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.)
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.
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 (Ekpe 2009; Chesney 2012). 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 (McCollum 1967; Holt 1968; Day 1974). 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 the regulation of calcium and phosphate homeostasis, but it has broader roles as well 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/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 where there is significant biological plausibility is the association of low 25(OH)D levels with benign paroxysmal positioning vertigo (Han et al 2020).
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