presentation by monocytes, macrophages, microglia, and astrocytes. The mitigated immune activation involves at least the vitamin D receptor and IL10/IL10R signaling and possibly the function of Treg cells that are vital in controlling autoimmunity (133). In studies of patients with multiple sclerosis with higher vitamin D levels, the number of Treg cells is unchanged; however, the suppressive effects of the Treg cells are substantially increased compared to those with lower vitamin D levels.

Causes of vitamin D insufficiency and deficiency. Vitamin D insufficiency/deficiency is associated with reduced sunlight exposure and intensity, regardless of disease status. Persons with darker skin tones need a higher intensity of UVB exposure to produce the same amounts of vitamin D as those with lighter skin tones. However, given sufficient exposure to UVB, there seems to be no difference in the vitamin D synthesis pathways between people of different skin tones (23; 88). Additionally, patients with malabsorption or protein-wasting syndromes, on enzyme-inducing antiepileptic medications, or with disorders associated with higher vitamin D metabolism (sarcoidosis, tuberculosis, primary hyperparathyroidism) are all at higher risk for vitamin D deficiency (106). Finally, alterations in the genes involved in vitamin D synthesis and breakdown may lead to differences in vitamin D levels.

Issues of association and causality. With all the neurologic conditions that have been associated with multiple sclerosis, an important and often overlooked issue is whether the association is causal or noncausal and, if causal, in which direction causality exists. One possibility, for example, is that some level of vitamin D at a critical period may stimulate the development of multiple sclerosis. Various speculative mechanisms have been suggested as to why this might occur. A second possibility is that the observed association may operate the other way—ie, that multiple sclerosis might lead to a change in vitamin D levels. In fact, this is not speculative because moderate or severe multiple sclerosis is associated with much greater disability, which leads to less activity and less sun exposure, thereby resulting in lower levels of vitamin D (107). A third possibility is effect modification, ie, the magnitude of the effect of the primary exposure on an outcome (ie, the association) differs depending on the level of a third variable. For example, age may be an effect modifier in a causal association between vitamin D deficiency and incident multiple sclerosis: vitamin D deficiency at a very young age may trigger a sequence of biochemical or immunological changes that lead to the development of multiple sclerosis, whereas it will have no effect at an older age. There is still a causal relationship, but it only operates during a critical window. When a crude analysis is done, there is a modest association. However, when a stratified analysis is done, there is a strong association at a young exposure age, but no association at an older exposure age. Note, though, that effect modification does not necessarily imply causality: effect modification can operate with both causal and noncausal associations.

Direct causal relationship between a putative exposure (vitamin D deficiency) and an outcome (multiple sclerosis)

The bold arrow indicates the direction of causality. (Contributed by Dr. Douglas J Lanska.)
Reversed causal association between vitamin D deficiency and multiple sclerosis

The bold arrow indicates the direction of causality. (Contributed by Dr. Douglas J Lanska.)
Crude and stratified analyses with effect modification: the strength of the association varies by a third variable

In this case, the effect of vitamin D deficiency on the development of multiple sclerosis varies by age of exposure to vitamin D deficiency. Note, however, that effect modification does not necessarily imply causality: effect m...

In the prior possibilities, there is a causal relationship between vitamin D levels and multiple sclerosis, but the direction of causality differs, or the strength of association varies, with an additional variable. There are additional ways that vitamin D levels and multiple sclerosis can be associated but without a causal relationship: (1) bias, in which a systematic error in the design, recruitment, data collection, or analysis results in a mistaken estimation of the true effect of an exposure on the outcome; and (2) confounding, in which there is an unmeasured variable, the confounding variable, that influences both the supposed cause and effect. However, for a confounding variable to explain the observed association between two other variables, it has to be at least as strongly associated with each of these other variables. Importantly, when an analysis is stratified analysis by the confounding variable, there is no association between the exposure (vitamin D deficiency) and the outcome (multiple sclerosis) at each level of the confounding variable.

A possible form of confounding

The bold arrows indicate the direction of causality. The thin crossed arrow indicates that there is no causal relationship. (Contributed by Dr. Douglas J Lanska.)
Crude and stratified analyses with a confounding variable

An association between a putative exposure and an outcome may be present in a crude analysis but is eliminated when stratifying by the confounding variable. (Contributed by Dr. Douglas J Lanska.)

The Bradford-Hill criteria for establishing an association as causal include the following: (1) strength of the association (the stronger the association between a risk factor and outcome, the more likely the relationship is to be causal); (2) consistency of findings (eg, observing the same findings among different populations, in different study designs, and different times); (3) specificity of the association (1-to-1 relationship between cause and outcome); (4) temporal sequence of association (ie, exposure must precede outcome); (5) biological gradient (ie, a change in disease rates should follow from corresponding changes in exposure, or in other words there is a dose-response relationship); (6) biological plausibility (ie, the presence of a potential and plausible biological mechanism); (7) coherence (ie, does the relationship agree with current knowledge of the natural history and biology of the disease?); and (8) experiment (eg, does experimentally altering the exposure alter the frequency of the outcome?) (53).

For example, the Bradford-Hill criteria have not yet been met to demonstrate that vitamin D status causes multiple sclerosis, and even if there is a causal relationship between vitamin D status and multiple sclerosis, it is not clear whether at least part of the relationship is due to lower sun exposure in less active individuals with significant neurologic disease and associated disability. The same issue applies to other neurologic disorders for which associations with vitamin D status have been reported, including Parkinson disease, cognitive dysfunction, myasthenia gravis, etc. Thus, vitamin D levels in individuals with diseases may serve simply as a sickness index, with low vitamin D levels correlated with greater sickness or disability. Simply recognizing vitamin D deficiency shortly before clinical recognition of a neurodegenerative disorder does not imply that vitamin D deficiency caused or accentuated the neurodegenerative disorder; in many of the published studies like this (eg, Alzheimer disease, Parkinson disease, etc.), it is likely that the neurodegenerative was present and may have contributed to the development of vitamin D deficiency rather than the other way around, if the two have anything at all to do with one another.

Accepting these major caveats about reported associations between numerous diseases and vitamin D levels, there are still potential benefits of recognizing and correcting low vitamin D levels in people with, for example, an existing disability that limits their activity and, therefore, their sun exposure. For example, low vitamin D levels contribute to falls as well as falls with injuries (eg, fractures).

Clinical applications

	• One major potential confounding factor in association studies of vitamin D and various neurologic disorders is that 25(OH)D is a proxy for UVB radiation from sunshine, which in turn is associated with functional ability, independence, and self-determined behaviors.
	• Simply demonstrating an association of vitamin D with any neurologic disorder should not be interpreted as proof that vitamin D caused the neurologic disorder in question.
	• Although lower levels of vitamin D have been associated with worse prognosis in various neurologic disorders, it is unclear if this is because low vitamin D levels contribute to disease progression or if, instead, low vitamin D levels serve as a marker for more profound functional impairment, effectively selecting individuals with more severe disease.
	• Several lines of evidence suggest or support an important role for vitamin D in the pathophysiology of multiple sclerosis.
	• Results from longitudinal studies evaluating the association of vitamin D with incident dementia and cognitive impairment have been inconsistent.
	• The Institute of Medicine currently estimates the daily requirement of vitamin D is 400 IU/day but recommends a dietary allowance of 600 IU/day for those more than 1 year old to 70 years old.
	• Vitamin D deficiency in the general population is generally defined as 25(OH)D levels of less than 20 ng/ml and insufficiency as less than 30 ng/mL.
	• A common replacement strategy for vitamin D deficiency is to treat with 50,000 IU D2 capsules weekly for 8 to 12 weeks followed by 1000 to 2000 IU D3 daily.
	• Life-threatening vitamin D intoxication has been reported due to intake of ultra-high doses in patients with multiple sclerosis (exceeding 50,000 units of cholecalciferol per day over several months).
	• A calcium level should be checked after 1 month on a high-dose vitamin D2 regimen, and in any case, it is advisable to recheck a 25(OH)D level after several months of replacement if prior levels were deficient.
	• The appropriate levels of 25(OH)D in people with neurologic disorders are unknown, and it may be that the target levels differ by disease state.

One major potential confounding factor in association studies of vitamin D and various neurologic disorders is that 25(OH)D is a proxy for UVB radiation from sunshine, which in turn is associated with functional ability, independence, and self-determined behaviors (107). Thus, simply demonstrating an association of vitamin D with any neurologic disorder should not be interpreted as proof that vitamin D caused the neurologic disorder in question. Consequently, although people with Parkinson disease and stroke have lower vitamin D levels than those without these diseases, it is unclear if this is because low vitamin D levels contribute to disease risk or if, instead, this is simply a consequence of immobility and other factors caused by the disease (145). Similarly, although lower levels of vitamin D have been associated with worse prognosis in multiple sclerosis, Parkinson disease, amyotrophic lateral sclerosis, and stroke, it is unclear if this is because low vitamin D levels contribute to disease progression or if instead low vitamin D levels serve are a marker for more profound functional impairment, effectively selecting individuals with more severe disease (145). Among people with multiple sclerosis with low-grade disability, physical activity was positively associated with vitamin D levels, independent of estimated sunlight exposure time (12).

Ultraviolet light suppression of experimental autoimmune encephalomyelitis (a mouse model of multiple sclerosis) is independent of vitamin D and its receptor (61).

Multiple sclerosis. Several lines of evidence suggest or support an important role for vitamin D in the pathophysiology of multiple sclerosis but do not prove a causal relationship, alone or collectively (122; 111; 127): (1) the striking geographic distribution of multiple sclerosis that correlates with sun exposure; (2) seasonal fluctuations in multiple sclerosis risk according to month of birth; (3) the reduction in multiple sclerosis severity during pregnancy, when vitamin D levels are physiologically elevated; (4) the increased risk of multiple sclerosis with vitamin D deficiency; and (5) the increased frequency of exacerbations and the increased rate of progression among patients with multiple sclerosis who are vitamin D deficient.

