Environmental factors in MS

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The search for environmental factors which may be associated with an increased incidence of MS is of great importance to the patients, because it indicates what may also be valuable measures against the disease. Already this assumption is, however, based on a certain amount of hope: there is no guarantee that it is possible to revert the process by supplying factors which may have been missing or avoiding deleterious factors which were abundant before the disease was discovered. Even so, the MS patient will generally accept this uncertainly and still behave according to the suggestions which can be derived by the ecological studies. And indeed, some of these factors can be demonstrated to influence the disease process. A basic hypothesis must be that MS could occur in many more persons (genetically disposition) than the one in whom it is actually diagnosed; therefore, at least in some of them, environmental factors were crucial for the expression - or lack of expression - of the disease.
    Many studies and even quite a number of reviews have been performed, making the work on these factors somewhat more simple. As usual in medical publications, there are many factors which are controversially discussed, and I shall try to avoid any mention of those. Being succinct is, of course, not compatible to completeness, for which purpose the reader is referred to articles. The factors of potential interest to the MS patients can be summarized in just two sections: "Sunshine" and "Diet" [1,2,3,4], to be briefly described in the following. A third topic relating to previous infections is not conclusive and will be dealt with separately.

Sunshine, radiation and latitude - and Vitamin D

It is well documented that the latitude alone is an important factor in MS, the disease being more frequent, the further away from Equator you come. This alone is no proof of sunlight, but some observations indicate that mountainous regions (with more sunshine and less filtering effect of the atmosphere) are favorable to MS, while regions with more humid (and cold) weather are of opposite impact. Conversely, strong sunlight associated with high temperatures is bad for many MS-patients [38]. More difficult is the distinction, if the sunlight or the natural radiation (which does not entirely come from the sun) is of importance. Three mechanisms are suggested: 1) a direct impact upon the retina of the eye (relating to optic neuritis, a very frequent initial symptom in MS while presence of lesions in the optic nerve are found in post-mortem investigation of nearly all patients); 2) availability of vitamin D (or, more specifically, vitamin D3) through photosynthesis in the skin; and 3) inhibition of the secretion of melatonin from the pineal gland, which can be explained as an immunosuppressant effect of the sunlight [5].
    The concept of using Vitamin D against MS derives at least back to 1973 [31]. This old observation, which has so far not reached the state of an official recommendation, has recently been supported by other studies, including many for its use against other autommune diseases. I suppress remarks about the duration of certain recognitions among physicians.
    Citing a study in which exogenous 1,25-dihydroxyvitamin D3, the hormonal form of vitamin D3, can completely prevent experimental autoimmune encephalomyelitis [33], Hayes et al. hypothesized that under low-sunlight conditions, insufficient vitamin D3 is produced, limiting production of 1,25-dihydroxyvitamin D3 and thus providing a risk for MS [6]. In Switzerland, lowlanders had a higher incidence of MS than highlanders, which was then attributed to the sun. In Norway, the relation was reverse, which was then attributed to coastal persons preference for fish, leading to the next topic. Another association between MS and low levels of vitamin D was given by the finding of Nieves et al. [22]. Conversely, Schwartz [23] suggested that another stimulation of calcium metabolism might explain why pregnancy (until about 3 months after birth) protect against progression in MS. Now there seems to be a basis for MS-Patients to get interested in this vitamin. Embry et al. [32] showed that the seasonal variation of Vitamin-D concentration in blood is reversely proportional to the amount of lesions found in MS. Cantorna et al. [34] demonstrated immunoregulatory properties of the substance.  A recent study by Munger et al. [35] offers support for a protective effect of vitamin D intake on risk of developing MS. Dietary vitamin D intake was examined directly in relation to risk of MS in two large cohorts of women. Intake of vitamin D from supplements was inversely associated with risk of MS. However, whereas most vitamins have only economically adverse effects in high doses, Vitamin D interacts strongly with calcium metabolism and carries the risk of overdose, with consequences for ossification and renal function. There is a functional antagonism with glucocorticoids (but that would rather invite for adding the vitamin in periods of steroid treatment). Overdose must be feared to manifestate with 1 mg daily or more. On the contrary, the dose required for preventing rachitis in children is only about 10 micrograms per day. It seems that 50-100 micrograms daily are required [35] to permit immunological activity from Vitamin D3, but then, the amount included in other sources (e.g. fish oil) should not be forgotten. Several pharmacological preparations are available and are associated with huge price differences.

