Vitamin D and multiple sclerosis: An update.

The most recent findings linking exposure to sun and vitamin D insufficiency to multiple sclerosis (MS) are reviewed. Due to insufficient sunshine and changing lifestyles, hypovitaminosis D is widespread in temperate countries. Numerous epidemiological studies have strongly suggested that sunshine and vitamin D insufficiency contributes to MS risk in these countries. Moreover, several large genetic studies in MS patients have recently stated unequivocally that diverse abnormalities involving vitamin D metabolism are related to the risk of the disease. The important implications of such results are discussed here. Then, the interactions of hypovitaminosis D with the other genetic and environmental protective and risk factors, such as the allele HLA DRB1*1501, Epstein-Barr virus infection, obesity, smoking and sexual hormones, are summarized. Vitamin D insufficiency and sufficiency could be a risk and a protective factor, respectively, among many other factors possibly continuously modulating the global MS risk from the mother's pregnancy to the triggering of MS in adulthood. However, many interactions between these different factors occur more particularly between conception and the end of adolescence, which corresponds to the period of maturation of the immune system and thymus and may be related to the dysimmune nature of the disease. The main mechanisms of action of vitamin D in MS appear to be immunomodulatory, involving the various categories of T and B lymphocytes in the general immune system, but neuroprotector and neurotrophic mechanisms could also be exerted at the central nervous system level. Furthermore, several controlled immunological studies performed in MS patients have recently confirmed that vitamin D supplementation has multiple beneficial immunomodulatory effects. However, there is still an enduring absence of major conclusive randomized clinical trials testing vitamin D supplementation in MS patients because of the quasi-insurmountable practical difficulties that exist nowadays in conducting and completing over several years such studies involving the use of a vitamin. Nevertheless, it should be noted that similar robust statistical models used in five different association studies have already predicted a favorable vitamin D effect reducing relapses by 50-70%. If there is now little doubt that vitamin D exerts a beneficial action on the inflammatory component of MS, the results are as yet much less clear for the progressive degenerative component. Lastly, until more information becomes available, vitamin D supplementation of MS patients, using a moderate physiological dose essentially correcting their vitamin insufficiency, is recommended.

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis.

The contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis (MS) is reviewed. Among the multiple recently discovered actions of vitamin D, an immunomodulatory role has been documented in experimental autoimmune encephalomyelitis and in humans. This action in the peripheral immune system is currently the main known mechanism through which vitamin D might influence MS, but other types of actions could be involved within the central nervous system. Furthermore, vitamin D insufficiency is widespread in temperate countries and in patients with MS at the earliest stages of the disease, suggesting that the deleterious effects related to vitamin D insufficiency may be exerted in these patients. In fact, many genetic and environmental risk factors appear to interact and contribute to MS. In genetics, several human leukocyte antigen (HLA) alleles (more particularly HLA-DRB1*1501) could favour the disease whereas some others could be protective. Some of the genes involved in vitamin D metabolism (e.g. CYP27B1) also play a significant role. Furthermore, three environmental risk factors have been identified: past Epstein-Barr virus infection, vitamin D insufficiency and cigarette smoking. Interactions between genetic and environmental risk or protective factors may occur during the mother's pregnancy and could continue during childhood and adolescence and until the disease is triggered in adulthood, therefore possibly modulating the MS risk throughout the first decades of life. Furthermore, some clinical findings already strongly suggest that vitamin D status influences the relapse rate and radiological lesions in patients with MS, although the results of adequately powered randomized clinical trials using vitamin D supplementation have not yet been reported. While awaiting these incontrovertible results, which might be long in coming, patients with MS who are currently in vitamin D insufficiency should be supplemented, at least for their general health status, using moderate doses of the vitamin.

When should we measure vitamin D concentration in clinical practice?

