2. Management of MS symptoms with Nutrition
Polyphenol-rich Berries
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Polyphenols have shown benefits in EAE mouse models[18][30].

Multiple Sclerosis has no cure. Inflammation-dependent relapse is treated with Conventional Therapies such as interferon beta injection, but these do not treat every MS symptom and often come with unpleasant side effects. Diets and supplementation are employed by 50 to 75% of individuals with MS as symptom management tools[1][2].The following are a selection of the vitamins, minerals, fatty acids, and dietary practices under investigation to relieve MS symptoms.

1 Vitamins

Water-soluble vitamins (C and Bs) and fat-soluble vitamins (A, D, E, and K) work in our bodies as cofactors for enzymatic reactions. Their levels can decrease via improper absorbance, use in reactions, and storage. Water-soluble vitamins need to be ingested daily and are excreted when in excess, while fat soluble vitamins are stored in fat cells and released when needed. Daily intakes of vitamins depend on age, pregnancy status, sex, and other factors[3].

1.1 Vitamin B12

The Placebo Effect
Source:https://www.youtube.com/watch?v=yfRVCaA5o18

Dietary Sources

Vitamin B12 plays an important role as a cofactor for myelin formation and maintenance[4]. B12 deficiency is almost indifferentiable from MS on an MRI and some comorbidity has been documented[4][5]. Recent correlative data has shown mixed results on the association of B12 deficiency and MS with most data favoring the lack of any association[4][5][6][7]. A recent study by Najafi et al did not see any association between the deficiency of B12 and MS age of onset, duration, or disability status[5]. B12 deficiency is no longer believed to be an underlying cause for MS[1].

Wade et al tested intramuscular B12 injection as a treatment of MS in combination with L-phenylalanine and lofepramine. In both groups, B12 injection was given and showed significant decrease in disability using Guy’s neurological disability (GNDS) scale. A randomized control trial (RCT) is necessary to determine if this effect was a placebo since both groups were given the B12 injection[8]. To date B12 injection is used in combination with conventional treatment to treat severe fatigue in some patients, but this is most likely a placebo effect[1].

1.2 Vitamin D

Dietary Sources

MS prevalence increases with distance from the equator. The amount of vitamin D an individual produces, via exposure to sunlight, decreases with greater distance from the equator. It is hypothesized that this decrease in Vitamin D predisposes individuals, especially women, to MS[1] through regulation of the immune system[9]. It has also been hypothesized that increasing Vitamin D intake may be protective against MS[1][9]. There is much support for the later hypothesis including two nurses’ heath prospective cohort studies with almost 200,000 women followed for 10 or 20 years analyzed in Munger et al (2004). They concluded that higher vitamin D intake reduced the risk of developing MS in women[9].

A newborn’s risk of developing MS was assessed and found to decrease with increased maternal intake of Vitamin D during gestation and increased breast milk consumption by the newborn[10]. This trend does not continue into adolescence: higher vitamin D intake did not significantly affect the risk of MS development and high whole milk consumption (3 servings per day) increased the risk[11]. Whole milk consumption was not found to affect the risk of MS development in the analysis of the Nurses health Studies and needs to be further examined[11]. It can be hypothesized that the increased consumption of whole milk products increase saturated fat intake and may led to increased risk for MS (see saturated fat or The Swank Diet)[12][13].

Vitamin D3 (the active form of Vitamin D) has been successful in reversing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, through modification of pro-inflammatory T-cell levels[14]. This has been suggested as a possible mechanism by which vitamin D decreases the risk of MS. There is little reliable and controlled evidence for vitamin D supplementation in humans. The one trial reviewed by The Cochrane Collaboration determined that 2000-4000 IU/day of vitamin D had low risk and potential benefits such as decreased relapse rate, decreased disability, and suppression of T-cell proliferation. They also determined that it was necessary to conduct more high-powered RCTs to confirm the results[15].

Figure%201.png

[26]

2 Fats

Geographically, the distribution of MS has been more concentrated in areas where the diet is high in saturated fat and less concentrated in areas of high polyunsaturated fat intake[2]. As such, costal environment with high intake of fish have lower incidence of MS than those landlocked[12]. Ratios of ω3: ω6 PUFAs differ in foods and oils and have been shown to affect cardiovascular and myelin health through derivatives generated in the body (see figure 2)[1]. These derivatives change inflammation and/or membrane fluidity. The optimal ratio of ω3: ω6 for health is considered between 2:1 and 3:1 while the average individual in a developed country consumes at ratios as low as 1:25. Recommendations are to consume a ratio of at least 1:4[16] and to keep a low saturated fat[1][12].