Slowly, also MS-Physicians are giving attention to this unpatented drug: Mahon et al. [36] found that Vitamin D supplementation of MS patients for 6 months was associated both with increased vitamin D status and serum TGF-beta 1. TNF-alpha, IFN-gamma and IL-13 were not changed. The consequences of these discrete findings are, however, obscure.

Dietary factors

More than any other factor, the composition of ingested fatty acids are in focus of the attention [7]. They have been so for long. The fact that reference to them is not part of the recommendations a patient with MS received is a consequence of, that neither is it proved that they are of importance in the development of MS, nor that a different intake can actually alter the disease. But beware, before you stop interest in them, you should know that evidence is strong for these environmental factors as factors in the disease progress, even though methodological problems are eternally discussed what epidemiological studies are concerned. However, if it is difficult to study the ecological importance of these factors, it is not easier to solve the second part of the question: if dietary measures can actually help those who have already caught the disease.
    An indirect indicator of the dietary problems is given with the relatively more frequent incidence of MS in association with improved social status, possibly through increased digestion of meat products, in particular smoked meat. The decreased incidence of MS in Denmark, Norway and Holland during the years 1938-48 can be understood as a similar consequence of the second world war [8].
Which fatty acids are meant? It is currently not quite clear to me, but I am trying to work through. Vegetabile acids are particularly rich in saturated acids (palmitin and stearic acids), an intermediate position is held by oil acid (omega-9), linolic and arachnoic acid (omega-6) and linolenic acid (omega-3) whereas two acids, almost restricted to fish products, are polyunsaturated: eucosapentaenic and docosahexaenic acid (omega-3). Conversely, fish products contains all the before mentioned fatty acids as well. They are, however, particularly rich in the fat-soluble vitamins D and E, which may also be of importance for the dietary approach to a number of diseases.
    The importance of vit-D has been emphasized above, considering the impact of sunlight on MS. Indeed, in the above cited study of Hayes et al. [6], the credit which in other publications is given to fish-rich diet was transferred to the abundant content of vitamin D3 in fish oil.
    Gallai et al. [9] showed that dietary supplementation with omega-3 polyunsaturated acids in both MS-patients and normal controls led to a significant decrease in the levels of IL-1 beta and TNF-alpha, and this reduction was more pronounced after 3-6 months of supplementation. Moreover, it beneficially affected prostaglandin E2 and leukotriene B4 production in white blood cells of both groups.
    Many other substances have been associated with MS but are not to be presented unanimously: butter fats, other cow milk specific compounds [3], various animal digests, in particular smoked meat, margarine, coffee, chocolate, beer calcium, riboflavin, eggs, sugar, oats, wheat and probably many more items. It would be a rather unattractive diet which would pay tribute to all these factors. However, some of these substances are more incriminated to be involved, at least at an early time of life but possibly persistantly. The possibility that cow milk is increminated in MS is far from new, but has perhaps almost been forgotten. Lack of breastfeeding and excessive consumption of cow's milk during infancy has long been postulated as an important factor in the appearance of multiple sclerosis later in life. Data from New Zealand [24] suggested a link between high childhood milk intake and MS. Examining a correlation between MS and dairy product consumption in 27 countries, Malosse et al. [25] found a good correlation between liquid cow milk and MS prevalence, a somewhat lower for cream and butter consumption but no correlation for cheese. In another study, the same working group [26] found significant correlations between (a) cow milk production per inhabitant, (b) national bovine density per inhabitant, and (c) local bovine geographic density on one side and MS prevalence on the other. Recently (2001), a Canadian study group [27] found that that immune responses to one cow milk protein, butyrophilin, can lead to encephalitis through antigenic mimicry (see: virus infection) with myelin oligodendrocyte glycoprotein; they also found an abnormal immunity to several other cow milk proteins in MS patients; and they were able to identify one specific epitope, BSA(193), which was targeted by most MS but not diabetes patients.  Similarly, German and Austrian authors [28] incriminated Butyrophilin as a possible cause of molecular mimicry to MOG, explaining how cow milk products may give rise to a pathogenic autoimmune response, possibly causing or influencing MS.
    Other dietary measures are suggested elsewhere (evaluation in progress).

