Patients with secondary progressive MS have a more severe disease course than patients with a benign course. The stepwise accumulating disability following exacerbations is believed to be caused by axonal injury in the focal white matter lesions in the central nervous system through inflammatory mechanisms [5
]. A slowly progressive axonal degeneration may be the mechanism responsible for the progressive worsening in progressive multiple sclerosis (both secondary and primary).
Magnesium is neuroprotective in models of white matter ischemia and traumatic axonal injury [7
], and improves neurological outcome in patients with neural damage due to lacunar infarctions [8
]. The exact mechanism of neuroprotection by magnesium remains unclear, but may be relevant for explaining a possible inverse association between magnesium intake and tissue damage in MS. This neuroprotective property of magnesium in lesions affecting the white matter of the central nervous system may be relevant for explaining a possible inverse association between magnesium intake and tissue damage in MS. Magnesium regulates more than 300 metabolic processes [9
] yet the exact mechanisms providing axonal protection remain uncertain. Those that may be implicated in playing a protective role include energy metabolism, membrane stability, protein and DNA synthesis [10
], and inhibition of the inducible enzyme nitric oxide synthase (iNOS) [11
]. The appearance of iNOS in astrocytes and macrophages in lesions of MS gives rise to the production of high amounts of nitric oxide (NO) as well as superoxide radicals. These radicals can promote oligodendrocyte injury, demyelination, and axonal damage [12
]. Axons may degenerate because NO can inhibit mitochondrial respiration, leading to intraaxonal accumulation of Na+
]. Inhibition of iNOS by magnesium would therefore be considered neuroprotective.
Interestingly, a small post mortem study showed that magnesium concentrations in central nervous tissue and visceral organs obtained from MS patients were significantly lower than seen in controls [14
]. The most marked reduction of Mg content was observed in CNS white matter including the demyelinated plaques of MS patients. Whether or not these significantly lower Mg contents found in CNS and visceral organs of MS patients may play an essential role in the demyelinating process remain unclear, but this lower Mg content might have a relation with a reduced nutritional intake as found by our results. We found a lower intake of magnesium in the total MS group compared to the Dutch population (p = 0.001).
On a high calcium diet, vitamin D supplementation prevents experimental autoimmune encephalomyelitis [15
], which serves as an animal model for the inflammatory component of MS. However, this protective effect was abolished with a low calcium diet, and restored with a high calcium diet [16
], indicating that the positive effect of vitamin D can be increased by calcium. Interestingly, a pilot study in a small group of MS patients found that dietary supplement with magnesium, calcium and vitamin D resulted in a significant decrease in relapse rate [17
]. A low calcium intake may therefore be considered negative to MS disease course, and may be reflected in our results, since the primary progressive MS patients have a lower calcium intake than the patients with a benign disease course.
Iron is considered an important factor in the pathogenesis of multiple sclerosis [18
]. Iron may cause neuronal damage by acting as a catalyst for hydroxyl radical formation [19
], leading to lipid peroxidation [20
] and stimulating oxidative damage to proteins [21
]. Limitation of iron intake may provide protection from developing experimental autoimmune encephalomyelitis [22
]. The difference in iron intake between the secondary and primary progressive patients found in this clinical study suggests that iron may play a role in MS disease progression.
Compared to the Dutch population, protein, cholesterol and folic acid intake was significantly lower in the MS group. Folates and vitamin B12
have fundamental roles in the central nervous system at all ages, especially the methionine-synthase mediated conversion of homocysteine to methionine, which is essential for nucleotide synthesis. Deficiencies in folic acid (as vitamin B6
or vitamin B12
) are associated with elevated plasma levels of homocysteine. Elevated plasma homocysteine levels in patients with secondary progressive MS compared to healthy controls have been found [23
], suggesting a possible link between the vitamin B status and MS progression. In an earlier study we found higher homocysteine levels in MS patients as compared to healthy controls, but this was unrelated to disease progression, or deficiencies in vitamins B6
or folic acid [24
As others [25
], we could not find an association between antioxidant intake (vitamin C, E, and selenium) or serum levels and MS disease progression.
In lipid research, limitation of saturated fatty acid intake [26
], and supplementation with unsaturated fatty acids in combination with more vegetables [27
] would favour prognosis in relapsing-remitting MS. This may be related to anti-inflammatory properties of the omega-3-fatty acids [28
]. We did not find a difference in the fatty acids intake between the MS groups and no relation to disease course severity.
We found no difference in the serum levels of the vitamins or trace elements between the MS groups. This may raise the question if the found differences in intake are biologically relevant. Serum levels of several vitamins and elements are maintained in a homeostasis to a certain degree, even if there is a shortage in the body or an excess. For example; magnesium is mobilised from bone if necessary to maintain a steady serum level. This implicates that, although serum levels are within normal range, the metabolism at tissue level may be altered and lead to biological relevant effects.
In general, supplementation of nutrients may especially be needed in the presence of disease, where an altered metabolic state may enhance the need for certain nutrients, vitamins or trace elements. Compared to the daily recommended allowance, the intake of folic acid, magnesium, zinc, copper and selenium were lower in our MS patients (Additional file 1
.) and total energy intake (kcal) as well. Also total energy intake of the MS patients was lower than the energy intake of the Dutch population. This may reflect the higher risk for malnutrition in MS patients, because of handicap, obesity or medications [2
], and may suggests a need for dietary counseling.
There are limitations to our study that can serve as a base for future studies.
The results point towards magnesium, calcium and iron intake as possible candidates to be implicated in MS disease course. Ideally, a prospective dietary study in patients with recently diagnosed MS should be undertaken to find out if the differences in nutritional intake found can be confirmed to be involved in disease course modulation.
In MS patients, disability may influence dietary intake, since the more disabled may be more dependent on other persons to cook for them. Also, after receiving the diagnosis MS, patients may alter their dietary habits in an attempt to influence the disease. It is difficult for controlling these factors, but in this study the patients stressed that they did not change their diet over the last years nor were they on special diets. Furthermore, the BMI did not differ between the groups, suggesting that there seems no tendency for over- or underweight related to disease course.
Although it is difficult to interpret the findings of any nutritional survey because of the complex interaction with nutrients and human metabolism, and potential biases that can be difficult corrected for, the findings of this study may suggest a role for food intake in MS. Because the intake of several nutrients on the MS patient group was below the daily recommended allowance, we feel that MS patients should be made aware of possible nutritional deficiencies. To obtain an optimal nutritional intake, our MS patients may be advised to take dietary supplementation of magnesium, zinc, copper and selenium. A source of magnesium is bread, grain products, vegetables and diary products. Zinc can be found in meat, bread, cheese, nuts and shell-fish. Copper is present in vegetables, bread, meat, fruit and cacao products. Selenium can be found in meat, bread and fish. For the patients with a (secondary) progressive course of MS, additional calcium supplements may be advised (milk, cheese, vegetables, nuts). These findings are of importance because up to this date, no effective neuroprotective therapy is available for MS patients.