Geographic distribution. Multiple sclerosis has increased prevalence in geographic areas with lower sunlight levels (109), including places further from the equator but also within relatively small areas such as Switzerland, where multiple sclerosis is more common at lower elevations with less sunlight intensity.

International distribution of disability-adjusted life years per 100,000 for multiple sclerosis

International distribution of disability-adjusted life years per 100,000 for multiple sclerosis. (Attribution: Lokal Profil Map. Modified by Douglas Lanska. Data source: World Health Organization. Organisation Mondiale de la Santé...

This observation led to the theory that a lack of sunlight exposure was associated with the development of multiple sclerosis. Later, variations in sun exposure led to the idea that vitamin D was the intermediary responsible for the observed geographical variations in multiple sclerosis frequency. However, sun exposure may have direct effects on MRI measures of neurodegeneration in multiple sclerosis independent of vitamin D levels (149). In one study, increased summer sun exposure was associated with increased grey matter volume and increased total brain volume after adjustment for disability, whereas inclusion of 25(OH)D levels did not substantially affect this association (149).

The prevalence of multiple sclerosis increases by up to 10-fold between the equator and 60° north and south (121). The drivers of this gradient are thought to be environmental, with latitude serving as a proxy for ultraviolet radiation and, thus, vitamin D production. Utilizing lifetime residence calendars collected as part of the New Zealand National Multiple Sclerosis Prevalence Study, the authors constructed lifetime latitudinal gradients for multiple sclerosis from birth to "prevalence day" in 2006. Of 2127 subjects who completed the life course questionnaire, 1587 (75%) were born in New Zealand. The prevalence gradient was present at birth and at birth was, in fact, stronger than at census day. The slope of the gradient persisted until the age of 12 before gradually declining. Internal and external migration into New Zealand had little effect on the gradient except to somewhat decrease the significance of the gradient. The lifetime prevalence gradients were largely driven by females with relapsing-remitting multiple sclerosis.

Month of birth. A large study of over 25,000 patients with multiple sclerosis in England and Scotland found that the monthly distribution of births for the combined risk of multiple sclerosis and other immune-mediated diseases differed from that of the general population, with a peak in April and a trough in October. Risk of multiple sclerosis showed a seasonal pattern (62). Additionally, there were significant inverse correlations between the combined risk of multiple sclerosis and other immune-mediated diseases, estimates of UVB exposure during the second trimester, and vitamin D levels during the third trimester (31).

Migration. Results of migration studies showed an increased risk of multiple sclerosis if migration from high- to low-risk areas occurred after 15 years of age, whereas risk of multiple sclerosis was reduced for those migrating earlier in life (ie, before 15 years of age) (62).

Pregnancy. The prevalence of vitamin D deficiency is higher among pregnant women with multiple sclerosis than among pregnant controls without multiple sclerosis (64). The risk of multiple sclerosis relapse during pregnancy is significantly lower for women than in the postpartum period (26), possibly resulting from variations in 25(OH)D levels during pregnancy and postpartum. However, data regarding the association of vitamin D levels and relapses in the postpartum period do not necessarily support this hypothesis, and it is likely that other factors in addition to vitamin D contribute to relapses in the postpartum period (79).

A meta-analysis of four case-control studies assessed the association between gestational vitamin D levels and the risk of multiple sclerosis in offspring (66). Higher levels of gestational vitamin D had a significant protective effect on risk of multiple sclerosis in offspring.

Seasonal variations in vitamin D levels reflect disability status. 25(OH)D levels are seasonal, with peak levels typically in July/August and nadir in January/February. The seasonal variation of 25(OH)D levels is inversely associated with clinical disease activity in patients with multiple sclerosis, with the nadir of 25(OH)D levels preceding the peak in the prevalence of relapses by two months (51), but this may simply be due to the relationship between vitamin D levels and disability and activity.

A study from Japan came to similar conclusions (107). Serum 25(OH)D levels were significantly lower in spring than in summer and autumn. Seasonal fluctuations in 25(OH)D were demonstrated in patients with Expanded Disability Status Scale (EDSS) scores of 3.5 or less, but not in those with scores of 4.0 or more. Furthermore, negative correlations between 25(OH)D levels and measures of disability were found in each season: the disability measures used were the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS, which combines the EDSS and disease duration in an attempt to stratify patients with multiple sclerosis by rate of progression) (107). The authors appropriately concluded that seasonal fluctuations in 25(OH)D levels may be affected by physical disabilities (107).

In a study of the relationship between serum 25(OH)D levels and age of first symptom onset among 40 recently diagnosed multiple sclerosis patients, the authors observed bias among previously reported associations between 25(OH)D and multiple sclerosis disease measures resulting from the nonrandom distribution of sampling by season (136). After correcting for seasonal 25(OH)D, the serum 25(OH)D level was not correlated with age at onset.

Vitamin D metabolism and gene-vitamin D interactions and their influence on the development and course of multiple sclerosis. Gene-vitamin D interactions influence the development and course of multiple sclerosis (125; 69; 77; 86; 13; 07). Unfortunately, available data are contradictory about these gene polymorphisms and their impact on the development and course of multiple sclerosis (35). A study of genes involved in the vitamin D signaling pathway in families with more than one member affected by multiple sclerosis did not identify any gene variants that could explain the presence of the disease (115). However, a meta-analysis of 30 case-control studies suggested significant associations between several vitamin D receptor (VDR) gene polymorphisms and multiple sclerosis susceptibility; specifically, the TaqI polymorphism was associated with multiple sclerosis susceptibility, and two others were associated with multiple sclerosis susceptibility in Asian populations (ie, the BsmI polymorphism with increased risk, and the ApaI polymorphism with decreased risk) (60).

Several cytochrome P450 (CYP) components are involved in vitamin D metabolism. CYP2R1 encodes vitamin D 25-hydroxylase, a microsomal hydroxylase enzyme that converts vitamin D into the active ligand for the vitamin D receptor. A polymorphism of the gene encoding one of the vitamin D hydroxylation enzymes (CYP2R1) is associated with a reduced risk of multiple sclerosis, and this association was stronger in patients negative for the multiple sclerosis susceptibility haplotype HLA-DR15 (125). In contrast, heterozygote carriers of a low-frequency (minor allele frequency = 2.5%) synonymous coding variant of CYP2R1 (ie, g.14900931G> A (p.Asp120Asp) (rs117913124[A])) have an increased risk of vitamin D insufficiency and an increased odds of multiple sclerosis (92). A rare variant in the CYP27B1 gene encoding a vitamin D-activating enzyme confers a significant increase in the risk of developing multiple sclerosis (77), but other studies have not found a substantial independent effect of genetic variants of CYP27B1 on the risk of multiple sclerosis (03).

CYP24A1 encodes mitochondrial 1,25-dihydroxyvitamin D(3) 24-hydroxylase, catalyzing the degradative hydroxylation of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 into 24-hydroxylated products. In a nested case-control study of patients with multiple sclerosis and controls, patients with multiple sclerosis and CC genotype of rs2248137 CYP24A1 had significantly lower serum 25(OH)D3 levels than those with GG and GC genotype (04).

In addition, protein kinase C genes may modulate the association between 25(OH)D and multiple sclerosis relapse because the relationship between 25(OH)D level and the hazard of relapse varied significantly for different alleles of intronic single-nucleotide polymorphisms in the protein kinase C gene family.

Other studies have had conflicting results concerning the risk of multiple sclerosis with the vitamin D receptor polymorphisms Taq1, Fok1, and Bsml, although several studies have reported that the risk of multiple sclerosis for these polymorphisms is also dependent on the presence of the HLA-DR15 haplotype (50; 22; 13; 71; 146; 30; 99). One study has suggested that the Bsml VDR gene polymorphism is associated with the decreased susceptibility to multiple sclerosis in the Slovak population (22), whereas another found a significant positive association between multiple sclerosis and the T/T genotype of BsmI polymorphism (13). An association between multiple sclerosis susceptibility and the FokI ff genotype was found in one Portuguese study, but not with disease form or progression (14).

Although most circulating vitamin D metabolites are bound to vitamin D binding protein, inconsistent associations have been demonstrated between vitamin D binding protein concentrations and measures of occurrence or progression of multiple sclerosis (130; 90), and genotypic variants in vitamin D binding protein have not been shown to have an independent effect on the risk of multiple sclerosis (03; 147). In one study, higher 25(OH)D levels were associated with a lower risk of multiple sclerosis in whites who carried at least one copy of the C allele of the rs7041 vitamin D-binding protein polymorphism, but no association was found in white AA carriers, blacks, or Hispanics (80).

In a cohort of 100 multiple sclerosis patients, Agnello and colleagues evaluated the possible influence of several single nucleotide polymorphisms (SNPs) in vitamin D-related genes on multiple sclerosis severity (05). They genotyped 18 SNPs in the following genes: NAD synthetase 1 (NADSYN1), CYP2R1, vitamin D binding protein (group-specific component; GC), vitamin D receptor (VDR), retinoid X receptor-α (RXRA), klotho (KL), CYP24A1, and CYP27A1. No significant associations were identified between SNPs, alone or in combination, and multiple sclerosis severity.

In multiple sclerosis patients, two months of vitamin D treatment significantly altered the expression of DNA repair genes (MYH, OGG1, MTH1, and NRF2) (07).