Influence of some environmental factors upon the disease process

Swank [10] treated 146 patients 1949-69 and 144/150 of them until 1983/1984 [11,12] with a strong low-fat diet and claimed improvement in all disease impacts of MS, as compared with studies of other authors (see: Studies on MS). Moreover, the progression and mortality found in this study, though smaller than found in other materials, is still much higher as what is found in modern studies under immunotherapy.
     Only five studies to the therapeutic impact of fatty acids upon MS are known (to me): in a clinical study, the application of 3 g fish oil daily resulted in less progression than the control group, in which 3 g olive oil was given [13]. Similarly, a metaanalysis of three controlled (and partly inconclusive) studies gave credit to patients treated with 8.6-23 g/day linoleic acid (in two of these studies given as sunflower oil) [14]. In a Norwegian study [29], the relapse-rate and disability score of 16 MS-patients decreased in response to supplementation with fish oil and the vitamins A, D and E.
     A number of other concepts have been developed. The attempt to reduce the content of linoleic acid can hardly be taken serious (but is followed by many MS-patients), since this acid is omnipresent in practically all nutritions - leave alone that it has also been described as beneficial. Its level has been found decreased in MS-patients with acute disease (without such a diet). Moreover, linoleic acid does not reflect the functions of dihomo-gamma-linolenic and arachidonic acid, and the endogenous rate of conversion of linoleic to arachidonic acid is slow.
    The mere supply of polyunsaturated omega-3-fatty acids, in particular eicosapentaenacid (found to a high degree in fish-oil), have been shown capable of reducing the production of arachidonic acid derived eicosanoids, which promote inflammation and are associated with both septic shock and chronic inflammatory diseases [15]. From the same review, the following statement is taken: "several human studies have shown that supplementation of the diet of healthy volunteers results in reduced ex vivo production of IL-1, IL-6, TNF and IL-2 by peripheral blood mononuclear cells. Similar findings have been made in patients with rheumatoid arthritis and multiple sclerosis. Animal studies indicate that dietary fish oil reduces the response to endotoxin and to pro-inflammatory cytokines, resulting in increased survival; such diets have been beneficial in some models of bacterial challenge, chronic inflammation and auto-immunity." Also Endres et al. [16] found that IL-1 and TNF can be blocked in humans in response to intake of polyunsaturated fatty acids (see later abbreviations, link not active).
Harbige speculates in a review [17] that "Suppression of autoantibody and T lymphocyte proliferation, apoptosis of autoreactive lymphocytes, and reduced pro-inflammatory cytokine production by high-dose fish oils are all likely mechanisms by which n-3 fatty acids ameliorate autoimmune disease. However, these could be undesirable long-term effects of high-dose fish oil which may compromise host immunity."
    In experimental (murine) models of autoimmune disease [18,19], dietary supplementation with fish oil improved all parameters considerably, in particular survival (50% at 12 months) as compared to corn oil (all dead at 8 months). The same working group [20] found that dietary fish oil appears to promote programmed cell death and prevent accumulation of self-reactive immune cells in lymphoid organs. Fernandes [21] reported that vegetable oil could increase autoimmune disease by increasing the free radical formation, in turn by decreasing the antioxidant enzyme mRNA levels. In contrast, omega-3 lipid intake in the presence of an antioxidant supplement appears to exert protection against autoimmunity by enhancing antioxidant enzymes and TGF beta mRNA levels.

In summary,

there are good reasons for MS patients to direct part of their caloric intake away from animal towards maritime products, possibly enforced by regular fish-oil intake. Whether the one could replace the other remains unknown. There is no valid basis for recommending any extremes, such as a total exclusion of animal products. Similarly, I have found no convincing evidence for the dietary attempt to reduce linoleic acids. The possible influence of vitamins are later reviewed in another section amino acids. The addition of 50 mg Vitamin-D3 seems appropriate but take care to avoid excesses. Contrary to most vitamins, overdose of Vitamin-D may pose serious adverse effects (hypercalcaemia with various associated problems). The suggestion made for dairy products is worth a test (of several months duration) but also represents a serious alteration in most people's digestive tradition.
    As for sunshine, it is cheap (when appearing for your house door) and might have additional positive effects – but then, excessive sunlight and high temperatures have also been reported as bad for MS [38], in turn possibly relating to Vitamin-D deficiency when the exposure is completely avoided.
    And how to study the matter? Unfortunately, the current tendency (2002) to advocate RCT for all clinical questions will block the search for other studies still for some more years to come. And even worse: the once who advocate vitamin D for MS are often the ones who do not believe in randomised studies and are still waiting for the alternatives to be promoted. If the patients can wait so long, is another question.


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Revised June 10th, 2004