MULTIPLE SCLEROSIS

– MAKING PERSONALISED MEDICINE MORE PRACTICAL

 

FJ Cronje 1, SJ van Rensburg 2, MJ Kotze 3

1 Interdisciplinary Medicine, Stellenbosch University, Cape Town, South Africa Chemical Pathology, NHLS and Stellenbosch University, Cape Town, South Africa

2  Division of Chemical Pathology, Department of Pathology, NHLS and Stellenbosch University, Cape Town, South Africa

3  Division of Anatomical Pathology, Department of Pathology, Stellenbosch University, Cape Town, South Africa

 

Introduction

 

Multiple sclerosis (MS) is a chronic neurodegenerative and demyelinating disease of the central nervous system [1]. It affects approximately 5-30 per 100,000 of the population in medium frequency countries, including South Africa, with a prevalence rate of 1 per 700 [2]. Based on 2006 data, at least 63,497 people are suffering from MS in South Africa [2]. 

 

MS remains surrounded by controversy and scientific contradiction [3-5]. Histopathological evidence remains inconclusive on whether MS is primarily an autoimmune inflammation or a primary loss of oligodendrocytes with a secondary inflammatory response [6,7]. Puzzling aetiology, divergent risk factors, diagnostic uncertainty and a variable clinical progression continue to plague consensus on diagnosis and management [5, 8-11].

 

Four clinically defined sub-types of MS are recognised: Relapsing-remitting (RRMS), Secondary Progressive (SPMS); Primary Progressive (PPMS) and Progressive Relapsing Multiple Sclerosis (RPMS). The category of Benign MS is assigned retrospectively in the absence of disease progression over 10 to 15 years [12]. In a recent survey of 430 South Africans with MS, 46% had RRMS, 13 % SPMS, and 12% PPMS [2].

 

Present Treatment Paradigms and their limitations

 

Since Charcot’s first description of post mortem sclerosing plaques and a clinical triad of nystagmus, intention tremor, and scanning speech (dysarthria) in 1868 [13], MS has been the target of a vast variety of treatments [14]. Scientific evidence largely supports the use of disease modifying drugs (DMD’s) for RRMS although a recent well-conducted RCT has challenged the long-term benefits of Interferon beta [15-21]. The rationale behind the use of DMD’s lies in their ability to alter or desensitise presumed T- and B-cell-directed destruction of myelin or cytotoxicity related to activated microglia [27]. DMD’s are costly, however, and some require regular injections [25]. Patient education may improve DMD compliance, but lack of medical insurance or denial of coverage for DMD’s often present insurmountable barriers to their use. Also, DMD’s do not work for everyone [28, 29]. For instance, between 20 to 55% of patients with RRMS do not respond to Interferon beta [30-32].  Unpleasant side-effects are common and MS symptoms may even be exacerbated [21, 31-35]. Lowered relapse rates do not assure the absence of disease progression nor does it predict the level of ultimate debilitation [36, 37]. The prescription of DMD’s is therefore complicated and actual utilization figures bear this out: In a South African survey, DMD’s were not used by 32% of respondents; 30% were on methotrexate; and only 22% on interferon beta [2].

 

The choice of whether or not to use DMD’s is not the only challenge that patients face: The diagnosis of MS is often inconclusive following the first clinical episode of acute demyelination [38].  Given the gravity and implications of making the diagnosis, doctors frequently delay pronouncing it [39, 40]. Isolated radiological findings, although suggestive of MS, are not necessarily pathognomonic and are not treated in the absence of clinical manifestations [41]. The net result, not infrequently, is an indefinite period of uncertainty without any specific intervention [39, 42, 43]. During this time patients frequently pursue complementary and alternative medicine (CAM) with or without their health care provider’s involvement or consent [44-47]. Unless this dynamic is understood and accommodated in the overall care of the MS patient, patient-doctor relationships may suffer [48]. Ignorance, discomfort, lack of confidence or prejudice towards CAM may manifest in the form of a generalised criticism of all non-pharmacological therapies or an insistence on DMD’s even when these are not indicated. Unspoken fatalism towards the presumed autoimmune nature of the disease may also discourage the HCP from motivating patients to play an active role in preserving their health [49]. Worse still, HCP’s may even actively dissuade patients from appropriate exercise or nutrition by expressing unsubstantiated concerns that these may aggravate or provoke MS relapses. All this ambiguity and uncertainty often leaves patients stranded in a “no man’s land” where DMD’s are not an option and all other possibilities are not encouraged or even dismissed.