Although it is still unclear whether differences in vitamin D-associated single nucleotide polymorphisms (SNPs) cause differences in multiple sclerosis incidence or disease course, different SNPs may affect the metabolic effects of vitamin D supplementation. In a study of 34 subjects, the SNPs related to vitamin D binding protein showed no difference in 25(OH)D levels at baseline, but carriers of the rs7041 risk allele showed lower 25(OH)D levels compared to noncarriers after 48 weeks of supplementation (98). Similarly, for SNPs related to the vitamin D metabolism enzymes CYP27B1 and CYP24A1, neither showed a difference at baseline, but carriers of the rs12368653 risk allele showed higher 25(OH)D levels compared to noncarriers after 48 weeks of supplementation.

Influence of vitamin D status on putative risk factors for multiple sclerosis. 25(OH)D levels are inversely correlated with antibody reactivity against Epstein-Barr nuclear antigen-1 (123). Nearly all patients with multiple sclerosis show serological markers of past Epstein-Barr virus infection, and the proportion of Epstein-Barr virus-positive individuals is positively associated with latitude, independent of multiple sclerosis status (32). The relationship between vitamin D levels, prior Epstein-Barr virus infection, and the development of multiple sclerosis is still uncertain.

Influence of vitamin D status on immunological biomarkers in multiple sclerosis. Results of studies concerning the effects of vitamin D on inflammatory markers have been inconsistent (09; 105; 119; 39; 52). Several studies found that vitamin D3 intake influences anti- and proinflammatory cytokines (eg, transforming growth factor beta 1 or TGF-β1, interleukin 10 or IL-10, etc.), suggesting that high-dose vitamin D might promote an anti-inflammatory state in these patients (09; 105; 39; 52). Other studies, however, found that high-dose oral vitamin D3 supplementation prominently increased serum 25(OH)D levels without affecting markers of systemic inflammation (119).

In patients with relapsing-remitting multiple sclerosis, vitamin D deficiency is associated with decreased interferon-γ secretion by CD4+ T cells and a negative correlation between baseline serum vitamin D and interferon-γ production (102).

Vitamin D deficiency and multiple sclerosis incidence and prevalence. Observational studies have shown that patients with multiple sclerosis have lower mean 25-hydroxy vitamin D levels than healthy controls (73; 114), but whether this is a causal or noncausal association has not been clear (33; 139). Patients with multiple sclerosis also have a high incidence of osteopenia and osteoporosis (73), which is likely to be multifactorial, with contributions including lower mobility, lower vitamin D levels, and medication effects (eg, corticosteroids).

Several studies have suggested that low vitamin D levels increase the incidence of multiple sclerosis. In a retrospective study of 100 hospitalized patients with clinically isolated syndromes, low serum vitamin D levels were associated with an increased risk of developing multiple sclerosis during a median follow-up of 7 years (93). Among Caucasian United States military personnel, multiple sclerosis incidence decreases by 41% for every 20 ng/ml (50 nmol/L) greater serum 25(OH)D (103). However, 25(OH)D levels at birth were not associated with a later risk of developing multiple sclerosis (141).

Adolescence seems to be a vulnerable period for the action of vitamin D in terms of multiple sclerosis incidence. In the Norwegian component of the multinational case-control study Environmental Factors In Multiple Sclerosis, self-reported vitamin D supplement use (in the form of cod liver oil) at 13 to 18 years of age was associated with a reduced risk of multiple sclerosis, whereas supplementation during childhood did not alter the risk of developing multiple sclerosis (28). In a cross-sectional study that included 1161 Danish patients with multiple sclerosis, younger age at onset was significantly associated with low exposure to summer sun in adolescence (84; 85).

In a case-control study of incident multiple sclerosis, higher serum 25(OHD) levels were associated with a lower risk of multiple sclerosis in whites but not in Hispanics or blacks (81). The aberrant results for Hispanic and black patients challenge the biological plausibility of vitamin D deficiency as a cause of multiple sclerosis (81).

In a nested case-control study performed with presymptomatic serum samples identified through cross-linkage of multiple sclerosis registries and Swedish biobanks and involving 660 pairs of matched cases and controls, levels of free 25(OH)D3 were inversely associated with subsequent risk of multiple sclerosis (47).

Vitamin D deficiency and relapse risk, disease activity on MRI, clinical manifestations, and clinical progression in multiple sclerosis. Additionally, 25-hydroxy vitamin D levels are inversely associated with subsequent relapse rate in children and adults (100; 126; 08) and with disability progression (101; 08) in multiple studies, even if not all studies were able to confirm these results (42). Those with lighter skin coloration (ie, more ready synthesis of vitamin D in the skin with exposure to sunlight) have decreased odds of disability (Expanded Disability Status Scale scores ≥ 6) compared to those with darker skin tones (144). In a cross-sectional study, controlling for intelligence and disease duration (but not severity), higher vitamin D levels were associated with better nonverbal performance in patients with multiple sclerosis (76).

In a cross-sectional study of Mexican patients with relapsing-remitting multiple sclerosis, no association was found between vitamin D levels and Expanded Disability Status Scale (EDSS) scores, annualized relapse rates, rates of progression (measured with a progression index), or duration of disease (117).

In a Moroccan population of patients with multiple sclerosis, there was no association between serum levels of vitamin D and multiple sclerosis, type of multiple sclerosis, degree of disability, or disease severity (128).

In a cohort study as part of the BENEFIT trial (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment), 278 patients with clinically isolated syndrome completed the 11-year assessment; lower vitamin D levels after clinical onset predicted worse long-term cognitive function and neuronal integrity (as judged by serum neurofilament light chain concentrations) (27).

In this prospective cohort study of 88 patients with relapsing-remitting multiple sclerosis, higher seasonally adjusted 25(OH)D levels were associated with lower 10-year EDSS progression, an association driven mainly by low 25(OH)D levels during spring, as well as seasonally adjusted levels below 80 nmol/L (143).

A scoping review of vitamin D and depressive symptoms in adults with multiple sclerosis noted that of the 11 selected studies, seven showed a "potential correlation between low vitamin D levels and depressive symptoms" (25). By itself, this is impossible to interpret. It may simply be explained by vitamin D levels serving as a surrogate measure of disability status and disability being a confounder of the apparent association between vitamin D and depression.

In a systematic review to assess the effects of vitamin D supplementation on clinical and imaging outcomes in patients with multiple sclerosis, most of the 15 trials investigating relapse events reported no significant effect of vitamin D supplementation, and 8 of 13 randomized controlled trials found that vitamin D supplementation had no effect on disability compared to controls, but recent trials reported a significant reduction in new MRI lesions in the CNS of multiple sclerosis patients during supplementation with vitamin D3 (82).

In a randomized, controlled clinical trial conducted in Australia and New Zealand to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome delays time to conversion to definite multiple sclerosis, vitamin D3 supplementation was safe and well tolerated, but no reduction in multiple sclerosis disease activity by vitamin D3 supplementation was demonstrated after a high-risk clinically isolated syndrome (17).

A metaanalysis of five studies with 345 individuals found that a significant reduction in fatigue was perceived in people with multiple sclerosis when vitamin D supplementation was compared with a placebo (89).

Vitamin D deficiency and disease activity on MRI. Low 25-hydroxy vitamin D levels early in the disease course (first 12 months) are also associated with a significantly higher rate of new active lesions on MRI, and a higher yearly increase in T2 lesion volume (101; 08; 40). In a large cohort study of 469 patients with either clinically isolated syndrome or relapsing-remitting multiple sclerosis, 25-hydroxy vitamin D levels were inversely correlated with disease activity on MRI over five years of longitudinal follow-up. Every 10 ng/ml increase in serum 25(OH)D was associated with a 15% reduction in the risk of a new T2 lesion and a 32% reduction in the risk of a new T1 gadolinium-enhancing lesion (101). In a prospective cohort study of 1482 patients with RRMS, assessing 25(OH)D levels and subsequent disease course, average 25(OH)D levels were significantly inversely correlated with the cumulative number of new active lesions on MRI, with a 50.0 nmol/L increase in serum 25(OH)D levels associated with a 31% lower rate of new lesions, and with the lowest rate of new lesions observed among patients with 25(OH)D levels greater than 100.0 nmol/L (42).

In a prospective cohort study of 133 patients with relapsing-remitting multiple sclerosis, there were no statistically significant correlations between clinical outcomes and vitamin D serum levels or supplementations, but significantly fewer new T2-weighted lesions were observed in patients with vitamin D supplementations in 24 months of observation (43); moreover, an optimal or higher level of vitamin D (> 30 ng/mL) maintained throughout the entire observation period was associated with a significantly lower number of new T2-weighted lesions in 24 months of observation.

25-hydroxy vitamin D levels are not associated with brain volume or lesional measures in progressive multiple sclerosis, contrary to what has been described in relapsing-remitting multiple sclerosis (01).

Treatment trials of vitamin D in multiple sclerosis. In a year-long randomized, open-label trial for 49 patients with mostly relapsing-remitting multiple sclerosis (45 of the 49 patients) of either escalated-dose vitamin D (maximum of 28,000 IU/day) or up to 4000 IU/day in the control group, the intervention group had a reduced rate of relapse compared with the control group (16). Because the trial was open-label and the control group was allowed to take meaningful levels of vitamin D supplementation, the results are not conclusive for efficacy.

In a double-blind, placebo-controlled trial of vitamin D3 supplementation for one year as adjunctive therapy to IFN-β in Finnish patients with multiple sclerosis, vitamin D supplementation with 20,000 IU weekly was associated with significant reductions in gadolinium-enhancing lesions on T1-weighted images as well as a trend toward reductions in both T2 lesion volume and Expanded Disability Status Scale (EDSS) scores (132). In a follow-up subgroup analysis examining those with more advanced multiple sclerosis (at least one clinical relapse in the year prior to study enrollment or at least one enhancing MRI lesion at baseline), the results were even more pronounced, suggesting that vitamin D supplementation may have additional benefit for patients with more aggressive multiple sclerosis (02).

