BM VanAmerongen1,4*, CD Dijkstra1, P Lips2 and CH Polman3
1Department of Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, The Netherlands ; 2Department of Endocrinology, VU Medical Center, Amsterdam, The Netherlands; 3Department of Neurology, VU Medical Center, Amsterdam, The Netherlands; and 4Department of Dental Basic Sciences (ACTA), VU Medical Center, Amsterdam, The Netherlands

European Journal of Clinical Nutrition

MS is a chronic, immune-mediated inflammatory and neurodegenerative disease of the central nervous system (CNS), with an etiology that is not yet fully understood. The prevalence of MS is highest where environmental supplies of vitamin D are lowest.
It is well recognized that the active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25-(OH)2D), is a natural immunoregulator with anti-inflammatory action. The mechanism by which vitamin D nutrition is thought to influence MS involves paracrine or autocrine metabolism of 25OHD by cells expressing the enzyme 1a-OHase in peripheral tissues involved in immune and neural function. Administration of the active metabolite 1,25-(OH)2D in mice and rats with experimental allergic encephalomyelitis (EAE, an animal model of MS) not only prevented, but also reduced disease activity. 1,25-(OH)2D alters dendritic cell and T-cell function and regulates macrophages in EAE. Interestingly, 1,25-(OH)2D is thought to be operating on CNS constituent cells as well.

Vitamin D deficiency is caused by insufficient sunlight exposure or low dietary vitamin D3 intake. Subtle defects in vitamin D metabolism, including genetic polymorphisms related to vitamin D, might possibly be involved as well. Optimal 25OHD serum concentrations, throughout the year, may be beneficial for patients with MS, both to obtain immune-mediated suppression of disease activity, and also to decrease disease-related complications, including increased bone resorption, fractures, and muscle weakness.

Introduction
Multiple sclerosis (MS) is a slowly progressive, often disabling disease of the central nervous system (CNS), characterized by disseminated patches of demyelination in the brain and spinal cord. This disease results in multiple and varied neurologic symptoms and signs, usually with exacerbations and remissions at the onset: relapsing-remitting (RR) MS, followed in later years by a more chronic progressive course: secondary progressive (SP) MS. A primary progressive form (PP) of MS is also recognized. Women are affected more often than men. Age at onset of the clinical symptoms is typically between 20 and 40 y. It is uncertain whether MS is a single disease or whether the varying clinical patterns, for example, the relapsing and progressive forms, represent distinct entities (Noseworthy, 1999). In some MS patients (10– 20%), the course of the disease can be classified as benign as they do not develop the characteristic disabilities (McAlpine, 1961; Ramsaransing et al, 2001). Plaques of demyelination, with perivascular inflammation and destruction of oligodendroglia, preceded by violation of the blood–brain barrier (BBB), are scattered throughout the white matter of the CNS. Apart from demyelination, axonal damage occurs in early stages of MS (Trapp et al, 1999; Bjartmar et al, 2003). Within one person, recent inflamed and more chronic lesions may coexist. Between MS patients, four basic patterns of neuropathological lesion characteristics suggest distinct, divergent disease mechanisms (Lucchinetti et al, 1996).

A role for vitamin D in MS has been suggested (Goldberg, 1974a, b; Hayes et al, 1997; Hayes, 2000). The key questions concerning vitamin D are, one: is MS prevented by an adequate supply of vitamin D3, two: is MS aggravated by vitamin D deficiency, three: is MS aggravated by a vitamin D metabolic disorder, including four: a genetic vitamin D related disorder?

This review provides some epidemiological and ecological evidence for the preventive role that vitamin D nutrition may play in decreasing susceptibility to MS. The putative preventive effect of adequate supply of vitamin D3 is supported by results obtained in EAE. In EAE 1,25-(OH)2D prevents the onset when administered before EAE induction and ameliorates the severity and duration of EAE when given after EAE induction (Table 1). Widespread seasonal variation in serum 25OHD levels has been reported especially in temperate climates, with low 25OHD levels in winter. A vitamin D-deficient diet in mice and rats resulted in an increased susceptibility to EAE, and 1,25-(OH)2D deprivation aggravated the clinical signs of EAE (Cantorna et al, 1996; Garcion et al, 2003). Likewise, once MS is apparent, low 25OHD levels may aggravate its severity. Living in a temperate climate may cause annually recurring seasonal low serum 25OHD concentrations in MS patients.

Low serum 25OHD concentrations may be responsible for upsetting the balance in the neuro-immune system of MS patients, causing reversible and irreversible neuro-immunological damage aggravating RRMS. The cumulative negative effects over the years may contribute to the secondary progressive course of MS. Further studies are required to establish the seasonal fluctuations in serum concentrations of vitamin D metabolites in MS patients. The effects of sunlight on the clinical manifestations of MS may be influenced by the fact that this may not be a direct effect, but indirect. There might be a time lag of 2 months between sunlight and 25OHD and a time lag of 4 months between sunlight and MRI lesions. A 25OHD reference interval may need to be determined to distinguish inadequate from adequate levels. The quantitative relation between vitamin D3 input and the resulting serum 25OHD concentration needs to be investigated, as it has been speculated that patients with MS may have a higher vitamin D requirement (Goldberg, 1974a; Cantorna et al, 1996; Hayes et al, 1997; Hayes, 2000; Vieth, 1999; DeLuca & Cantorna, 2001; Holick, 2002; Mahon et al, 2003). More research is also needed to address the question if MS might be aggravated by a vitamin D-related metabolic or genetic disorder. It is hypothesized that vitamin D deficiency might only lead to MS in susceptible individuals, and a poor vitamin D status might expose an unknown, possibly gene-related, etiology.

Finally, we need to answer the question: ‘Do we need 1,25- (OH)2D analogs for the treatment of MS, as pharmacological doses of 1,25-(OH)2D are accompanied by adverse side effects, or is it simply a matter of enough vitamin D3 all year round and enough time for it to take effect?’

Until more evidence is provided, it is suggested that MS patients living in temperate climates should have their serum 25OHD concentration checked in winter, January– March in the northern and July–September in the southern hemisphere, respectively, or use a vitamin D3 supplement and follow the recommendations for vitamin D3 and calcium published by their National Council on Food and Nutrition. The dietary reference intakes on vitamin D and calcium for the USA and Europe have been published by the FNB, Institute of Medicine in 1997 and by the SCF of the European Commission in 2002, respectively, and have since been updated (FNB, Institute of Medicine, 1997; SCF, 2002; Heaney et al, 2003a). Alternatively, the reader is referred to the most recent recommendations for the required daily intake of vitamin D3 and calcium given for bone loss, osteoporosis, and fractures (Chapuy et al, 1992; Lips, 2001).

For the moment, it would be wise to aim at a serum 25(OH)D level >50nmols/L either by augmenting sunlight exposure or by a vitamin d3 supplement of 10mg (400iu) per day. Such a dose is safe, and side effects are virtually nonexistent (Lips, 2001). Further studies should be done to evaluate if higher levels of 25OHD are necessary in the management of MS to prevent exacerbations. In contrast, the use of the active metabolite 1,25-(OH)2D carries the danger of hypercalcemia, hypercalciuria, and renal failure, and should be restricted to clinical investigational use under close supervision.