The many recently published data on vitamin D have raised much interest in the medical community. One of the consequences has been a great increase in the prescription of vitamin D concentration measurements in clinical practice. It must be reminded that only the measurement of 25-hydroxyvitamin D (25(OH)D) concentration is indicated to evaluate vitamin D status. Furthermore, since vitamin D insufficiency is so common, since treatment is inexpensive and has a large safety margin, and since we already have much data suggesting that besides its classic effects on bone and mineral metabolism, vitamin D may potentially be helpful for the prevention/management of several diseases, perhaps should it be prescribed to everyone without prior testing? In our opinion, there are however groups of patients in whom estimation of vitamin D status is legitimate and may be recommended. This includes patients in whom a "reasonably" evidence-based target concentration (i.e., based on randomized clinical trials when possible) should be achieved and/or maintained such as patients with rickets/osteomalacia, osteoporosis, chronic kidney disease and kidney transplant recipients, malabsorption, primary hyperparathyroidism, granulomatous disease, and those receiving treatments potentially inducing bone loss. Other patients in whom vitamin D concentration may be measured are those with symptoms compatible with a severe vitamin D deficiency or excess persisting without explanation such as those with diffuse pain, or elderly individuals who fall, or those receiving treatments which modify vitamin D metabolism such as some anti-convulsants. Measurement of Vitamin D concentrations should also be part of any exploration of calcium/phosphorus metabolism which includes measurement of serum calcium, phosphate and PTH.

Widespread vitamin D insufficiency: A new challenge for primary prevention, with particular reference to multiple sclerosis.

In the past 10 years, our knowledge of vitamin D has been revolutionized on two main points. Firstly, this vitamin is not only crucial for bone and calcium metabolism but also exerts major hormonal actions via its active metabolite (calcitriol) and specific receptors in almost all organs. The diverse non-classical actions of vitamin D-i.e. anti-inflammatory, immunomodulatory, antiproliferative and as a neurotransmitter-could have protective and preventive effects for a wide variety of pathologies, such as autoimmune diseases, cancer, infections and cardiovascular affections. Secondly, daily vitamin D requirements have been redefined thanks to many recent metabolic and pathological studies and are about 10 times higher than the amount considered sufficient until a few years ago. The fact that sunshine is the essential natural source of vitamin D and is limited in temperate and Nordic countries, coupled with the fact that modern lifestyle increasingly removes people from exposure to the sun, could explain why a great majority of the general population in these countries are in a state of vitamin D insufficiency. A lack of vitamin D can therefore also be observed in all pathologies but it may play a pathogenic role only in some of them. The incrimination of hypovitaminosis D as a risk factor is a reasonable assumption when several different research approaches used in a given pathology have consistently concluded that vitamin D is likely involved in that pathology. In multiple sclerosis, taken here as a prime example, there is a substantial rationale for vitamin D involvement, based on the findings of different experimental, epidemiological, genetic and immunological studies. Possible curative effects of vitamin D, in addition to a preventive action, are currently being tested but have not yet been demonstrated in most pathologies. However, these two questions appear to be clearly distinct and may involve notably different mechanisms. Lastly, since vitamin D insufficiency exists in most people living in mid- or high-latitude countries, vitamin D could exert multiple major preventive actions, simple supplementation is both safe and inexpensive and, for a vitamin-hormone, supplementation seems obligatory from a general preventive medical point of view alone, it follows that vitamin D supplementation should be organized in these countries to treat all those currently in a state of insufficiency, patients and 'normal' subjects alike, without further delay.

Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice.

BACKGROUND: There is increasing evidence that, in addition to the well-known effects on musculoskeletal health, vitamin D status may be related to a number of non-skeletal diseases. An international expert panel formulated recommendations on vitamin D for clinical practice, taking into consideration the best evidence available based on published literature today. In addition, where data were limited to smaller clinical trials or epidemiologic studies, the panel made expert-opinion based recommendations. METHODS: Twenty-five experts from various disciplines (classical clinical applications, cardiology, autoimmunity, and cancer) established draft recommendations during a 2-day meeting. Thereafter, representatives of all disciplines refined the recommendations and related texts, subsequently reviewed by all panelists. For all recommendations, panelists expressed the extent of agreement using a 5-point scale. RESULTS AND CONCLUSION: Recommendations were restricted to clinical practice and concern adult patients with or at risk for fractures, falls, cardiovascular or autoimmune diseases, and cancer. The panel reached substantial agreement about the need for vitamin D supplementation in specific groups of patients in these clinical areas and the need for assessing their 25-hydroxyvitamin D (25(OH)D) serum levels for optimal clinical care. A target range of at least 30 to 40 ng/mL was recommended. As response to treatment varies by environmental factors and starting levels of 25(OH)D, testing may be warranted after at least 3 months of supplementation. An assay measuring both 25(OH)D(2) and 25(OH)D(3) is recommended. Dark-skinned or veiled individuals not exposed much to the sun, elderly and institutionalized individuals may be supplemented (800 IU/day) without baseline testing.