In a smaller trial of vitamin D2 supplementation that was also randomized and double-blinded, there was no MRI difference after 6 months in patients receiving 6000 IU D2 compared to those receiving 1000 IU D2 (134). This study was limited by a small sample size of 23 patients and by the varied use of disease-modifying therapies for multiple sclerosis.

In a prospective cohort study of 170 patients with relapsing-remitting multiple sclerosis treated with natalizumab, correction of hypovitaminosis D by simply recommending oral vitamin D3 supplements resulted in significant increases in 25(OH)D serum levels, which were associated with decreases in the annualized relapse rates (84; 85).

In a randomized, double-blind, placebo-controlled clinical trial of high-dose vitamin D supplementation involving 94 patients with relapsing-remitting multiple sclerosis, mental quality of life improved significantly after taking high-dose vitamin D (50,000 IU of vitamin D3 every 5 days for 3 months) (10).

Unfortunately, the promising results in some studies are offset by negative results in other trials, so presently available low-quality evidence suggests no evident benefit of vitamin D treatment on clinically important outcomes among people with multiple sclerosis (65; 63; 148). A meta-analysis of studies published through 2012 encompassing 129 patients with multiple sclerosis treated with high-dose vitamin D and 125 controls with multiple sclerosis who were not treated found no significant association between high-dose vitamin D treatment and risk of multiple sclerosis relapses (65). Another meta-analysis of studies published through October 2017 identified 12 randomized controlled trials enrolling 933 participants with multiple sclerosis, 11 of which addressed treatment with vitamin D3 (63). After 52 weeks of follow-up, vitamin D3 had no effect on either the annualized relapse rate, the Expanded Disability Status Scale (EDSS) scores, or gadolinium-enhancing T1 lesions on MRI (63). A separate meta-analysis through October 2017 confirmed those results and concluded that vitamin D appeared to have no therapeutic effect on disability (based on the EDSS score or the annualized relapse rate in the patients with multiple sclerosis). Another meta-analysis found nonsignificant trends in favor of vitamin D for all outcome measures, particularly when only placebo-controlled studies were included (97).

In the SOLAR study, 229 patients with relapsing-remitting multiple sclerosis were randomized to high-dose vitamin D3 6670 IU/d orally for four weeks, followed by 14,000 IU/d for 44 weeks, or matching placebo in addition to ongoing treatment with subcutaneous used interferon-β-1a (59). At 48 weeks there was no significant difference in the primary endpoint, ie, the proportion of patients with no evidence of disease activity. Although the SOLAR study did not establish a benefit for high-dose vitamin D3 as add-on therapy interferon-β-1a, based on the primary outcome, findings from exploratory outcomes suggested some protective effects on development of new MRI lesions in patients with relapsing-remitting multiple sclerosis. Specifically, compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions on MRI, and for change from baseline in total volume of T2 lesions. In addition, in a supplemental report from this study, supplementation of high-dose vitamin D3 for 48 weeks was not associated with lower neurofilament light chain levels, a biomarker of disease activity and neuroaxonal injury in relapsing-remitting multiple sclerosis (129).

In the CHOLINE study, 181 patients with relapsing-remitting multiple sclerosis were randomized to high-dose oral vitamin D3 100,000 IU or placebo every other week for 96 weeks (18). Inclusion criteria were (1) a low serum 25(OH)D concentration (< 75 nmol/L or 30 ng/ml); (2) prior treatment with interferon beta-1a (44 μg subcutaneously three times per week) for 2 to 6 months before randomization; and (3) at least one documented relapse during the previous two years. The primary outcome measure was the change in the annualized relapse rate at 96 weeks. The treatment was well tolerated, but only about half of the patients in the treatment and control groups completed the two years of follow-up. Although the primary end point was not met, a potential treatment effect of cholecalciferol was nevertheless suggested based on modest effects on secondary endpoints, with a reduction in the annualized relapse rate, the number of new T1 lesions on MRI, the volume of hypointense T1 lesions, and disability progression.

None of the randomized controlled trials of vitamin supplementation in relapsing-remitting multiple sclerosis met their primary clinical endpoints in their intention-to-treat cohorts (59; 131). In contrast, in observation studies each 25 nmol/l increase in 25-hydroxyvitamin D levels was associated with a 14% to 34% reduction in relapse risk and a 15% to 50% reduced risk of new lesions on MRI (131). The discrepancy between the results of controlled trials and observational studies may be due to confounding and/or "reverse causality" in the observational studies (131).

Vitamin D status has no major influence on IFN-β1a treatment effects (118; 18; 59).

The Multiple Sclerosis Society of Canada convened a panel of expert scientists, clinicians, and patient advocates to form recommendations for vitamin D intake in persons with multiple sclerosis (11).

For people at risk of developing multiple sclerosis, the panel's vitamin D recommendations were consistent with those for the general public in Canada and the United States: adults should ensure a daily intake of 600 to 4000 IU vitamin D to achieve and maintain a normal vitamin D status corresponding to a serum 25(OH)D level of 50 to 125 nmol/L. The panel recommended monitoring 25(OH)D levels in pregnant women, newborn infants, and all youth at risk of multiple sclerosis.

For persons living with multiple sclerosis, the existing evidence did not allow prediction of a vitamin D intake that might modify the clinical course. The panel recommended measuring 25(OH)D levels in children and adolescents on diagnosis of a first clinical demyelinating event and monitoring 25(OH)D levels every 6 months during vitamin D supplementation to achieve a target of 25(OH)D level of 75 nmol/L (30 ng/ml). In addition, the panel emphasized the importance of achieving this minimum serum 25(OH)D concentration to protect bone health because people living with multiple sclerosis are at increased risk of osteoporosis, falls, and bone fractures.

A systematic review of vitamin D supplementation and mental health in patients with multiple sclerosis found that "there may be a positive effect of vitamin D supplementation in MS patients, which was stated in all of the studies analyzing quality of life, as well as in one study analyzing depressive symptoms" (46). However, the assessment and analytic level of this systematic review was low.

Cognitive impairment and dementia. Results from longitudinal studies evaluating the association of vitamin D with incident dementia and cognitive impairment have been inconsistent. Results from a prospective study of 858 Italians 65 years of age or older revealed that having a baseline 25(OH)D level below approximately 10 ng/ml (25 nmol/L) was associated with 1.6-fold increased risk (odds ratio of 1.6) for developing cognitive impairment compared to those with a baseline 25(OH)D level of approximately 30 ng/ml (70nmol/L) or more (87). Kuzma and colleagues presented somewhat contrasting results from two different cohort studies in the same paper. In a cohort study of 1291 participants from the U.S. Cardiovascular Health Study (CHS) who were dementia-free at baseline, severe vitamin D deficiency was associated with visual memory decline, whereas in a cohort study of 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, vitamin D deficiency was not associated with verbal memory decline (78). In a cohort of 1182 Swedish men (mean age of 71 years) followed for a median of 12 years, there was no association between baseline vitamin D status and long-term risk of dementia or cognitive impairment (108).

In a cross-sectional study of 146 patients with mild Alzheimer disease, reduced plasma 25(OH)D levels were associated with low Mini-Mental State Examination (MMSE) scores (124); the observed association was not attributable to differences in white matter hyperintensities on MRI.

In a large community-based sample of Framingham Heart Study participants, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function, but no association was found between vitamin D deficiency and either incident all-cause dementia or clinically characterized Alzheimer disease (72). In a study of healthy adults, because “supratherapeutic levels” of vitamin D were associated with significantly better performance on verbal fluency, the author suggested that 25(OH)D levels exceeding 40 ng/ml (100 nmol/L) may be optimal for at least some aspects of executive functioning (110); however, it may simply reflect that higher functioning individuals are more likely to take vitamin D supplements. In addition, although vitamin D deficiency has been associated with smaller hippocampal volume and poorer neuropsychological function in cohort studies, randomized trials have not demonstrated a benefit of vitamin D supplementation on improving cognition. In a randomized double-blind placebo-controlled trial of calcium and vitamin D supplementation (1000 mg of calcium carbonate and 400 IU of vitamin D3) in 4143 women aged 65 and older without probable dementia at baseline, there was no association between treatment assignment and incident cognitive impairment (120).

In another large community cohort from the Atherosclerosis Risk in Communities (ARIC) Study, midlife serum 25(OH) D concentrations were associated with incident dementia but not with performance on neuropsychological testing, functional ability, or depressive symptoms, 20 years later (38).

In a meta-analysis of 12 prospective cohort studies and four cross-sectional studies, there were significant associations between vitamin D deficiency and both dementia and Alzheimer disease; the associations were stronger between severe vitamin D deficiency (< 10 ng/ml) and both dementia and Alzheimer disease, compared with those associations for moderate vitamin D deficiency (10-20 ng/ml) (20).

In another meta-analysis of seven prospective cohort studies and one retrospective cohort study involving 1953 cases of dementia and 1607 cases of Alzheimer disease, levels of vitamin D were inversely associated with risk of dementia and Alzheimer disease (67). The risk of dementia decreased with increasing 25(OH)D levels to a level of approximately 25 ng/ml, whereas the risk of Alzheimer disease decreased continuously along with the increase of serum 25(OH)D up to approximately 35 ng/ml. No conclusive evidence was available regarding serum 25(OH)D levels of more than 35 ng/ml.

