Multiple Sclerosis: Etiologic and Therapeutic Considerations

Todd A. Born, ND

Multiple sclerosis is the most common autoimmune, inflammatory, demyelinating disease of the central nervous system (CNS), with exact cause(s) being unknown. The disorder is variable in its clinical and pathologic nature, with multiple pathways leading to tissue injury.¹ The major pathological/clinical manifestations are due to inflammation, demyelination, and axon degeneration; the leading theory is that damage is caused by auto-reactive lymphocytes.^2,3 As the disease progresses, there is microglial activation and chronic neurodegeneration.

Epidemiology

Multiple sclerosis (MS) affects more women than men.^4,5 The female-to-male ratio of MS has been steadily increasing over the last 60 years, from 1.4 to 2.3.⁶ The median and mean ages of MS onset are 23.5 and 30 years of age, respectively, with women having a peak age of onset of about 5 years earlier.⁶ Relapsing-remitting MS tends has an average onset of 25 to 29 years, which may convert to progressive MS at a mean age of 40 to 44 years.⁶ The mean age of onset for primary-progressive MS is 35 to 39 years. Although rare, onset of MS can occur as late as the seventh decade.⁶

It has been observed that MS patients are more likely than controls to have other automimmune disorders.^7-9 Alternatively, a possible infectious stimulus of the immune system has been reported in the literature.^10,11 There are many viral theories associated with MS, but no evidence exists for viruses contributing to MS development.¹² That being said, there is increasing attention centered on the Epstein Barr Virus (EBV) –the cause of infectious mononucleosis – as possibly causing or triggering MS.^13,14

EBV seropositivity among adult MS patients is near 100%.¹⁵ With age-matched controls, where EBV seropositivity is low, children with MS are more likely to be seropositive for EBV.¹⁶ While these findings do not confirm that EBV is an etiologic agent, they are suggestive and warrant further study, especially given the fatigue that is seen so often in this patient population. It is this author’s opinion that this is a perfect opportunity for naturopathic intervention.

Does Where We Live Matter?

The incidence and prevalence of MS varies geographically.^17,18 The highest rate in the world is found in the Orkney Islands, at 300 cases per 100 000 persons. Other high-frequency regions include Europe, Russia, southern Canada, northern United States, New Zealand, and southeast Australia. In many of these areas, the prevalence is more than 100 per 100 000. The current differences may be partly due to race: Caucasians, especially Northern Europeans, appear to be most susceptible, while people of Asian, African, or Native-American origin have the lowest risk.

A commonly held belief is that latitude plays a role, due to increasing incidence of MS from south to north.¹⁹ The Nurses’ Health Study revealed adjusted rate ratios of 3.5 for the northern United States, and of 2.7 for the middle tiers relative to the southern tier.²⁰ What’s also interesting to note in this study is that persons migrating from a high-to-low-risk area after the age of puberty are thought to carry their high risk with them, whereas those that migrate during childhood seem to have the risk associated with whichever area they move to.

This universal association was challenged by findings from a 2010 systematic review and meta-analysis of epidemiologic studies of MS, published in the journal Lancet Neurology.⁵ The results showed that, while the prevalence (total number of cases) of MS increased with latitude in Western Europe, North America, and Australia/New Zealand, the incidence (newly diagnosed) of MS increased with latitude only in Australia/New Zealand. Thus, there was no latitudinal gradient for MS incidence in the northern hemisphere.

Roles of Vitamin D and Month of Birth

There is a long debate about vitamin D, sunshine exposure, and MS risk. One purported explanation of decreased prevalence and incidence in lower latitudes is a protective effect of sunlight, either via vitamin D production or other effects of ultraviolet (UV) exposure.²¹ The following observations support this hypothesis:

• A number of studies have found an inverse relationship between sun exposure, UV radiation exposure, or 25-hydroxy vitamin D (25-OH-D) serum levels, and the risk or prevalence of MS.^22,23
• An analysis of data from the Nurses’ Health Study and Nurses’ Health Study II observed that the risk of developing MS was significantly reduced for women taking ≥400 IU/day of vitamin D (relative risk 0.59, 95% CI 0.38-0.91).²⁴
• A longitudinal cohort study of 469 MS patients found that in multivariate analyses, each 10 ng/ml increase in 25-OH-D level was associated with a 15% lower risk of a new T2 lesion (incidence rate ratio [IRR], 0.85; 95% confidence interval [CI], 0.76-0.95; p = 0.004) and a 32% lower risk of a gadolinium-enhancing lesion.²⁵

