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Part 2 is also online
Introduction
Multiple sclerosis (MS) is a neurological disorder affecting anywhere from 250,000 to 450,000 people in the US.1 MS is a chronic inflammatory disease of the central nervous system (CNS) with underlying immune abnormalities.2 The disease is more common in women than men and peaks at age 20 to 40. Multiple sclerosis presents differently in different patients with the symptoms ranging from mild neurological impairments to debilitating deficits of motor, cognitive, and visual function. Multiple sclerosis pathogenesis is believed to involve an autoimmune response within the CNS, resulting in demyelination and axonal injury. Inflammation and demyelination seem to be the primary pathology in the relapsing forms of MS, whereas neurodegeneration seems to dominate in the progressive forms of the disease.3 There is no definitive cause or cure for MS, and multiple etiologies are discussed in the literature.
Etiology
The cause of multiple sclerosis is not known. There are data to support both genetic and environmental influences and new research to support new thoughts on the etiology.
Genetic predisposition has been established by an association with human leukocyte antigen (HLA) DR2. 60% of patients with MS are HLA DR2 positive. The exact mode of inheritance is unknown. There is also an increased risk of MS in someone with a first degree relative who has the disorder and this risk is unexplained by shared environment.4 Half-siblings of affected persons have half the risk of full siblings of developing MS, and adopted siblings have no greater risk than the general population.5 There is clearly some underlying genetic component.
Smoking is an environmental risk factor for MS that contributes to both increased disease susceptibility and more rapid disease advancement. The relative risk for MS development is approximately 1.5 for smokers compared with nonsmokers.6 The link between cigarette smoking and MS was established years ago. Smoking cessation is an important aspect to managing patients with MS.
Latitude and vitamin D levels are also well established factors in the development of multiple sclerosis. A recent meta-analysis confirms an association of increased risk of MS in persons living in northern latitudes around the globe.7 This association is linked to decreased exposure to ultraviolet radiation (UVR)/vitamin D. Persons with MS have low serum levels of vitamin D, and periods of low vitamin D exposure precede occurrence of high lesion activity on MRI images and periods of high vitamin D precede low lesion activity in people with MS.8 Vitamin D supplementation may play a role in decreasing the risk of MS.9 The role of vitamin D in the treatment of people with MS needs to be clarified in larger clinical trials.
Viruses are another known factor in the development of MS supported by the presence of bands of oligoclonal IgG (OCBs) in MS brain and cerebral spinal fluid (CSF) that persist throughout the lifetime of the patient. No single virus has been connected to the disease, and some researchers believe that more than one infectious agent causes or triggers disease. The varicella zoster virus (VZV) and Epstein-Barr virus (EBV) have been implicated. The detection of VZV in CSF and peripheral blood mononuclear cells (MNCs) of MS patients suggested a link between VZV infection and MS and was reinforced by the presence of herpesvirions and VZV in CSF and peripheral blood within one week after exacerbations of patients with relapsing-remitting MS.10 Epidemiological studies have revealed an increased risk for MS in EBV-seropositive individuals. Serum and CSF of MS patients show enhanced immunoreactivity to the EBV-specific proteins of MS patients and EBV has been found in the postmortem brain of patients with MS.10,11 There is limited information on the benefit of using antiviral medication or herbs in managing MS.
Hormones play a role in the development of multiple sclerosis as evidenced by the increased rates of MS in women more than men, and a decrease in MS symptoms in pregnant women, especially in the third trimester. A later onset of disease in male patients compared with female patients coincides with a decline in testosterone in men. In women with MS, late pregnancy is associated with a significant reduction in relapses, while there is a rebound increase in relapses postpartum.12 One study followed 254 women with MS to one year postdelivery and showed that relapse rates were reduced by nearly 80% during the third trimester.13 But whether or not hormones can be used in the treatment of MS is still evolving. A recent study used 8 mg a day of estriol in women with MS for 6 months to observe the effects of estrogen treatment. The dose yielded estriol levels in the blood that approximated 6-month pregnancy levels in humans. The results showed that relapsing remitting patients treated with oral estriol (8 mg/day) demonstrated decreased gadolinium enhancing lesion numbers and volumes on MRI. When estriol treatment was stopped, enhancing lesions increased to pretreatment levels.13 When estriol treatment was reinstituted, enhancing lesions again were significantly decreased. Estriol treatment also significantly increased cognitive function. In another study, 10 male MS patients were treated with 10 g of gel containing 100 mg of testosterone in a cross-over design for 12 months. All patients had improvement in cognitive performance and slowing of brain atrophy as measured by MRI. There was no significant effect of testosterone treatment on gadolinium-enhancing lesions on MRI.12 Animal models of multiple sclerosis also support the role of estrogen and testosterone therapy in the management of the disease.