2.1 Polyunsaturated Fatty Acids (PUFAs)

PUFAs include omega 3 and omega 6 fatty acids; omega 3s are best known for their anti-inflammatory properties, while omega 6, linoleic acid, is generally pro-inflammatory. Vegetable fats are often high in PUFAs while animal fats are high in saturated fat. Several mechanisms have been proposed on how PUFAs can be used to treat MS including anti-inflammation, immune-modulation, erythrocyte aggregation, and changes in myelin membrane composition[2].

A quantitative review of six methodically screened randomized control trials by Farinotti et al in 2012 determined that the progression of MS was unaffected by 2 year supplementation of PUFAs via fish oil capsules, although there may be a small trend of decreasing relapse rate. Supplementation was given for both omega 6 and omega 3 at low and high concentrations. Nevertheless, there were no reported adverse effects of taking the supplementation[2].

2.1a Hemp and Evening Primrose Oil

In a double-blind randomized clinical trial on 100 relapsing-remitting MS (RRMS) patients undergoing conventional interferon treatment, it was found that 18-21 g/day supplementation with hemp and primrose oil (1:4 ω3: ω6 ratio) for 6 months led to a decrease in relapse rate and disability (measured through extended disability status score (EDSS)) when compared to an equal amount of olive oil (ω9) supplementation. Hemp and primrose oil supplementation significantly decreased pro-inflammatory cytokines interleukin-17 (IL-17) and interferon gamma (IFN-y) and significantly increased anti-inflammatory cytokine IL-4 to indicate an overall decreased in inflammation. Olive oil supplementation significantly increased the previous pro-inflammatory cytokines[16].

Figure%202.png

[27]

2.2 Saturated Fat

High animal fat intake has long been associated with increased MS incidence in epidimeological studies[1]. The trend was first documented by Swank in 1949 and led to proposition of the Swank diet (see proposed diets below). Swank and Goodwin hypothesize that increased saturated fat is the cause of MS. This is most likely not the case, but high saturated fat has shown to aggravate MS symptoms and progression[1][12][13].

3 Oxidative Stress

Progression of relapsing remitting MS and secondary progressive MS has been associated with increasing brain inflammation. Active microglial and macrophages drive the inflammatory damage of neurons through the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS). MS cortical lesions contain oxidative neuronal damage such as DNA strand breaks, myelin and mitochondrial damage[17]. Due to the pathological influence of oxidative species in MS, dietary antioxidants such as uric acid, CoQ10, vitamins A, C, and E, polyphenols, and flavonoids, have been investigated for supplementation[18].

Figure%203.png

[28]

3.1 Antioxidant Vitamins

Vitamin A, E, and C work as anti-oxidants in the body by donating electrons to free radical and in turn neutralizing them[18]. Vitamin A is also anti-inflammatory and has been found to be protective against disease development in EAE mice studies by slowing the progression of the disease and delaying its onset [18][19]. In humans, MS plaque tissue has lower levels of vitamin E although the CSF levels of the vitamin do not differ between MS patients and controls. It has been found that the levels of the antioxidant vitamins are lower in patients in relapse compared to patients in remission. It is hypothesized that there is increased need for antioxidants during remission, however the cause-effect relation has not been proven[18]. The suggestion of Vitamin A as a supplement for MS has been hesitated due to the deleterious side effects of overconsumption, which includes visual deficits, death, and congenital malformation in fetuses[19].

3.2 Uric Acid

Uric Acid is an antioxidant derived from the breakdown of purines (Adenosine and Guanine) in the body. It can prevent the development of EAE in mice through inhibiting free radical driven cellular apoptosis and by keeping inflammatory cells out of the central nervous system (CNS). Although Uric acid levels have not been found to be predictive for MS development, like Vitamin D, the levels of Uric acid decrease during relapse like the anti-oxidant vitamins. It is thought that low uric acid can serve as a sign of disease activity[18]. Only a single trial its supplementation in RRMS patients has shown that increasing uric acid levels decreases EDSS score and lesion number. Although, another showed no effect of uric acid supplementation when interferons were co-administratered[18].

3.3 Coenzyme Q10 (CoQ10)

Coenzyme Q10 is an antioxidant present in the mitochondria and is essential for the building of adenosine triphosphate (ATP), the energy currency of the cell[20]. CoQ10 levels do not differ significantly between MS patients and controls[20], however supplementation (500 mg/day) increased superoxide dismutase (antioxidant) activity and decreased monodialdehyde (oxidative stress) levels. Supplementation did not change EDSS scores[21].