 

Personalizing Medical Advice in MS:

 

The indications for DMD’s fall outside the scope of this article and are usually determined by a neurologist [50-52]. However, there is more to managing MS than preventing demyelination by means of immunosuppression [48]. Interventions may be indicated to address fatigue, occupational disability, mental health co-morbidities, pain and altered body image concerns [53-58]. MS patients typically favour remedies that are pragmatic to offset the feelings of helplessness [59, 60].  In this setting, HCP’s may find it quite challenging to come up evidence-based, economically viable and practical health recommendations that are also meaningful to the patient [60].

 

Whilst by no means exhaustive, there are at least four areas that offer opportunities for pro-active discussions. They are also relevant at any stage of the disease, whether or not patients are on concurrent DMD’s:

 

  • Remaining physically & mentally active:

Demyelination is not the only pathophysiological feature of MS [61]. Direct axonal and neuronal damage appears to continue even between relapses [62]. This gradual deterioration eludes conventional neuro-imaging surveillance which usually focuses primarily on the inflammatory and sclerotic components of the disease [63, 64]. So the “white spots on the MRI” are not the whole story [65]. In fact it appears to be the “invisible” neurodegenerative components that determine the ultimate physical and mental disability [66]. As such, strategies for preserving cognitive function, preventing social isolation and optimising physical health are important and should be encouraged actively while avoiding fatigue and overexertion [67-69]. 

 

  • Support myelin maintenance & repair:

Myelin is synthesised and repaired on an ongoing basis [70].  Oligodendrocyte precursors (adult stem cells that are normally present in the brain) are able to replace damaged myelin [71]. However, MS patients have a higher turnover of glia and myelin and this imposes increased nutritional demands on repair mechanisms [72]. Not surprisingly, MS patients often develop deficiencies [46, 73-76]; these include iron, all the components of the folate-vitamin B12-methionine methylation system, vitamin D, essential amino acids and essential (unsaturated) fatty acids [77, 78]. These deficiencies are rarely appreciated or addressed, even though readily reversible. Importantly, consistent availability of all these components is a prerequisite for optional myelin synthesis and repair [46, 73-76]. Therefore, regular dietary intake is essential to meet increased demands and becomes critical during MS relapses. Clinical improvements have been recorded in MS patients following a specific supplementation regimen [76].  Such supplementation may also be associated with improved cognitive function and preservation of brain volume in normal individuals [79, 80]. Whilst patient-selected arbitrary supplementation is quite common, formal assessment may better differentiate patients who need individualised iron, Vit B12 and Vit D supplementation [81, 82]. When nutritional strategies are based on objective assessments (biochemical tests), they are generally adopted with greater confidence and commitment [61].

 

  • Avoid toxic & oxidative stress – e.g., assisting patients to avoid exposure to cigarette smoke:

Oligodendrocytes and their precursors are vulnerable to reactive oxygen species, excitotoxicity and hypoxia [83]. Lipid peroxidation by free radicals plays a large role in myelin damage [84, 22]. As such, lifestyle choices have the potential to impact MS [85]. Avoiding external toxicities and supporting the body’s various detoxification and antioxidant strategies are appropriate. These include glutathione, copper-zinc and manganese superoxide dismutase (CuZnSOD / MnSOD), catalase (containing iron) and glutathione peroxidase (containing selenium), as well as the antioxidant vitamins (e.g., Vit C, Vit E and beta carotene). In addition, avoiding active or passive smoking, moderate alcohol intake and appropriate exercise are all important considerations. As with nutrition, the greatest challenge lies in motivating patients to want to make the change and to take responsibility for their health [86]. Therefore, the HCP’s attitude towards promoting health preservation is essential for patient commitment. In our experience health messages that promote “preserving the body’s ability for self-renewal” are more motivating than those that propose “doing what you can to delay the inevitable”.

 

  • Pathology Supported Genetic Testing:

MS patients have a number of potential genetic risk factors [87]. Whilst not correctable at our present state of knowledge or technology [88], several important enzyme-related single nucleotide polymorphisms (SNP’s) can be addressed indirectly through lifestyle and nutritional interventions: Focused genetic testing may identify these SNP’s and offer various enzyme supporting, enhancing or regenerating strategies [89-91]. Again, objective information adds confidence and promotes a greater willingness to participate [92]. Patient motivation is critical for success. Therefore, any proposed recommendations should be realistic and verifiable [93]. Linking small and simple lifestyle changes to a patient’s present routines is often more effective than trying to implement radical changes or complicated regimens [94, 95].