A randomized, double-blind, placebo-controlled trial in 210 patients with Alzheimer disease found that daily oral vitamin D supplementation (800 IU/day) for 12 months may improve cognitive function and decrease Aβ-related biomarkers in such patients (68). Participants in the intervention group received 12 months of vitamin D 800 IU/day. Significant improvements were noted in levels of various Aβ-related biomarkers: plasma Aβ42, amyloid beta precursor protein (APP), BACE1, APP mRNA, and BACE1 mRNA. Significant improvements were also noted in measures of cognitive function, including information, arithmetic, digit span, vocabulary, block design and picture arrangement scores, as well as full-scale IQ.

A systematic review and meta-analysis of the associations of vitamin D receptor genetic variants in six studies (with collectively 1256 cases and 1205 controls) found that the vitamin D receptor (VDR) genetic variant rs731236 was significantly correlated with Alzheimer disease (44).

In HIV-positive persons, severe hypovitaminosis D [25(OH)D levels less than 10 ng/mL] was independently associated with a higher risk of neurocognitive impairment (142).

Parkinson disease. Although vitamin D deficiency exists in patients with early, untreated Parkinson disease who typically have few, if any, mobility limitations (36), vitamin D levels correlate with the degree of functional independence (138). Patients with Parkinson disease who have either higher 25(OH)D levels or the vitamin D receptor genotype Fok1 have milder Parkinson disease, even in multivariate analyses controlling for variables such as disease duration (135). Low vitamin D levels contribute to low bone mineral density and augment fracture risk in these fall-prone individuals.

A systematic review and meta-analysis of the associations of vitamin D receptor genetic variants in 10 studies (with collectively 2356 cases and 2815 controls) found that the vitamin D receptor genetic variants rs7975232 and rs2228570 were significantly correlated with Parkinson disease (44). In another study, expression of the vitamin D receptor was higher in all patients compared with controls and in male patients compared with male controls (45). Vitamin D receptor transcripts could differentiate patients with total Parkinson disease from total controls with an AUC [area under the curve] value of 0.86.

In a comparative pathological study, the vitamin D-activating enzyme CYP27B1 (1α-hydroxylase) exclusively identified a subpopulation of astrocytes in patients with Parkinson disease (95). The authors speculated that CYP27B1-positive astrocytes could display neuroprotective features as they sequester alpha-synuclein oligomers.

Stroke. The role of vitamin D for primary or secondary prevention or recovery from stroke remains uncertain. Low vitamin D levels are associated with incident stroke (48; 91; 70; 06; 137), but it is unclear if this is a causal association or whether it simply reflects behavioral issues (eg, lack of physical activity) that separately affect stroke risk factors. Low vitamin D levels are associated with increased rates of several stroke risk factors, including hypertension, diabetes, and dyslipidemia (104; 91). In one study, subjects with severely low 25(OH)D levels (≤9.33 ng/ml) had a 3.1-fold increased risk of ischemic stroke compared to those with high levels, but adjustment for systolic blood pressure levels abrogated this association (91). Alfieri and colleagues found that vitamin D deficiency is associated with C-reactive protein, acute ischemic stroke, and short-term disability outcomes, which they concluded suggested a role of vitamin D deficiency in the inflammatory response and pathophysiology of stroke (06).

The results of prospective studies that have longitudinally measured both vitamin D levels and stroke rates have had conflicting results. Randomized control trials of vitamin D supplementation for stroke prevention have had methodological problems that limit the interpretation of results, and there have been no trials of supplementation for secondary prevention or stroke recovery (112).

Low vitamin D levels are a potential risk factor for in-hospital stroke-associated pneumonia (58).

Post-stroke depression. Vitamin D deficiency is associated with depression in stroke patients (48; 75). Low serum 25(OH)D levels within 24 hours after admission for stroke are associated with poststroke depression 1-month poststroke (48). Cigarette smoking is associated with lower vitamin D levels, and the frequency of depression in smokers is significantly higher than that in nonsmokers, suggesting that higher rates of depression in smokers with acute ischemic stroke may be associated with lower vitamin D levels induced by smoking (116).

Recommended doses of vitamin D. The Institute of Medicine currently estimates the daily requirement of vitamin D is 400 IU/day but recommends a dietary allowance of 600 IU/day for those more than 1 year old to 70 years old. Vitamin D deficiency in the general population is generally defined as 25(OH)D levels of less than 20 ng/ml and insufficiency as less than 30 ng/mL. Different replacement and supplementation strategies have been proposed (54). A common replacement strategy for vitamin D deficiency is to treat with 50,000 IU D2 capsules weekly for 8 to 12 weeks followed by 1000 to 2000 IU D3 daily. Life-threatening vitamin D intoxication has been reported due to intake of ultra-high doses in patients with multiple sclerosis (exceeding 50,000 units of cholecalciferol per day over several months) (41). It is advisable to check a calcium level after 1 month on a high-dose vitamin D2 regimen, and in any case, it is advisable to recheck a 25(OH)D level after several months of replacement if prior levels were deficient.

The appropriate levels of 25(OH)D in people with neurologic disorders are unknown, and it may be that the target levels differ by disease state. In multiple sclerosis, a 2004 study of Caucasian military personnel found that those with 25(OH)D levels greater than 99.1 nmol/L (approximately 40 ng/ml) had a much lower risk of multiple sclerosis compared to those with lower levels (103), and in 2010 studies showed that levels up to 60 ng/mL showed linear inverse associations with attacks; levels above that range have not been studied sufficiently to determine if higher levels confer further marginal benefits (100; 126).