3.4 Polyphenols

Polyphenols and Flavonoids, antioxidant commonly found in wine, blueberries, and dark chocolate, have shown immunomodulatory effects in EAE. Supplementation with 1 cup of blueberries in mice decreased prevalence of EAE by 50% in the chronic mouse model of MS. Green tea, which also contains polyphenols, has shown neutrophil mediated immune modulatory effects in the EAE model[18].

Figure%204.png

[29]

4 Proposed Diets

The dietary fix-all cure for MS is very appealing to patients and many different diets have been proposed by nutritionists and physicians. It is important to consider the risk, benefits, and scientific literature on the proposed MS diets since nutrient deficiency can aggravate MS symptoms and brain deterioration[1].

4.1 The Swank Diet

Dr. Swank was the first to suggest a dietary intervention for MS in 1949 when he discovered an association between the epidemiological prevalence of MS and saturated fat intake[12][13]. Dr. Swank and Dr. Goodwin have hypothesized that the cause of MS is the aggregation of saturated fat rich chylomicrons, which block capillaries, and lesions in the CNS result from starvation of the tissues following the blockage16. This hypothesis unfortunately cannot account for all of the MS symptoms but his interventions have shown positive results in alleviating MS symptoms, decreasing length of relapse, and decreasing relapse rate[1]. The Swank diet restricts saturated fat to 15-17g/day and supplements cod liver and vegetable oils high in PUFAs. Foods containing animal fats (butter, cheese, margarine) are then restricted and high fish consumption (3-5 times/week) is encouraged[12][13]. Dr. Swank has posted in the scientific literature, concentrated in the journal Nutrition, from 1949-2003. His findings are well documented although many of his trials are without controls, which in turn makes it difficult assess trends in data[1]. Shorter trials similar to the Swank diet undergone with controls have shown benefits[1]. Swank has followed up with many of his MS patients and those whom have adhered to the diet have lived significantly longer and healthier than those whom did not adhere[1][12][13].

4.2 The Wahls Protocol

Dr. Terry Wahls Tedx Talk
source: https://www.youtube.com/watch?v=KLjgBLwH3Wc

Dr. Terry Wahls is a physician whom was diagnosed with multiple sclerosis in 2000. She treated herself out a reclining wheelchair with a Paleolithic diet, supplementation, neuromuscular electrical stimulation therapy,mediation, and increasing amounts of exercise[22]. Her ‘protocol’ is now in a book for purchase. She has co-authored a single uncontrolled pilot trial with 10 patients following her diet for a year and resulted in a significant decrease in fatigue[23]. More research is necessary to determine the extent of the effects of The Wahls Protocol although no adverse effects were reported in the study[23].

5 Overall Health

In managing MS, most research concludes that staying healthy has the greatest benefit[1]. As seen in the table 1, vitamins and minerals act as co-factors necessary for the breakdown of omegas into their functional components in the body. Vitamin deficiency has been shown to aggravate MS symptoms. For example, vitamin A deficiency leads to prolonged inflammation response in EAE mice models and it is possible that Vitamin A insufficiency may make treatment with Vitamin D supplementation less effective[19]. Vitamin D deficiency in MS patients is associated with decreased wellbeing and neurological outcome[15].

Exercise is difficult for many MS patients but an increase exercise has been shown to lead increase exercise tolerance[24]. In an analysis of over 2000 individuals with MS, it was found that good dietary habits were associated with better physical and mental health and lower levels of disability. Those that consumed at least 5 servings of vegetables and 2 servings of fruit daily were associated with better quality of life and a decreased likelihood of having high disability. Dietary habit score was a predictor for decreased relapse rate and less chance of increasing disease activity[25].