 

Explaining the value of lifestyle choices and nutritional support for MS

 

MS is a complex disease. Given the controversy still surrounding the use of DMD’s after decades of rigorous and well-funded research, it is improbable that a clear answer will emerge on the impact of various dietary interventions or nutritional supplements on disease progression [23]. Basic biochemistry testing can assist in determining those factors that are in greatest need of intervention and then to build sound lifestyle recommendations around maintaining them at optimal levels. There are also many resources to assist in communicating the value of better lifestyle choices with patients. Although many would be considered basic common sense, these small, simple, practical and beneficial choices should be encouraged actively [96].

 

Summary

 

Multiple sclerosis is a prevalent and devastating disease. Pharmacological interventions are indicated during relapses and in certain forms of the disease. However, many patients fall outside of the criteria for specific intervention. For these individuals in particular, the assessment of specific and modifiable lifestyle, biochemical and genetic risk factors may offer an objective, personalised and practical way to lower their risk for deterioration and to support the ongoing synthesis, maintenance and repair of myelin. The authors hope that this article will assist in motivating and equipping primary HCP’s and their patients alike to play a more active role in preserving health.

 

 

References

 

  1. Waubant E. Overview of treatment options in multiple sclerosis. J Clin Psychiatry 2012;73:e22.

  2. Modi G, Mochan A, du Toit M, Stander I. Multiple sclerosis in South Africa. S Afr Med J 2008;98:391-3.

  3. Ontaneda D, Hyland M, Cohen JA. Multiple sclerosis: new insights in pathogenesis and novel therapeutics. Annu Rev Med 2012;63:389-404.

  4. Tenembaum SN. Ethical challenges in paediatric clinical trials in multiple sclerosis. Ther Adv Neurol Disord 2012;5:139-46.

  5. Steiner I, Mosberg-Galili R. Quo vadis multiple sclerosis? Inflammopharmacology 2010;18:261-2.

  6. Sawcer S, Hellenthal G, Pirinen M, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011;476:214-9.

  7. Putzki N, Hartung HP. Fundamentals of the pathophysiology of MS - therapeutic approaches. In: Treatment of multiple sclerosis: Unimed (Bremen); 2009.

  8. Solomon AJ, Klein EP, Bourdette D. "Undiagnosing" multiple sclerosis: The challenge of misdiagnosis in MS. Neurology 2012;78:1986-91.

  9. Goodin DS, Traboulsee A, Knappertz V, et al. Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon beta-1b trial in multiple sclerosis. J Neurol Neurosurg Psychiatry 2012;83:282-7.

  10. Rudick RA. The elusive biomarker for personalized medicine in multiple sclerosis: The search continues. Neurology 2012.

  11. Compston A. 'The marvellous harmony of the nervous parts': the origins of multiple sclerosis. Clin Med 2004;4:346-54.

  12. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996;46:907-11.

  13. Charcot JM. Histologie de la sclerose en plaques. Gazette des hopitaux 1868; 41:554-55.

  14. Lublin F. History of modern multiple sclerosis therapy. J Neurol 2005;252 Suppl 3:iii3-iii9.

  15. Qizilbash N, Mendez I, Sanchez-de la Rosa R. Benefit-risk analysis of glatiramer acetate for relapsing-remitting and clinically isolated syndrome multiple sclerosis. Clin Ther 2012;34:159-76 e5.

  16. Liu J, Wang L, Zhan SY, Xia Y. Daclizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev 2012;4:CD008127.

  17. La Mantia L, Vacchi L, Di Pietrantonj C, et al. Interferon beta for secondary progressive multiple sclerosis. Cochrane Database Syst Rev 2012;1:CD005181.

  18. Pucci E, Giuliani G, Solari A, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev 2011:CD007621.

  19. He D, Zhou H, Han W, Zhang S. Rituximab for relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev 2011:CD009130.

  20. Oliver BJ, Kohli E, Kasper LH. Interferon therapy in relapsing-remitting multiple sclerosis: a systematic review and meta-analysis of the comparative trials. J Neurol Sci 2011;302:96-105.

  21. Nikfar S, Rahimi R, Abdollahi M. A meta-analysis of the efficacy and tolerability of interferon-beta in multiple sclerosis, overall and by drug and disease type. Clin Ther 2010;32:1871-88.

  22. Laule C, Pavlova V, Leung E, et al. Diffusely Abnormal White Matter in Multiple Sclerosis: Further Histologic Studies Provide Evidence for a Primary Lipid Abnormality With Neurodegeneration. Journal of Neuropathology & Experimental Neurology 2013;72:42-52 10.1097/NEN.0b013e31827bced3.

  23. Farinotti M, Vacchi L, Simi S, Di Pietrantonj C, Brait L, Filippini G. Dietary interventions for multiple sclerosis. Cochrane Database Syst Rev 2012;12:CD004192.