Media

References

01: Abbatemarco JR, Fox RJ, Li H, Ontaneda D. Vitamin D and MRI measures in progressive multiple sclerosis. Mult Scler Relat Disord 2019;35:276-82. PMID 31445221
02: Aivo J, Lindsrom BM, Soilu-Hanninen M. A randomised, double-blind, placebo-controlled trial with vitamin D3 in MS: Subgroup analysis of patients with baseline disease activity despite interferon treatment. Mult Scler Intl 2012;2012:802796. PMID 22919492
03: Agnello L, Scazzone C, Lo Sasso B, et al. VDBP, CYP27B1, and 25-hydroxyvitamin D gene polymorphism analyses in a group of Sicilian multiple sclerosis patients. Biochem Genet 2017;55(2):183-92. PMID 27904983
04: Agnello L, Scazzone C, Lo Sasso B, et al. CYP27A1, CYP24A1, and RXR-α polymorphisms, vitamin d, and multiple sclerosis: a pilot study. J Mol Neurosci 2018;66(1):77-84. PMID 30088172
05: Agnello L, Scazzone C, Lo Sasso BL, et al. Role of multiple vitamin D-related polymorphisms in multiple sclerosis severity: preliminary findings. Genes (Basel) 2022;13(8):1307. PMID 35893044
06: Alfieri DF, Lehmann MF, Oliveira SR, et al. Vitamin D deficiency is associated with acute ischemic stroke, C-reactive protein, and short-term outcome. Metab Brain Dis 2017;32(2):493-502. PMID 27975188
07: Amirinejad R, Shirvani-Farsani Z, Naghavi Gargari B, Sahraian MA, Mohammad Soltani B, Behmanesh M. Vitamin D changes expression of DNA repair genes in the patients with multiple sclerosis. Gene 2021;781:145488. PMID 33588040
08: Ascherio A, Munger KL, White R, Köchert K, et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol 2014;71(3):306-14. PMID 24445558
09: Ashtari F, Toghianifar N, Zarkesh-Esfahani SH, Mansourian M. Short-term effect of high-dose vitamin D on the level of interleukin 10 in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial. Neuroimmunomodulation 2015;22(6):400-4. PMID 26401986
10: Ashtari F, Toghianifar N, Zarkesh-Esfahani SH, Mansourian M. High dose vitamin D intake and quality of life in relapsing-remitting multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial. Neurol Res 2016;38(10):888-92. PMID 27597724
11: Atkinson SA, Fleet JC. Canadian recommendations for vitamin D intake for persons affected by multiple sclerosis. J Steroid Biochem Mol Biol 2020;199:105606. PMID 31981800
12: Bauer A, Lechner I, Auer M, et al. Influence of physical activity on serum vitamin D levels in people with multiple sclerosis. PLoS One 2020;15(6):e0234333. PMID 32525921
13: Bermúdez-Morales VH, Fierros G, Lopez RL, et al. Vitamin D receptor gene polymorphisms are associated with multiple sclerosis in Mexican adults. J Neuroimmunol 2017;306:20-4. PMID 28385183
14: Bettencourt A, Boleixa D, Guimarães AL, et al. The vitamin D receptor gene FokI polymorphism and multiple sclerosis in a northern Portuguese population. J Neuroimmunol 2017;309:34-7. PMID 28601283
15: Bollen SE, Bass JJ, Fujita S, Wilkinson D, Hewison M, Atherton PJ. The Vitamin D/Vitamin D receptor (VDR) axis in muscle atrophy and sarcopenia. Cell Signal 2022;96:110355. PMID 35595176
16: Burton JM, Kimball S, Vieth R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 2010;74(23):1852-9. PMID 20427749
17: Butzkueven H, Ponsonby AL, Stein MS, et al. Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome. Brain 2024;147(4):1206-15. PMID 38085047
18: Camu W, Lehert P, Pierrot-Deseilligny C, et al. Cholecalciferol in relapsing-remitting MS: a randomized clinical trial (CHOLINE). Neurol Neuroimmunol Neuroinflamm 2019;6(5):e597. PMID 31454777
19: 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 USA 1996;93(15):7861-4. PMID 8755567
20: Chai B, Gao F, Wu R, et al. Vitamin D deficiency as a risk factor for dementia and Alzheimer's disease: an updated meta-analysis. BMC Neurol 2019;19(1):284. PMID 31722673
21: Chesney RW. Theobald Palm and his remarkable observation: how the sunshine vitamin came to be recognized. Nutrients 2012;4(1):42-51. PMID 22347617
22: Cierny D, Michalik J, Škereňová M, Kantorová E, et al. ApaI, BsmI and TaqI VDR gene polymorphisms in association with multiple sclerosis in Slovaks. Neurol Res 2016;38(8):678-84. PMID 27338176
23: Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet 1982;1(8263):74-6. PMID 6119494
24: Cobb LH, Bailey VO, Liu YF, Teixido MT, Rizk HG. Relationship of vitamin D levels with clinical presentation and recurrence of BPPV in a Southeastern United States institution. Auris Nasus Larynx 2023;50(1):70-80. PMID 35659787
25: Concerto C, Rodolico A, Ciancio A, et al. Vitamin D and depressive symptoms in adults with multiple sclerosis: a scoping review. Int J Environ Res Public Health 2021;19(1):199. PMID 35010459
26: Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in ultiple sclerosis group. N Engl J Med 1998;339(5):285-91. PMID 9682040
27: Cortese M, Munger KL, Martínez-Lapiscina EH, et al. Vitamin D, smoking, EBV, and long-term cognitive performance in MS: 11-year follow-up of BENEFIT. Neurology 2020;94(18):e1950-60. PMID 32300060
28: Cortese M, Riise T, Bjornevik K, et al. Timing of use of cod liver oil, a vitamin D source, and multiple sclerosis risk: The EnvIMS study. Mult Scler 2015;21(14):1856-64. PMID 25948625
29: Day HG. Elmer Verner McCollum: 1879-1967. A biographical memoir. Washington, DC: National Academy of Sciences, 1974.
30: Diez CB, Pérez-Ramírez C, Maldonado-Montoro MD, et al. Association between polymorphisms in the vitamin D receptor and susceptibility to multiple sclerosis. Pharmacogenet Genomics 2021;31(2):40-47. PMID 33044390
31: Disanto G, Chaplin G, Morahan JM, et al. Month of birth, vitamin D and risk of immune mediated disease: a case control study. BMC Med 2012;10(1):69. PMID 22764877
32: Disanto G, Pakpoor J, Morahan JM, et al. Epstein-Barr virus, latitude and multiple sclerosis. Mult Scler 2013;19(3):362-5. PMID 22767435
33: Duan S, Lv Z, Fan X, Wang L, Han F, Wang H, Bi S. Vitamin D status and the risk of multiple sclerosis: a systematic review and meta-analysis. Neurosci Lett 2014;570:108-13. PMID 24769422
34: Ekpe J. The chemistry of light: the life and work of Theobald Adrian Palm (1848-1928). J Med Biogr 2009;17(3):155-60. PMID 19723967
35: Elkama A, Karahalil B. Role of gene polymorphisms in vitamin D metabolism and in multiple sclerosis. Arh Hig Rada Toksikol 2018;69(1):25-31. PMID 29604195
36: Evatt ML, DeLong MR, Kumari M, et al. High prevalence of hypovitaminosis D status in patients with early Parkinson disease. Arch Neurol 2011;68(3):314-9. PMID 21403017
37: Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 2005;29(1):21-30. PMID 15589699
38: Fashanu OE, Zhao D, Schneider ALC, et al. Mid-life serum Vitamin D concentrations were associated with incident dementia but not late-life neuropsychological performance in the Atherosclerosis Risk in Communities (ARIC) Study. BMC Neurol 2019;19(1):244. PMID 31640594
39: Feng X, Wang Z, Howlett-Prieto Q, Einhorn N, Causevic S, Reder AT. Vitamin D enhances responses to interferon-β in MS. Neurol Neuroimmunol Neuroinflamm 2019;6(6):e622. PMID 31582399
40: Ferre L, Clarelli F, Sferruzza G, et al. Basal vitamin D levels and disease activity in multiple sclerosis patients treated with fingolimod. Neurol Sci 2018;39(8):1467-70. PMID 29756179
41: Feige J, Salmhofer H, Hecker C, Kunz AB, Franzen M, Moré E, Sellner J. Life-threatening vitamin D intoxication due to intake of ultra-high doses in multiple sclerosis: a note of caution. Mult Scler 2019;25(9):1326-8. PMID 30358476
42: Fitzgerald KC, Munger KL, Köchert K, et al. Association of vitamin D levels with multiple sclerosis activity and progression in patients receiving Interferon Beta-1b. JAMA Neurol 2015;72(12):1458-65. PMID 26458124
43: Galus W, Chmiela T, Walawska-Hrycek A, Krzystanek E. Radiological benefits of vitamin D status and supplementation in patients with MS-A two-year prospective observational cohort study. Nutrients 2023;15(6):1465. PMID 36986195
44: Geng J, Zhang J, Yao F, Liu X, Liu J, Huang Y. A systematic review and meta-analysis of the associations of vitamin D receptor genetic variants with two types of most common neurodegenerative disorders. Aging Clin Exp Res 2020;32(1):21-7. PMID 30863943
45: Gholipour M, Honarmand Tamizkar K, Niknam A, et al. Expression analysis of vitamin D receptor and its related long non-coding RNAs in peripheral blood of patients with Parkinson's disease. Mol Biol Rep 2022;49(7):5911-7. PMID 35426550
46: Glabska D, Kołota A, Lachowicz K, Skolmowska D, Stachoń M, Guzek D. Vitamin D supplementation and mental health in multiple sclerosis patients: a systematic review. Nutrients 2021;13(12):4207. PMID 34959758
47: Grut V, Biström M, Salzer J, et al. Free vitamin D3 index and vitamin D-binding protein in multiple sclerosis: a presymptomatic case-control study. Eur J Neurol 2022;29(8):2335-42. PMID 35582958
48: Han B, Lyu Y, Sun H, Wei Y, He J. Low serum levels of vitamin D are associated with post-stroke depression. Eur J Neurol 2015;22(9):1269-74. PMID 25438665
49: Han K, Yun YM, Moon SG, Kim CH. Bone mineral density and serum 25-hydroxyvitamin D in subtypes of idiopathic benign paroxysmal positional vertigo. Am J Otolaryngol 2020;41(1):102313. PMID 31732302
50: Handel AE, Ramagopalan SV. Vitamin D and multiple sclerosis: an interaction between genes and environment. Mult Scler 2012;18(1):2-4. PMID 22247498
51: Hartl C, Obermeier V, Gerdes LA, Brügel M, von Kries R, Kümpfel T. Seasonal variations of 25-OH vitamin D serum levels are associated with clinical disease activity in multiple sclerosis patients. J Neurol Sci 2017;375:160-4. PMID 28320120
52: Hashemi R, Hosseini-Asl SS, Arefhosseini SR, Morshedi M. The impact of vitamin D3 intake on inflammatory markers in multiple sclerosis patients and their first-degree relatives. PLoS One 2020;15(4):e0231145. PMID 32251441
53: Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295-300. PMID 14283879
54: Holick MF. Vitamin D deficiency. New Engl J Med 2007;357(3):266-81. PMID 17634462
55: Holmoy T, Moen SM. Assessing vitamin D in the central nervous system. Acta Neurol Scand Suppl 2010;(190):88-92. PMID 20586743
56: Holt LE Jr. A tribute to Elmer V. McCollum. Am J Clin Nutr 1968;21(10):1136-7. PMID 4879632
57: Hong X, Christ-Franco M, Moher D, et al. Vitamin D supplementation for benign paroxysmal positional vertigo: a systematic review. Otol Neurotol 2022;43(7):e704-11. PMID 35878631
58: Huang GQ, Cheng HR, Wu YM, et al. Reduced vitamin D levels are associated with stroke-associated pneumonia in patients with acute ischemic stroke. Clin Interv Aging 2019;14:2305-14. PMID 32021127
59: Hupperts R, Smolders J, Vieth R, et al. Randomized trial of daily high-dose vitamin D3 in patients with RRMS receiving subcutaneous interferon β-1a. Neurology 2019;93(20):e1906-16. PMID 31594857
60: Imani D, Razi B, Motallebnezhad M, Rezaei R. Association between vitamin D receptor (VDR) polymorphisms and the risk of multiple sclerosis (MS): an updated meta-analysis. BMC Neurol 2019;19(1):339. PMID 31878897
61: Irving AA, Marling SJ, Seeman J, Plum LA, DeLuca HF. UV light suppression of EAE (a mouse model of multiple sclerosis) is independent of vitamin D and its receptor. Proc Natl Acad Sci U S A 2019;116(45):22552-5. PMID 31636184
62: Ismailova K, Poudel P, Parlesak A, Frederiksen P, Heitmann BL. Vitamin D in early life and later risk of multiple sclerosis-A systematic review, meta-analysis. PLoS One 2019;14(8):e0221645. PMID 31454391
63: Jagannath VA, Filippini G, Di Pietrantonj C, et al. Vitamin D for the management of multiple sclerosis. Cochrane Database Syst Rev 2018;9:CD008422.** PMID 30246874
64: Jalkanen A, Kauko T, Turpeinen U, Hämäläinen E, Airas L. Multiple sclerosis and vitamin D during pregnancy and lactation. Acta Neurol Scand 2015;131(1):64-7. PMID 25216350
65: 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(12):1571-9. PMID 23698130
66: Jasper EA, Nidey NL, Schweizer ML, Ryckman KK. Gestational vitamin D and offspring risk of multiple sclerosis: a systematic review and meta-analysis. Ann Epidemiol 2020;43:11-7. PMID 32014337
67: Jayedi A, Rashidy-Pour A, Shab-Bidar S. Vitamin D status and risk of dementia and Alzheimer's disease: a meta-analysis of dose-response. Nutr Neurosci 2019;22(11):750-9. PMID 29447107
68: Jia J, Hu J, Huo X, Miao R, Zhang Y, Ma F. Effects of vitamin D supplementation on cognitive function and blood Aβ-related biomarkers in older adults with Alzheimer's disease: a randomised, double-blind, placebo-controlled trial. J Neurol Neurosurg Psychiatry 2019;90(12):1347-52. PMID 31296588
69: Jones G, Prosser DE, Kaufmann M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D. Arch Biochem Biophys 2012;523(1):9-18. PMID 22100522
70: Judd SE, Morgan CJ, Panwar B, et al. Vitamin D deficiency and incident stroke risk in community-living black and white adults. Int J Stroke 2016;11(1):93-102. PMID 26763025
71: Kamisli O, Acar C, Sozen M, et al. The association between vitamin D receptor polymorphisms and multiple sclerosis in a Turkish population. Mult Scler Relat Disord 2018;20:78-81. PMID 29331875
72: Karakis I, Pase MP, Beiser A, et al. Association of serum vitamin D with the risk of incident dementia and subclinical indices of brain aging: The Framingham Heart Study. J Alzheimers Dis 2016;51(2):451-61. PMID 26890771
73: Kepczynska K, Zajda M, Lewandowski Z, Przedlacki J, Zakrzewska-Pniewska B. Bone metabolism and vitamin D status in patients with multiple sclerosis. Neurol Neurochir Pol 2016;50(4):251-7. PMID 27375138
74: Kesby JP, Eyles DW, Burne TH, McGrath JJ. The effects of vitamin D on brain development and adult brain function. Mol Cell Endocrinol 2011;347(1-2):121-7. PMID 21664231
75: Kim SH, Seok H, Kim DS. Relationship between serum vitamin D levels and symptoms of depression in stroke patients. Ann Rehabil Med 2016;40(1):120-5. PMID 26949678