Bibliography
1. Gaby, A. Multiple Sclerosis. Glob Adv Health Med. 2(1), 50-56 (2013).
2. Farinotti et al. Dietary Interventions for multiple Sclerosis (Review). The Chohrane Library. 12, 1-50 (2012).
3. Kneller K. [Vitamins in pediatrics]. Rev. Med. Brux. 33(4), 339-45. (2012).
4. Miller et. al. Vitamin B12, demyelination, remyelination and repair in multiple sclerosis. J Neurol Sci. 233, 93-97 (2005).
5. Najafi et al. Vitamin B12 Deficiency and Multiple Sclerosis; Is there Any Association? Int J Prev Med. 3(4), 286-289 (2012).
6. Kararizou et al. Plasma homocysteine levels in patients with multiple sclerosis in the Greek population. J Chin Med Assoc. 76(11), 611-4 (2013).
7. Meghaddasi et al. Homocysteine, vitamin B12 and folate levels in Iranian patients with Multiple Sclerosis: a case control study. Clin Neurol Neurosurg. 115(9), 1802-5 (2013).
8. Wade et al. A randomized placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the “Cari Loder regime”) in the treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 73, 246-9 (2002).
9. Munger et al. Vitamin D intake and incidence of multiple sclerosis. Neurology. 62(1), 60-5 (2004).
10. Mirzaei et al. Gestational Vitamin D and the risk of Multiple Sclerosis in Offspring. Ann Neurol. 70, 30-40 (2011).
11. Munger et al. Dietary intake of vitamin D during adolescence and risk of multiple sclerosis. J Neurol. 258(3), 479-85 (2011).
12. Swank, R. and Goodwin J. Review of MS Patient Survival on a Swank Low Saturated Fat Diet. Nutrition. 19(2), 161-2 (2003).
13. Swank, R. and Goodwin J. How Saturated Fats May Be a Causative Factor in Multiple Sclerosis and Other Diseases. Nutrition. 19, 478 (2003).
14. Pedersen et al. 1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking. J Neurosci Res. 85(11), 2480-90 (2007).
15. Jagannath et al. Vitamin D for the management of multiple sclerosis (Review). The Chohrane Library. 12, 1-25 (2010).
16. Rezapour-Firouzi et al. Immunomodulatory and therapeutic effects of Hot-nature diet and co-supplemented hemp seed, evening primrose oils intervention in multiple sclerosis patients. Complement Ther. Med. 21, 473-480 (2013).
17. Friese, M. A., Schattling, B., and Fugger, L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat. Rev. Neurol. (2014).
18. Geldern, G. and Mowry E. The influence of nutritional factors on the prognosis of multiple sclerosis. Nat. Rev. Neurol. 8, 678-689 (2012).
19. Fragoso, Y. D., Stoney P. N., and McCaffery P. J. The Evidence for a Beneficial role of Vitamin A in Multiple Sclerosis. CNS Drugs. (2014).
20. Lance, J., McCabe, S., Clancy, R., and Pierce J. Coenzyme Q10- A therapeutic Agent. Medsurg Nurs. 21(6), 367-371 (2012).
21. Sanoobar, M. et al. Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with relapsing-remitting multiple sclerosis. Int. J. Neurosci. 123(11), 776-782 (2013).
22. Wahls T. (2014). How I Beat Progressive MS with a Paleo Diet & Functional Medicine. Retrieved from http://www.mindbodygreen.com/0-12809/how-i-beat-progressive-ms-with-a-paleo-diet-functional-medicine.html
23. Bisht et al. A Multimodal Intervention for Patients with Secondary Progressive Multiple Sclerosis: Feasibility and Effect on Fatigue. J Altern. Complement. Med. (2014).
24. Hansen et al. Is long-term exercise intervention effective to improve cardiac autonomic control during exercise in subjects with multiple sclerosis? A randomized control trial. Eur. J. Phys. (2014).
25. Hadgkiss et al. The association of diet with quality of life, disability, and relapse rate in an international smaple of people with multiple sclerosis. Nutr. Neurosci. (2014).
26. Figure #2. The polyunsaturated fatty acids biosynthetic pathway. Adapted from “Immunomodulatory and therapeutic effects of Hot-nature diet and co-supplemented hemp seed, evening primrose oils intervention in multiple sclerosis patients,” by Rezapour-Firouzi et al, Complementary Therapies in Medicine, 21, p. 478. Copyright 2013 by Elsevier Ltd. Adapted with permission.
27. Figure #1. Nutritional factors and their potential effects on MS. Adapted from “The influence of nutritional factors on the prognosis of multiple sclerosis,” by Geldern, G. and Mowry E., Nature Reviews Neurology, 8, p. 680. Copyright 2012 by Macmillian Publishers Ltd. Adapted with permission.
28. Figure #1. Oxidative Stress Leading to Apoptosis. Adapted from “Coenzyme Q10- A therapeutic Agent,” by Lance, J., McCabe, S., Clancy, R., and Pierce J., Medsurg Nursing, 21(6), p. 368. Copyright 2012 by Medsurg nursing.
29. Note. Influence of dietary factors on MS disease activity. Adapted from “The influence of nutritional factors on the prognosis of multiple sclerosis,” by Geldern, G. and Mowry E., Nature Reviews Neurology, 8, p. 681. Copyright 2012 by Macmillian Publishers Ltd. Adapted with permission.

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