Nicotine-induced nystagmus correlates with midpontine activation.

The pathomechanism of nicotine-induced nystagmus (NIN) is unknown. The aim of this study was to delineate brain structures that are involved in NIN generation. Eight healthy volunteers inhaled nicotine in darkness during a functional magnetic resonance imaging (fMRI) experiment; eye movements were registered using video-oculography. NIN correlated with blood oxygen level-dependent (BOLD) activity levels in a midpontine site in the posterior basis pontis. NIN-induced midpontine activation may correspond to activation of the dorsomedial pontine nuclei and the nucleus reticularis tegmenti pontis, structures known to participate in the generation of multidirectional saccades and smooth pursuit eye movements.

Neuropsychiatric disturbances in presumed late-onset cobalamin C disease.

BACKGROUND: Combined methylmalonic aciduria and homocystinuria cobalamin C type (cobalamin C disease) is an inborn metabolic disorder consisting of an impaired intracellular synthesis of the 2 active forms of vitamin B12 (cobalamin), namely, adenosylcobalamin and methylcobalamin, that results in increased levels of methylmalonic acid and homocysteine in the blood and urine. Most patients present in the first year of life with systemic, hematological, and neurological abnormalities. Late-onset forms are rare and had not been comprehensively characterized. They could be easily misdiagnosed. OBJECTIVE: To describe clinical and biochemical features of the disease in 2 siblings affected with presumed late-onset cobalamin C disease. DESIGN: Case report and review of the literature. SETTING: Neurological intensive care unit of a university hospital. OBSERVATION: We describe 2 patients with neurological deterioration due to presumed cobalamin C disease. A 16-year-old girl was initially seen with psychosis and severe progressive neuropathy requiring mechanical ventilatory support and her 24-year-old sister had a 2-year disease course of subacute combined degeneration of the spinal cord. A metabolic workup displayed increased methylmalonic acid levels, severe hyperhomocysteinemia, and low plasma methionine levels. The diagnosis was then confirmed by demonstration of impaired synthesis of adenosylcobalamin and methylcobalamin in cultured skin fibroblasts and Epstein-Barr virus-infected lymphocytes. Under specific treatment the younger sister's condition dramatically improved. CONCLUSIONS: Although complementation studies have not been conducted, it is most likely these patients had cobalamin C disease. This study emphasizes the possibility of late-onset disease with purely neurological manifestations. Left untreated, this treatable condition can lead to death or irreversible damage to the nervous system. Screening for intracellular vitamin B12 dysmetabolism should, therefore, be considered in the investigation of adults with unexplained neurological disease, particularly when they are initially seen with a clinical picture suggestive of vitamin B12 deficiency.

Intraoperative frontal eye field stimulation elicits ocular deviation and saccade suppression.

Cortical stimulation is a useful way of elucidating the cortical control of eye movements. The aim of this study was to determine the type of eye movements evoked in response to intraoperative electrical stimulation of the frontal eye field (FEF) region in a fully awake patient during surgery for a frontal lobe glioma. A train of low-intensity electrical pulses within an area in the precentral gyrus evoked contraversive smooth eye movements (SEM) recorded electro-oculographically. Stimulation of an anterior sub-region of this electrically determined FEF disclosed both SEM and suppression of self-paced saccades. However, electrical stimulation of this region evoked no saccades in agreement with pre-operative fMRI using a self-paced saccade paradigm, which did not show activation within the ipsilateral FEF. In humans, intraoperative FEF stimulation may elicit recordable contraversive SEM, and interfere with oculomotor behaviour, suppressing self-paced saccades.