A 2013 article by Disanto et al, published in JAMA Neurology, describes links between being born in the month of May (the peak of MS risk in England), vitamin D level, and risk of developing MS.²⁶ The British researchers theorize that fetal defects in thymic function and inadequate circulating levels of vitamin D may explain the well-recognized influence of birth month on MS risk. Why May? It is postulated that low circulating levels of 25-OH-D are common, as the winter and spring months do not allow the pregnant mother to produce adequate amounts of this prohormone. Infants born in November had a mean of 50.9 nmol/L (20.39 ng/mL), compared to 38.4 nmol/L (15.38 ng/mL) in those born in May.²⁶ The researchers also found an inverse correlation between cord blood 25-OH-D and auto-reactive CD4+ cells. Correlation doesn’t necessarily equate to causation, but this is further evidence linking vitamin D and risk of MS. Torkildsen et al, in a meta-analysis of 15 published studies and 2 congress abstracts, also found this association, as well as the effect of month or season of birth on MS risk.²⁷

There are other autoimmune diseases that are associated with birth month, including  celiac disease, type 1 diabetes, Grave’s disease, Hashimoto’s, Crohn’s disease, and even narcolepsy.^28-33 Whether these tie in with vitamin D status has not been elucidated; these studies may point more to viral triggers and month of birth.

The Importance of Vitamin D Testing

Given the common prevalence of vitamin D insufficiency and frank deficiency, it would behoove clinicians to test vitamin D status in their patients, particularly during pregnancy.

The “optimal” level of 25-OH-D has yet to be determined, and new data suggest that this can be different, depending on ethnicity, liver status, genetics, and weight.^34-36 These factors make dosing more difficult to determine, though dosing should be based upon sun exposure for given latitudes and seasons.

To simplify matters, one may state that 25-OH-D levels should be checked after 3 or 4 months for 12 months, ensuring it doesn’t go much beyond 125-150 nmol/L (50-60 ng/mL), until you know how that individual responds to a particular vitamin D dose.^37,38

Other Considerations & Summary

Current data reveal that dietary nutrients have multiple effects, such as being able to convert cell metabolism from anabolism to catabolism, and downregulate inflammation through their interactions with enzymes, transcriptional factors, and nuclear receptors.³⁹ The combination of hypocaloric and low-fat diets with specific vitamins and other nutrients, including fish oil and polyphenols, may slow down the progression of MS, as well as expedite wellness in MS patients.³⁹

One of the more novel areas of interest is in the health of the gastrointestinal tract and its inhabitants. Changes in gut barrier function have been recorded in patients with MS, and preliminary studies using a mouse model have shown positive effects from the use of special bacteria in the gut to prevent demyelination.⁴⁰ Control of dysbiosis is thought to favorably influence the course of disease in MS.³⁹

In summary, exclusion of neurological triggers as described, and saturated animal fats and cow’s milk, along with caloric restriction, represent the Remove component of treatment; the Replace component should include relevant essential fatty acids, probiotics, nutrients and food groups that favor inflammation, and immune-support agents such as flavonoids, polyphenols, resveratrol, curcumin, olive oil, lycopene, green tea, alpha-lipoic acid, acetyl-glutathione, B12, and selenium.^39,41 Ensuring adequate vitamin D status in utero and throughout life appears to confer benefit in risk reduction and may provide some symptom management. Correct dosing should be based on periodic blood tests.

Todd Born, ND, is in private practice with his wife, Dr Lindsay Jones-Born, at Born Naturopathic Associates, Inc, in Alameda, CA (www.bornnaturopathic.com). He is licensed in California and Connecticut. He is also Product Manager at Allergy Research Group, LLC and a thought leader for UK-based “Clinical Education,” a free peer-to-peer service that offers clinicians a closed forum to ask clinical questions and receive evidence-based responses by experts in their fields. Dr Born graduated from Bastyr University in Seattle and completed his residency at the Bastyr Center for Natural Health and its 13th teaching clinic, with rotations at Seattle-area hospitals.