76: Koven NS, Cadden MH, Murali S, Ross MK. Vitamin D and long-term memory in multiple sclerosis. Cogn Behav Neurol 2013;26(3):155-60. PMID 24077575
77: Krizova L, Kollar B, Jezova D, Turcani P. Genetic aspects of vitamin D receptor and metabolism in relation to the risk of multiple sclerosis. Gen Physiol Biophys 2013;32(4):459-66. PMID 24067280
78: Kuzma E, Soni M, Littlejohns TJ, et al. Vitamin D and memory decline: two population-based prospective studies. J Alzheimers Dis 2016;50(4):1099-108. PMID 26836174
79: Langer-Gould A, Huang S, Van Den Eeden S, et al. Vitamin D, pregnancy, breastfeeding and postpartum multiple sclerosis relapses. Arch Neurol 2011;68(3):310-3. PMID 21059988
80: Langer-Gould A, Lucas RM, Xiang AH, et al. Vitamin D-binding protein polymorphisms, 25-hydroxyvitamin d, sunshine and multiple sclerosis. Nutrients 2018a;10(2):pii:E184. PMID 29414925
81: Langer-Gould A, Lucas R, Xiang AH, et al. MS Sunshine Study: sun exposure but not vitamin d is associated with multiple sclerosis risk in Blacks and Hispanics. Nutrients 2018b;10(3):pii:E268. PMID 29495467
82: Langlois J, Denimal D. Clinical and imaging outcomes after vitamin D supplementation in patients with multiple sclerosis: a systematic review. Nutrients 2023;15(8):1945. PMID 37111166
83: Lason W, Jantas D, Leśkiewicz M, Regulska M, Basta-Kaim A. The vitamin D receptor as a potential target for the treatment of age-related neurodegenerative diseases such as Alzheimer's and Parkinson's diseases: a narrative review. Cells 2023;12(4):660. PMID 36831327
84: Laursen JH, Sondergaard HB, Sorensen PS, Sellebjerg F, Oturai AB. Association between age at onset of multiple sclerosis and vitamin D level-related factors. Neurology 2016a;86(1):88-93. PMID 26446064
85: Laursen JH, Søndergaard HB, Sørensen PS, Sellebjerg F, Oturai AB. Vitamin D supplementation reduces relapse rate in relapsing-remitting multiple sclerosis patients treated with natalizumab. Mult Scler Relat Disord 2016b;10:169-73. PMID 27919484
86: Lin R, Taylor BV, Simpson S Jr, et al. Novel modulating effects of PKC family genes on the relationship between serum vitamin D and relapse in multiple sclerosis. J Neurol Neurosurg Psychiatry 2014;85(4):399-404. PMID 23868949
87: Llewellyn DJ, Lang IA, Langa KM, et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med 2010;170(13):1135-41. PMID 20625021
88: Lo CW, Paris PW, Holick MF. Indian and Pakistani immigrants have the same capacity as Caucasians to produce vitamin D in response to ultraviolet irradiation. Am J Clin Nutr 1986;44(5):683-5. PMID 3766454
89: López-Muñoz P, Torres-Costoso AI, Fernández-Rodríguez R, et al. Effect of vitamin D supplementation on fatigue in multiple sclerosis: a systematic review and meta-analysis. Nutrients 2023;15(13):2861. PMID 37447189
90: Maghbooli Z, Omidifar A, Varzandi T, Salehnezhad T, Sahraian MA. Reduction in circulating vitamin D binding protein in patients with multiple sclerosis. BMC Neurol 2021;21(1):168. PMID 33879066
91: Majumdar V, Prabhakar P, Kulkarni GB, Christopher R. Vitamin D status, hypertension and ischemic stroke: a clinical perspective. J Hum Hypertens 2015;29(11):669-74. PMID 25810064
92: Manousaki D, Dudding T, Haworth S, et al. Low-frequency synonymous coding variation in CYP2R1 has large effects on vitamin D levels and risk of multiple sclerosis. Am J Hum Genet 2017;101(2):227-38. PMID 28757204
93: Martinelli V, Dalla Costa G, Colombo B, et al. Vitamin D levels and risk of multiple sclerosis in patients with clinically isolated syndromes. Mult Scler 2014;20(2):147-55. PMID 23836877
94: Mayne CG, Spanier JA, Relland LM, Williams CB, Hayes CE. 1,25-Dihydroxyvitamin D3 acts directly on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelitis. Eur J Immunol 2011;41(3):822-32. PMID 21287548
95: Mazzetti S, Barichella M, Giampietro F, et al. Astrocytes expressing Vitamin D-activating enzyme identify Parkinson's disease. CNS Neurosci Ther 2022;28(5):703-13. PMID 35166042
96: McCollum EV. The paths to the discovery of vitamins A and D. J Nutr 1967;91(2):Suppl 1:11-6. PMID 5335920
97: McLaughlin L, Clarke L, Khalilidehkordi E, Butzkueven H, Taylor B, Broadley SA. Vitamin D for the treatment of multiple sclerosis: a meta-analysis. J Neurol 2018;265(12):2893-905. PMID 30284038
98: Mimpen M, Rolf L, Poelmans G, et al. Vitamin D related genetic polymorphisms affect serological response to high-dose vitamin D supplementation in multiple sclerosis. PLoS One 2021;16(12):e0261097. PMID 34855907
99: Moosavi E, Rafiei A, Yazdani Y, Eslami M, Saeedi M. Association of serum levels and receptor genes BsmI, TaqI and FokI polymorphisms of vitamin D with the severity of multiple sclerosis. J Clin Neurosci 2021;84:75-81. PMID 33485603
100: Mowry EM, Krupp LB, Milazzo M, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol 2010;67(5):618-24. PMID 20437559
101: Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol 2012;72(2):234-40. PMID 22926855
102: Mrad MF, El Ayoubi NK, Esmerian MO, Kazan JM, Khoury SJ. Effect of vitamin D replacement on immunological biomarkers in patients with multiple sclerosis. Clin Immunol 2017;181:9-15. PMID 28536054
103: Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006;296(23):2832-8. PMID 17179460
104: Muscogiuri G, Sorice GP, Ajjan R, et al. Can vitamin D deficiency cause diabetes and cardiovascular diseases. Present evidence and future perspectives. Nutr Metab Cardiovasc Dis 2012;22(2):81-7. PMID 22265795
105: Naghavi Gargari B, Behmanesh M, Shirvani Farsani Z, Pahlevan Kakhki M, Azimi AR. Vitamin D supplementation up-regulates IL-6 and IL-17A gene expression in multiple sclerosis patients. Int Immunopharmacol 2015;28(1):414-9. PMID 26188623
106: Nair R, Maseeh A. Vitamin D: The "sunshine" vitamin. J Pharmacol Pharmacother 2012;3(2):118-26. PMID 22629085
107: Niino M, Fukazawa T, Miyazaki Y, et al. Seasonal fluctuations in serum levels of vitamin D in Japanese patients with multiple sclerosis. J Neuroimmunol 2021;357:577624. PMID 34098399
108: Olsson E, Byberg L, Karlström B, Cederholm T, Melhus H, Sjögren P, Kilander L. Vitamin D is not associated with incident dementia or cognitive impairment: an 18-y follow-up study in community-living old men. Am J Clin Nutr 2017;105(4):936-43. PMID 28202477
109: Ostkamp P, Salmen A, Pignolet B, et al. Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity. Proc Natl Acad Sci U S A 2021;118(1):e2018457118. PMID 33376202
110: Pettersen JA. Vitamin D and executive functioning: Are higher levels better? J Clin Exp Neuropsychol 2016;38(4):467-77. PMID 26708262
111: Pierrot-Deseilligny C, Souberbielle JC. Vitamin D and multiple sclerosis: an update. Mult Scler Relat Disord 2017;14:35-45. PMID 28619429
112: Pilz S, Tomaschitz A, Drechsler C, Zittermann A, Dekker JM, Marz W. Vitamin D supplementation: a promising approach for the prevention and treatment of strokes. Curr Drug Targets 2011;12(1):88-96. PMID 20795935
113: Plantone D, Primiano G, Manco C, Locci S, Servidei S, De Stefano N. Vitamin D in neurological diseases. Int J Mol Sci 2022;24(1):87. PMID 36613531
114: Polachini CR, Spanevello RM, Zanini D, et al. Evaluation of delta-aminolevulinic dehydratase activity, oxidative stress biomarkers, and vitamin D levels in patients with multiple sclerosis. Neurotox Res 2016;29(2):230-42. PMID 26690779
115: Pytel V, Matías-Guiu JA, Torre-Fuentes L, et al. Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole-exome next generation sequencing. Brain Behav 2019;9(4):e01272. PMID 30900415
116: Ren W, Gu Y, Zhu L, et al. The effect of cigarette smoking on vitamin D level and depression in male patients with acute ischemic stroke. Compr Psychiatry 2016;65:9-14. PMID 26773985
117: Rito Y, Flores J, Fernández-Aguilar A, et al. Vitamin D and disability in relapsing-remitting multiple sclerosis in patients with a Mexican background. Acta Neurol Belg 2018;118(1):47-52. PMID 28975580
118: Rosjo E, Myhr KM, Loken-Amsrud KI, et al. Vitamin D status and effect of interferon-β1a treatment on MRI activity and serum inflammation markers in relapsing-remitting multiple sclerosis. J Neuroimmunol 2015a;280:21-8. PMID 25773151
119: Rosjo E, Steffensen LH, Jorgensen L, et al. Vitamin D supplementation and systemic inflammation in relapsing-remitting multiple sclerosis. J Neurol 2015b;262(12):2713-21. PMID 26429571
120: Rossom RC, Espeland MA, Manson JE, et al. Calcium and vitamin D supplementation and cognitive impairment in the women's health initiative. J Am Geriatr Soc 2012;60(12):2197-205. PMID 23176129
121: Sabel CE, Pearson JF, Mason DF, Willoughby E, Abernethy DA, Taylor BV. The latitude gradient for multiple sclerosis prevalence is established in the early life course. Brain 2021;144(7):2038-46.** PMID 33704407
122: Salzer J, Biström M, Sundström P. Vitamin D and multiple sclerosis: where do we go from here? Expert Rev Neurother 2014;14(1):9-18. PMID 24320602
123: Salzer J, Nyström M, Hallmans G, Stenlund H, Wadell G, Sundström P. Epstein-Barr virus antibodies and vitamin D in prospective multiple sclerosis biobank samples. Mult Scler 2013;19(12):1587-91. PMID 23549431
124: Shih EJ, Lee WJ, Hsu JL, Wang SJ, Fuh JL. Effect of vitamin D on cognitive function and white matter hyperintensity in patients with mild Alzheimer's disease. Geriatr Gerontol Int 2020;20(1):52-8. PMID 31773862
125: Simon KC, Munger KL, Kraft P, Hunter DJ, De Jager PL, Ascherio A. Genetic predictors of 25-hydroxyvitamin D levels and risk of multiple sclerosis. J Neurol 2011;258(9):1676-82. PMID 21431378
126: Simpson S, Taylor B, Blizzard L, et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol 2010;68(2):193-203. PMID 20695012
127: Simpson S Jr, der Mei IV, Taylor B. The role of vitamin D in multiple sclerosis: biology and biochemistry, epidemiology and potential roles in treatment. Med Chem 2018;14(2):129-43. PMID 28933265
128: Skalli A, Ait Ben Haddou EH, El Jaoudi R, et al. Association of vitamin D status with multiple sclerosis in a case-control study from Morocco. Rev Neurol (Paris) 2018;174(3):150-6. PMID 29525037
129: Smolders J, Mimpen M, Oechtering J, et al. Vitamin D3 supplementation and neurofilament light chain in multiple sclerosis. Acta Neurol Scand 2020;141(1):77-80. PMID 31657006
130: Smolders J, Peelen E, Thewissen M, Menheere P, Damoiseaux J, Hupperts R. Circulating vitamin D binding protein levels are not associated with relapses or with vitamin D status in multiple sclerosis. Mult Scler 2014;20(4):433-7. PMID 23959712
131: Smolders J, Torkildsen Ø, Camu W, Holmøy T. An update on vitamin D and disease activity in multiple sclerosis. CNS Drugs 2019;33(12):1187-99. PMID 31686407
132: Soilu-Hanninen M, Aivo J, Lindstrom BM, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2012;83(5):565-71. PMID 22362918
133: Smolders J, Damoiseaux J. Vitamin D as a T-cell modulator in multiple sclerosis. Vitam Horm 2011;86:401-28. PMID 21419282
134: Stein MS, Liu Y, Gray OM, et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology 2011;77(17):1611-8. PMID 22025459
135: Suzuki M, Yoshioka M, Hashimoto M, et al. 25-hydroxyvitamin D, vitamin D receptor gene polymorphisms, and severity of Parkinson's disease. Mov Disord 2012;27(2):264-71. PMID 22213340
136: Stridh P, Kockum I, Huang J. Seasonal variability of serum 25-hydroxyvitamin D on multiple sclerosis onset. Sci Rep 2021;11(1):20989. PMID 34697348
137: Talebi A, Amirabadizadeh A, Nakhaee S, Ahmadi Z, Mousavi-Mirzaei SM. Cerebrovascular disease: how serum phosphorus, vitamin D, and uric acid levels contribute to the ischemic stroke. BMC Neurol 2020;20(1):116. PMID 32234035
138: Tassorelli C, Berlangieri M, Buscone S, et al. Falls, fractures and bone density in Parkinson's disease: a cross-sectional study. Int J Neurosci 2017;127(4):299-304. PMID 27356592
139: Tiller C, Black LJ, Ponsonby AL, et al. Vitamin D metabolites and risk of first clinical diagnosis of central nervous system demyelination. J Steroid Biochem Mol Biol 2022;218:106060. PMID 35031430
140: Tuohimaa P, Keisala T, Minasyan A, Cachat J, Kalueff A. Vitamin D, nervous system and aging. Psychoneuroendocrinology 2009;34 Suppl 1:S278-86. PMID 19660871
141: Ueda P, Rafatnia F, Bäärnhielm M, et al. Neonatal vitamin D status and risk of multiple sclerosis. Ann Neurol 2014;76(3):338-46. PMID 24985080
142: Vergori A, Pinnetti C, Lorenzini P, et al. Vitamin D deficiency is associated with neurocognitive impairment in HIV-infected subjects. Infection 2019;47(6):929-35. PMID 31183805
143: Wesnes K, Myhr KM, Riise T, et al. Low vitamin D, but not tobacco use or high BMI, is associated with long-term disability progression in multiple sclerosis. Mult Scler Relat Disord 2021;50:102801. PMID 33636616
144: Woolmore JA, Stone M, Pye EM, et al. Studies of associations between disability in multiple sclerosis, skin type, gender and ultraviolet radiation. Mult Scler 2007;13(3):369-75. PMID 17439906
145: Yeshokumar AK, Saylor D, Kornberg MD, Mowry EM. Evidence for the importance of vitamin D status in neurologic conditions. Curr Treat Options Neurol 2015;17(12):51. PMID 26538263
146: Yucel FE, Kamıslı O, Acar C, Sozen M, Tecellioğlu M, Ozcan C. Analysis of vitamin D receptor polymorphisms in patients with familial multiple sclerosis. Med Arch 2018;72(1):58-61. PMID 29416220
147: Zhang X, Gao B, Xu B. No association between the vitamin D-binding protein (DBP) gene polymorphisms (rs7041 and rs4588) and multiple sclerosis and type 1 diabetes mellitus: a meta-analysis. PLoS One 2020;15(11):e0242256. PMID 33180889
148: Zheng C, He L, Liu L, Zhu J, Jin T. The efficacy of vitamin D in multiple sclerosis: a meta-analysis. Mult Scler Relat Disord 2018;23:56-61. PMID 29778041
149: Zivadinov R, Treu CN, Weinstock-Guttman B, et al. Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis. J Neurol Neurosurg Psychiatry 2013;84(10):1075-81. PMID 23385850