  24. Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA 2012;308:247-56.

  25. Chen SJ, Wang YL, Fan HC, Lo WT, Wang CC, Sytwu HK. Current status of the immunomodulation and immunomediated therapeutic strategies for multiple sclerosis. Clin Dev Immunol 2012;2012:970789.

  26. Phillips CJ, Humphreys I. Assessing cost-effectiveness in the management of multiple sclerosis. Clinicoecon Outcomes Res 2009;1:61-78.

  27. Katrych O, Simone TM, Azad S, Mousa SA. Disease-modifying agents in the treatment of multiple sclerosis: a review of long-term outcomes. CNS Neurol Disord Drug Targets 2009;8:512-9.

  28. Byun E, Caillier SJ, Montalban X, et al. Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis. Arch Neurol 2008;65:337-44.

  29. Rio J, Nos C, Tintore M, et al. Assessment of different treatment failure criteria in a cohort of relapsing-remitting multiple sclerosis patients treated with interferon beta: implications for clinical trials. Ann Neurol 2002;52:400-6.

  30. Vandenbroeck K, Comabella M. Single-nucleotide polymorphisms in response to interferon-beta therapy in multiple sclerosis. J Interferon Cytokine Res 2010;30:727-32.

  31. Axtell RC, Raman C. Janus-like effects of type I interferon in autoimmune diseases. Immunol Rev 2012;248:23-35.

  32. Devonshire V, Havrdova E, Radue EW, et al. Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol 2012;11:420-8.

  33. Werneck LC, Lorenzoni PJ, Radunz VA, Utiumi MA, Kay CS, Scola RH. Influence of treatment in multiple sclerosis disability: an open, retrospective, non-randomized long-term analysis. Arq Neuropsiquiatr 2010;68:511-21.

  34. Stangel M. Neurodegeneration and Neuroprotection in Multiple Sclerosis. Curr Pharm Des 2012.

  35. Humphries C. Progressive multiple sclerosis: The treatment gap. Nature 2012;484:S10.

  36. Sky R. Multiple sclerosis and the family physician. Can Fam Physician 1977;23:83-6.

  37. Martinelli V, Ghezzi A, Montanari E, Radaelli M, Comi G, Bossa R. Disclosing the diagnosis of multiple sclerosis: The Profile Project. J Neurol 2012.

  38. Sencer W. Suspicion of multiple sclerosis. To tell or not to tell? Arch Neurol 1988;45:441-2.

  39. Granberg T, Martola J, Kristoffersen-Wiberg M, Aspelin P, Fredrikson S. Radiologically isolated syndrome - incidental magnetic resonance imaging findings suggestive of multiple sclerosis, a systematic review. Mult Scler 2012.

  40. Heesen C, Schaffler N, Kasper J, Muhlhauser I, Kopke S. Suspected multiple sclerosis - what to do? Evaluation of a patient information leaflet. Mult Scler 2009;15:1103-12.

  41. Papathanasopoulos P, Messinis L, Lyros E, Nikolakopoulou A, Gourzoulidou E, Malefaki S. Communicating the diagnosis of multiple sclerosis: results of a survey among Greek neurologists. J Neurol 2008;255:1963-9.

  42. Leong EM, Semple SJ, Angley M, Siebert W, Petkov J, McKinnon RA. Complementary and alternative medicines and dietary interventions in multiple sclerosis: what is being used in South Australia and why? Complement Ther Med 2009;17:216-23.

  43. Mehta DH, Gardiner PM, Phillips RS, McCarthy EP. Herbal and dietary supplement disclosure to health care providers by individuals with chronic conditions. J Altern Complement Med 2008;14:1263-9.

  44. van Rensburg SJ, Kotze MJ, van Toorn R. The conundrum of iron in multiple sclerosis - time for an individualised approach. Metab Brain Dis 2012.

  45. Pucci E, Cartechini E, Taus C, Giuliani G. Why physicians need to look more closely at the use of complementary and alternative medicine by multiple sclerosis patients. Eur J Neurol 2004;11:263-7.

  46. Stoll SS, Nieves C, Tabby DS, Schwartzman R. Use of therapies other than disease-modifying agents, including complementary and alternative medicine, by patients with multiple sclerosis: a survey study. J Am Osteopath Assoc 2012;112:22-8.

  47. Murray TJ. The history of multiple sclerosis: the changing frame of the disease over the centuries. J Neurol Sci 2009;277 Suppl 1:S3-8.

  48. Castro-Borrero W, Graves D, Frohman TC, et al. Current and emerging therapies in multiple sclerosis: a systematic review. Ther Adv Neurol Disord 2012;5:205-20.