References

1. Weiner HL. Multiple sclerosis is an inflammatory T-cell-mediated autoimmune disease. Arch Neurol. 2004;61(10):1613-1615.
2. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502-1517.
3. Roach ES. Is multiple sclerosis an autoimmune disorder? Arch Neurol. 2004;61(10):1615-1616.
4. Alonso A, Hernan MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology. 2008;71(2):129-135.
5. Koch-Henriksen N, Sorensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010;9(5):520-532.
6. Olek MJ. Epidemiology and clinical features of multiple sclerosis in adults. Updated March 3, 2014. http://www.uptodate.com/contents/epidemiology-and-clinical-features-of-multiple-sclerosis-in-adults. Accessed April 15, 2014.
7. Karni A, Abramsky O. Association of MS with thyroid disorders. Neurology. 1999;53(4):883-885.
8. Heinzlef O, Alamowitch S, Sazdovitch V, et al. Autoimmune diseases in families of French patients with multiple sclerosis. Acta Neurol Scand. 2000;101(1):36-40.
9. Ramagopalan SV, Dyment DA, Valdar W, et al. Autoimmune disease in families with multiple sclerosis: a population-based study. Lancet Neurol. 2007;6(7):604-610.
10. Rutschmann OT, McCrory DC, Matchar DB, et al. Immunization and MS: a summary of published evidence and recommendations. Neurology. 2002;59(12):1837-1843.
11. Brahic M.  Multiple sclerosis and viruses. Ann Neurol. 2010;68(1):6-8.
12. Hernán MA, Zhang SM, Lipworth L, et al. Multiple sclerosis and age at infection with common viruses. Epidemiology. 2001;12(3):301-306.
13. Pender MP. Does Epstein-Barr virus infection in the brain drive the development of multiple sclerosis? Brain. 2009;132(Pt 12):3196-3198.
14. Bagert BA. Epstein-Barr virus in multiple sclerosis. Curr Neurol Neurosci Rep. 2009;9(5):405-410.
15. Levin LI, Munger KL, O’Reilly EJ, et al. Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol. 2010;67(6):824-830.
16. Alotaibi S, Kennedy J, Tellier R, et al. Epstein-Barr virus in pediatric multiple sclerosis. JAMA. 2004;291(15):1875-1879.
17. Ebers GC. Environmental factors and multiple sclerosis. Lancet Neurol. 2008;7(3):268-277.
18. Simpson S Jr, Blizzard L, Otahal P, et al. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry. 2011;82(10):1132-1141.
19. Alonso A, Hernan MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology. 2008;71(2):129-135.
20. Hernán MA, Olek MJ, Ascherio A. Geographic variation of MS incidence in two prospective studies of US women. Neurology. 1999;53(8):1711-1718.
21. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol. 2007;61(6):504-513.
22. van der Mei IA, Ponsonby AL, Dwyer T, et al. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. BMJ. 2003;327(7410):316.
23. Salzer J, et al. Vitamin D as a protective factor in multiple sclerosis. Neurology. 2012 Nov;79(21):2140-2145.
24. Munger KL, Zhang SM, O’Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62(1):60-65.
25. Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72(2):234-240.
26. Disanto G, Watson CT, Meier UC, et al. Month of birth and thymic output. JAMA Neurol. 2013;70(4):527-528.
27. Torkildsen O, Grytten N, Aarseth J, et al. Month of birth as a risk factor for multiple sclerosis: an update. Acta Neurol Scand Suppl. 2012;(195):58-62.
28. Lewy H, Meirson H, Laron Z. Seasonality of birth month of children with celiac disease differs from that in the general population and between sexes and is linked to family history and environmental factors. J Pediatr Gastroenterol Nutr. 2009;48(2):181-185.
29. Lewy H, Hampe CS, Kordonouri O, et al. Seasonality of month of birth differs between type 1 diabetes patients with pronounced beta-cell autoimmunity and individuals with lesser or no beta-cell autoimmunity. Pediatr Diabetes. 2008;9(1):46-52.
30. Krassas GE, Tziomalos K, Pontikides N, et al. Seasonality of month of birth of patients with Graves’ and Hashimoto’s diseases differ from that in the general population. Eur J Endocrinol. 2007;156(6):631-636.
31. Mikulecký M, Cierna I. Seasonality of births and childhood inflammatory bowel disease. Wien Klin Wochenschr. 2005;117(15-16):554-557.
32. Laron Z, Lewy H, Wilderman I, et al. Seasonality of month of birth of children and adolescents with type 1 diabetes mellitus in homogenous and heterogeneous populations. Isr Med Assoc J. 2005;7(6):381-384.
33. Dauvilliers Y, Carlander B, Molinari N, et al. Month of birth as a risk factor for narcolepsy. Sleep. 2003;26(6):663-665.
34. Binkley N, Novotny R, Krueger D, et al. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab. 2007;92(6):2130-2135.
35. Prosser DE, Jones G. Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci. 2004;29(12):664-673.
36. Gallagher JC, Peacock M, Yalamanchili V, Smith LM. Effects of vitamin D supplementation in older African American women. J Clin Endocrinol Metab. 2013;98(3):1137-1146.
37. Gonzalez C. Vitamin D Supplementation: An Update. 2010. Medscape Web site. http://www.medscape.com/viewarticle/731722_1. Accessed April 16, 2013.
38. Moyad MA. Vitamin D: A Rapid Review. Dermatol Nurs. 2009;21(1):25-30, 55.
39. Riccio P. The molecular basis of nutritional intervention in multiple sclerosis: a narrative review. Complement Ther Med. 2011;19(4):228-237.
40. Ochoa-Repáraz J, Mielcarz DW, Wang Y, et al. A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol. 2010;3(5):487-495.
41. Riccio P, Rossano R, Liuzzi GM. May diet and dietary supplements improve the wellness of multiple sclerosis patients? A molecular approach. Autoimmune Dis. 2011;2010:249842.