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Douglas J Lanska MD MS MSPH

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
See Profile

Former Authors

Bryan Smith MD
Ellen Mowry MD

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Vitamin D in neurologic disorders

Also Relevant

Medical complications of stroke
Multiple sclerosis: treatment of its symptoms
Myopathies associated with parathyroid disorders
Nutrition and the brain
Parkinson disease
- Traumatic intracerebral hemorrhage

Vitamin D in neurologic disorders …

Vitamin D in neurologic disorders

Introduction

Overview

Key points

Historical note and terminology

Description

Clinical applications

Media

References

Contributors

Author

Former Authors

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Brain death/death by neurologic criteria

Hepatic encephalopathy

Bowel dysfunction in neurologic disorders

Anti-IgLON5 disease

Coma due to primary brainstem and diencephalic lesions

Anti-LGI1 encephalitis

Giant cell arteritis

Transient visual loss

Vitamin D in neurologic disorders

Introduction

Overview

Key points

Historical note and terminology

Description

Clinical applications

Media

References

Contributors

Author

Former Authors

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Brain death/death by neurologic criteria

Hepatic encephalopathy

Bowel dysfunction in neurologic disorders

Anti-IgLON5 disease

Coma due to primary brainstem and diencephalic lesions

Anti-LGI1 encephalitis

Giant cell arteritis

Transient visual loss

This is an article preview.
Start a Free Account
to access the full version.