Solvent exposure has been linked to multiple sclerosis in several studies. A meta-analysis of 13 studies of organic solvents and the risk of MS found that organic solvents may cause MS.14 An occupational study on solvent exposure and MS found that painters, and construction and food processing workers who were exposed to solvent had increased risk for MS.15 Another study looked at nurse anesthetists' exposure to solvents and their risk of developing MS. The incidence of MS was higher in the nurse anesthetist group when compared with both the other nurse and teacher groups respectively.16 The study included exposure to volatile anesthetic agents used prior to 1985 before more stringent restrictions on solvent exposure were in place. Most studies on solvents and MS are related to occupational exposure. There is a strong need for research on low-dose solvent exposure from common household sources and the risk of MS. It is fairly easy to test patients for solvent exposure in the blood and urine. Detoxification methods including sauna therapy have shown a reduction of solvents in the body.17
Heavy metals have been implicated in risk for multiple sclerosis. A 2007 meta-analysis review of articles published from 1996 to 2006 showed an increase between mercury amalgam use and risk of MS.18 Also, serum mercury levels were correlated to MS in the general population in Iran. 74 patients with MS were compared with 74 age-matched controls. Serum mercury level in MS patients was significantly higher than controls, revealing that high mercury levels in serum might enhance MS development in susceptible individuals.19 There is one published case of a patient with MS undergoing heavy metal urine challenge testing with EDTA revealing elevated aluminum, lead, and mercury in the urine. After undergoing EDTA chelation treatments twice a month (totaling 60 treatments), the patient's symptoms of MS improved. 20
Stress has an impact on health for both the general population and for people with multiple sclerosis. A meta-analysis of 20 studies showed that stressful events in life are associated with an increased risk for MS for exacerbations.21 In patients with MS, the experience of at least one stressful event during a period of four weeks was associated with double the risk of an exacerbation within the next week.22 The results of a recent 2011 study do not support a major role of stress in the development of the disease, just in exacerbation of symptoms.23 However, older studies do suggest a link between stressful event and the development of the disease. A 1982 study showed that more MS patients had unwanted stress in the 2 years before onset than controls.24 A study done in 1989 showed that MS patients had more life-threatening events 6 months before onset than controls.25 There are benefits in educating patients with MS in stress management techniques and coping skills. In a randomized controlled trial of relapsing-remitting MS patients, an 8-week stress management program decreased both the number of weekly symptoms and the mean intensity per symptom.26 Another study on teaching MS patients stress management and coping techniques showed a decrease in new lesions on MRI.27
Celiac disease (CD) is a systemic disease related to intolerance to gluten and is often associated with different autoimmune and neurological diseases. A link between MS and celiac has been postulated for some time. Some patients with MS show high levels of antitissue transglutaminase-2 (TGt-2) antibodies, an important serological marker in the diagnosis of celiac disease. 98 patients with MS were found to have increase in titers of immunoglobulin G antibodies against gliadin and tissue transglutaminase compared with controls.28 Another study looked at the prevalence of celiac disease in multiple sclerosis patients and their first-degree relatives. It found an increased prevalence of CD in 8 of 72 MS patients (11.1%) and also in their first-degree relatives based on duodenal biopsy and blood tests.29 All 8 of the MS patients were female. All had a positive response to a gluten-free diet in MS symptoms. However, some studies do not show a link between gluten sensitivity, celiac disease, and multiple sclerosis. 217 patients with MS were evaluated for the presence of IgA and IgG celiac disease-related antibodies and compared with a sample of 200 controls not affected by neurological disorders. None of the 217 patients with MS presented IgG and IgA antigliadin, antiendomysial antibodies, antitissue transglutaminase, and antireticulin.30 This study did not show an increased frequency of celiac disease among patients with MS. The conflicting evidence means that this area requires more investigation. Testing MS patients for celiac could prove beneficial if it means early detection and possible improvement of symptoms on a gluten-free diet.
Air pollution and poor air quality are related to the risk of MS in women as well as exacerbation of symptoms. A study of outdoor air particulate matter (PM) in the Atlanta area linked PM-10 to etiology of MS in women.31 This is coarse particulate matter from smoke, dirt, and dust from factories, farming and roads, mold, spores, and pollen. PM-10 has an influence on systemic immune response and inflammation. Ambient air pollutants are known to induce systemic immune responses and to enhance existing peripheral inflammation. Ambient air quality and monthly MS relapse occurrence in southwestern Finland were compared, showing that the risk of a relapse was over fourfold when the concentration of PM-10 was at the highest quartile.32 Some medications can protect against the effects of poor air quality in MS patients. Beta-interferon is a common treatment for MS due to its immune-modulating properties. PM-10 can affect the immune system, making those exposed more susceptible to infections. In patients not using beta-interferon, MS relapses were more frequent than in those using beta-interferon, 1 month following the episodes when PM-10 was in the highest quartile in the air.33 Instead of using beta-interferon to protect MS patients against poor air quality, another option would be tighter regulations of industries and diesel trucks responsible for polluting the air with PM-10.
