Objective: Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk, but the therapeutic potential of vitamin D in established MS has not been explored. Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical, immunologic, and clinical outcomes in patients with MS prospectively.Methods: An open-label randomized prospective controlled 52-week trial matched patients with MS for demographic and disease characteristics, with randomization to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks), and further downtitrated to 0 IU/day. Calcium (1,200 mg/day) was given throughout the trial. Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups. Secondary endpoints included 25(OH)D and other biochemical measures, immunologic biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score. Results: Classification of evidence:This trial provides Class II evidence that high-dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high-dose supplementation. The trial, however, lacked statistical precision and the design requirements to adequately assess changes in clinical disease measures (relapses and Expanded Disability Status Scale scores), providing only Class level IV evidence for these outcomes. Neurology ® 2010;74:1852-1859 GLOSSARY ALP ϭ alkaline phosphatase; ALT ϭ alanine aminotransferase; AST ϭ aspartate aminotransferase; EAE ϭ experimental autoimmune encephalitis; EDSS ϭ Expanded Disability Status Scale; IL ϭ interleukin; LS ϭ least squares; MMP-9 ϭ matrix metalloproteinase-9; MS ϭ multiple sclerosis; PTH ϭ parathyroid hormone; TCS ϭ T-cell score; TIMP-1 ϭ tissue inhibitory of metalloproteinase-1; TNF␣ ϭ tumor necrosis factor-␣.Multiple sclerosis (MS) has a well-documented geographic distribution, with increasing prevalence and risk with increasing distance from the equator.1-4 Limited sunlight and UVB exposure, MS risk factors based on observational studies, are intermediaries between latitude and MS.2-5 Low serum 25(OH)D also appears to be a risk factor, and is a direct product of skin exposure to UVB. [4][5][6][7] e-Pub ahead of print on April 28, 2010, at www.neurology.org.

Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and is especially strong for multiple sclerosis.

Patients' serum 25(OH)D concentrations reached twice the top of the physiologic range without eliciting hypercalcemia or hypercalciuria. The data support the feasibility of pharmacologic doses of vitamin D3 for clinical research, and they provide objective evidence that vitamin D intake beyond the current upper limit is safe by a large margin.