Hemophilia and other coagulation disorders: neurologic aspects
Jun. 20, 2022
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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.
• 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.
The discovery of vitamin D (the sunshine vitamin) began with Scottish physician Theobald Palms 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 (29; 18). 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 (82; 47; 24). When combined with Palms 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, 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 (40).
• 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 Dbinding 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 Dbinding 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.
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 as vitamin D3 (cholecalciferol) from animal sources, and as vitamin D2 (ergocalciferol) plant and fungal sources.
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).
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.
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. 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 (32). 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 (64).
The neuroprotective effects of vitamin D may stem from a variety of mechanisms. 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) (46), downregulation of voltage-sensitive calcium channels, and upregulation of calcium-binding proteins, thus, reducing the potential for damage from free calcium (120).
CNS immune functions. The modulatory role of vitamin D on the neurologic immune response has largely been studied with the experimental autoimmune encephalomyelitis (EAE) mouse model. 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 (16). The mechanisms by which vitamin D can prevent or suppress EAE rely on inhibition of pathogenic CD4+ T cells (81) 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 (115). 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 (20; 76). 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 (91). 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 of 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. 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?) (44).
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 and cognitive dysfunction.
• 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. 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 (125). 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 (125). Among people with multiple sclerosis with low-grade disability, physical activity was positively associated with vitamin D levels, independent of estimated sunlight exposure time (11).
Ultraviolet light suppression of experimental autoimmune encephalomyelitis (a mouse model of multiple sclerosis) is independent of vitamin D and its receptor (51).
Multiple sclerosis. Several lines of evidence suggest or support an important role for vitamin D in the pathophysiology of multiple sclerosis (104; 95; 109): the striking geographic distribution of multiple sclerosis that correlates with sun exposure; seasonal fluctuations in multiple sclerosis risk according to month of birth; the reduction in multiple sclerosis severity during pregnancy, when vitamin D levels are physiologically elevated; the increased risk of multiple sclerosis with vitamin D deficiency; and 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 (93), 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.
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 (129). 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 (129).
Month of birth. A large study of over 25,000 multiple sclerosis patients 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 (52). 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 (26).
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) (52).
Pregnancy. The prevalence of vitamin D deficiency is higher among pregnant women with multiple sclerosis than among pregnant controls without multiple sclerosis (54). The risk of multiple sclerosis relapse during pregnancy is significantly lower for women than in the postpartum period (21), 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 (69).
A meta-analysis of four case-control studies assessed the association between gestational vitamin D levels and the risk of multiple sclerosis in offspring (56). Higher levels of gestational vitamin D had a significant protective effect on risk of multiple sclerosis in offspring.
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 (107; 59; 67; 74; 12; 06). Unfortunately, available data are contradictory about these gene polymorphisms and their impact on the development and course of multiple sclerosis (30). 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 (98). 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) (50).
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 (107). 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 (79). A rare variant in the CYP27B1 gene encoding a vitamin D-activating enzyme confers a significant increase in the risk of developing multiple sclerosis (67), 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 (41; 19; 12; 61; 126; 25; 84). One study has suggested that the Bsml VDR gene polymorphism is associated with the decreased susceptibility to multiple sclerosis in the Slovak population (19), whereas another found a significant positive association between multiple sclerosis and the T/T genotype of BsmI polymorphism (12). An association between multiple sclerosis susceptibility and the FokI ff genotype was found in one Portuguese study, but not with disease form or progression (13).
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 (112; 77), and genotypic variants in vitamin D binding protein have not been shown to have an independent effect on the risk of multiple sclerosis (03; 127). 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 (70).
In multiple sclerosis patients, 2 months of vitamin D treatment significantly altered the expression of DNA repair genes (MYH, OGG1, MTH1, and NRF2) (06).
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 (105). 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 (27). 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 (08; 90; 102; 34; 43). 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 (08; 90; 34; 43). Other studies, however, found that high-dose oral vitamin D3 supplementation prominently increased serum 25(OH)D levels without affecting markers of systemic inflammation (102).
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 (87).
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 (63; 97), but whether this is a causal or noncausal association has not been clear (28). Patients with multiple sclerosis also have a high incidence of osteopenia and osteoporosis (63), which is likely to be multifactorial, with contributions including lower mobility, lower vitamin D levels, and medication effects (eg, corticosteroids).
A number of 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 (80). 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 (88). However, 25(OH)D levels at birth were not associated with a later risk of developing multiple sclerosis (121).
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 (23). 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 (72; 73).
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 (71). The aberrant results for Hispanic and black patients challenge the biological plausibility of vitamin D deficiency as a cause of multiple sclerosis (71).
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 (85; 108; 07) and with disability progression (86; 07) in multiple studies, even if not all studies were able to confirm these results (37). 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 (124). 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 (66).
25(OH)D levels are seasonal, with peak levels 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 2 months (42).
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 (100).
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 (110).
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) (22).
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 (123).
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 (86; 07; 35). 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 5 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 (86). 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 (37).
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 (14). 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 1 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 (114). 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 (116). 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 relapsing-remitting multiple sclerosis patients 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 (72; 73).
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) (09).
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 (55; 53; 128). 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 whom were not treated found no significant association between high-dose vitamin D treatment and risk of multiple sclerosis relapses (55). 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 (53). 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 (53). 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 (83).
In the SOLAR study, 229 patients with relapsing-remitting multiple sclerosis were randomized to high-dose vitamin D3 6670 IU/d orally for 4 weeks, followed by 14,000 IU/d for 44 weeks, or matching placebo in addition to ongoing treatment with subcutaneous used interferon-β-1a (49). 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 (111).
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 (15). 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 2 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 2 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 (49; 113). 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 (113). The discrepancy between the results of controlled trials and observational studies may be due to confounding and/or "reverse causality" in the observational studies (113).
Vitamin D status has no major influence on IFN-β1a treatment effects (101; 15; 49).
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 (10).
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.
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 (75). 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 (68). 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 (92).
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 (106); 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 (62). 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 (94); 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 (103).
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 (33).
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) (17).
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 (57). 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 (58). 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 (38).
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 (122).
Parkinson disease. Although vitamin D deficiency exists in patients with early, untreated Parkinson disease who typically have few, if any, mobility limitations (31), vitamin D levels correlate with the degree of functional independence (119). Parkinson disease patients 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 (117). 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 (VDR) genetic variants rs7975232 and rs2228570 were significantly correlated with Parkinson disease (38).
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 (39; 78; 60; 05; 118), 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 (89; 78). 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 (78). 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 (05).
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 (96).
Low vitamin D levels are a potential risk factor for in-hospital stroke-associated pneumonia (48).
Post-stroke depression. Vitamin D deficiency is associated with depression in stroke patients (39; 65). Low serum 25(OH)D levels within 24 hours after admission for stroke are associated with poststroke depression 1 month poststroke (39). 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 (99).
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 (45). 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) (36). 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 (88), 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 (85; 108).
Douglas J Lanska MD FAAN MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health, the Medical College of Wisconsin, and IM Sechenov First Moscow State Medical University has no relevant financial relationships to disclose.See Profile
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