Summary
Multiple sclerosis (MS) is a chronic disabling disease of the CNS that affects approximately 400,000 people in the US. Multiple sclerosis pathogenesis is believed to involve an autoimmune response within the CNS. Although no one cause has been identified, several risk factors and etiologies are well known and some are lesser known. This Part 1 review explored known etiologies and related treatments: genetics, smoking, latitude, vitamin D, viruses, hormones, solvents, heavy metals, stress, celiac disease, and air pollution. Part 2 will focus on additional integrative treatments for persons with multiple sclerosis.
Marianne Marchese, ND
www.drmarchese.com
Dr. Marchese is the author of 8 Weeks to Women's Wellness: The Detoxification Plan for Breast Cancer, Endometriosis, Infertility, and other Women's Health Conditions. Dr. Marchese graduated from the National College of Naturopathic Medicine in 2002. She maintains a private practice in Phoenix, Arizona, and teaches gynecology at Southwest College of Naturopathic Medicine.
Notes
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7. Simpson S Jr, et al. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry. 201;82(10):1132-41.
8. Munger KL, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004;62(1): 60-65.
9. Shaygannejad v, et al. Effects of Adjunct Low-Dose Vitamin D on Relapsing-Remitting Multiple Sclerosis Progression: Preliminary Findings of a Randomized Placebo-Controlled Trial. Mult Scler Int. 2012;online April 11
10. Owens GP, et al. Viruses and multiple sclerosis. Neuroscientist. 2011;17(6): 659-676.
11. Levin LI, et al. Multiple sclerosis and Epstein-Barr virus. JAMA. 2003;289(12):1533-1536.
12. Gold SM, Voskul RR. Estrogen and testosterone therapies in multiple sclerosis. Prog Brain Res. 2009;175: 239-251.
13. Gold SM, Voskul RR. Estrogen treatment in multiple sclerosis. J Neurol Sci. 2009;286(1-2): 99-103.
14. Landtblom AM et al. Organic solvents and multiple sclerosis: a synthesis of the current evidence. Epidemiology 1996;7:429-433.
15. Riise R, Moen BE, Kyvik KR. Organic solvents and the risk of multiple sclerosis. Epidemiology 2002;13(6):718-720.
16. Landtblom A-M, et al. The risk for multiple sclerosis in female nurse anaesthetists: a register based study. Occup Environ Med. 2006;63(6):387-389.
17. Crinnion W. Sauna as a valuable clinical tool for cardiovascular, autoimmune, toxicant- induced and other chronic health problems. Altern Med Rev. 2011;16(3):215-225.
18. Aminzadeh KK, Etminan M. Dental amalgam and multiple sclerosis: a systemic review and meta-analysis. J Public Health Dent. 2007;67(1):64-66.
19. Attlar Am, et al. Serum mercury level and multiple sclerosis. Biol Trace Elem Res. 2012;146(2):150-3.
20. Fulgenzi a, et al. A case of multiple sclerosis improvement following removal of heavy metal intoxication: lessons learnt from Matteo's case. Biometals. 2012;25(3):569-76.
21. Mohr Dc, et al. Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis. BMJ. 2004;328:731-733
22. Buljevac D, et al. Self reported stressful life events and exacerbations in multiple sclerosis: prospective study. BMJ. 2003;327:646-649
23. Riise T, et al. Stress and the risk of multiple sclerosis. Neurology. 2011;76(22):1866-71.
24. Warren S, et al. Emotional stress and the development of multiple sclerosis: case-controlled evidence of a relationship. J Chronic Dis. 1982;35:821-831.
25. Grant I, et al. Severely threatening events and marked life difficulties preceding onset or exacerbation of multiple sclerosis. J Neurosurg Psychiatry. 1989;52:8-13.
26. Artemiadis AK, et al. Stress management and multiple sclerosis; a randomized controlled trial. Arch Clin Neuropsychol. 2012;27(4):406-16.
27. Mohr Dc, et al. Moderating effects of coping on the relationship between stress and the development of new brain lesions in multiple sclerosis. Psychosom Med. 2002;64(5):803-9.
28. Shor DB, et al. Gluten sensitivity in multiple sclerosis: experimental myth or clinical truth? Ann N Y Acad Sci. 2009;1173:343-9.
29. Rodigo L, et al. Prevalence of celiac disease in multiple sclerosis. BMC Neurol. 2011;7:11:31.
30. Nicoletti A, et al. Frequency of celiac disease is not increased among multiple sclerosis patients. Mult Scler. 2008;14(5):698-700.
31. Gregory AC 2nd, et al. Multiple Sclerosis disease distribution and potential impact of environmental air pollutants in Georgia. Sci Total Environ. 2008;396(1):42-51
32. Oikonen M, et al. Ambient air quality and occurrence of multiple sclerosis relapse. Neuroepidemiology. 2003;22(1):95-99.
33. Oikonen MK, Erälinna JP. Beta-interferon protects multiple sclerosis patients against enhanced susceptibility to infections caused by poor air quality. Neuroepidemiology. 2008;30(1):13-19.
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