  49. Solaro C, Messmer Uccelli M. Pharmacological management of pain in patients with multiple sclerosis. Drugs 2010;70:1245-54.

  50. Conway D, Cohen JA. Combination therapy in multiple sclerosis. Lancet Neurol 2010;9:299-308.

  51. Truini A, Barbanti P, Pozzilli C, Cruccu G. A mechanism-based classification of pain in multiple sclerosis. J Neurol 2012.

  52. Schumann R, Adamaszek M, Sommer N, Kirkby KC. Stress, Depression and Antidepressant Treatment Options in Patients Suffering from Multiple Sclerosis. Curr Pharm Des 2012.

  53. Knoop H, van Kessel K, Moss-Morris R. Which cognitions and behaviours mediate the positive effect of cognitive behavioural therapy on fatigue in patients with multiple sclerosis? Psychol Med 2012;42:205-13.

  54. Pfaffenberger N, Gutweniger S, Kopp M, et al. Impaired body image in patients with multiple sclerosis. Acta Neurol Scand 2011;124:165-70.

  55. Motl RW, Dlugonski D. Increasing physical activity in multiple sclerosis using a behavioral intervention. Behav Med 2011;37:125-31.

  56. Dennison L, Moss-Morris R. Cognitive-behavioral therapy: what benefits can it offer people with multiple sclerosis? Expert Rev Neurother 2010;10:1383-90.

  57. Mendel R, Traut-Mattausch E, Frey D, et al. Do physicians' recommendations pull patients away from their preferred treatment options? Health Expect 2012;15:23-31.

  58. Jelinek GA, Hassed CS. Managing multiple sclerosis in primary care: are we forgetting something? Qual Prim Care 2009;17:55-61.

  59. Filippi M, Rocca MA, Barkhof F, et al. Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol 2012;11:349-60.

  60. Manrique-Hoyos N, Jurgens T, Gronborg M, et al. Late motor decline after accomplished remyelination: impact for progressive multiple sclerosis. Ann Neurol 2012;71:227-44.

  61. Wood ET, Ronen I, Techawiboonwong A, et al. Investigating axonal damage in multiple sclerosis by diffusion tensor spectroscopy. J Neurosci 2012;32:6665-9.

  62. Nocentini U, Bozzali M, Spano B, et al. Exploration of the relationships between regional grey matter atrophy and cognition in multiple sclerosis. Brain Imaging Behav 2012.

  63. Vigeveno RM, Wiebenga OT, Wattjes MP, Geurts JJ, Barkhof F. Shifting imaging targets in multiple sclerosis: From inflammation to neurodegeneration. J Magn Reson Imaging 2012;36:1-19.

  64. Samann PG, Knop M, Golgor E, Messler S, Czisch M, Weber F. Brain Volume and Diffusion Markers as Predictors of Disability and Short-Term Disease Evolution in Multiple Sclerosis. AJNR Am J Neuroradiol 2012.

  65. Prakash RS, Snook EM, Motl RW, Kramer AF. Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis. Brain Res 2010;1341:41-51.

  66. Suh Y, Weikert M, Dlugonski D, Sandroff B, Motl RW. Physical activity, social support, and depression: possible independent and indirect associations in persons with multiple sclerosis. Psychol Health Med 2012;17:196-206.

  67. Dalgas U, Stenager E. Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis? Ther Adv Neurol Disord 2012;5:81-95.

  68. Zawadzka M, Rivers LE, Fancy SP, et al. CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell 2010;6:578-90.

  69. de Castro F, Bribian A. The molecular orchestra of the migration of oligodendrocyte precursors during development. Brain Res Brain Res Rev 2005;49:227-41.

  70. Zindler E, Zipp F. Neuronal injury in chronic CNS inflammation. Best Pract Res Clin Anaesthesiol 2010;24:551-62.

  71. Weinstock-Guttman B, Mehta BK, Ramanathan M, et al. Vitamin d and multiple sclerosis. Neurologist 2012;18:179-83.

  72. Saka M, Koseler E, Metin S, et al. Nutritional status and anthropometric measurements of patients with multiple sclerosis. Saudi Med J 2012;33:160-6.

  73. Morelli A, Ravera S, Calzia D, Panfoli I. Impairment of heme synthesis in myelin as potential trigger of multiple sclerosis. Med Hypotheses 2012;78:707-10.

  74. van Rensburg SJ, Kotze MJ, Hon D, et al. Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis. Metab Brain Dis 2006;21:121-37.

  75. Mayer M. Essential fatty acids and related molecular and cellular mechanisms in multiple sclerosis: new looks at old concepts. Folia Biol (Praha) 1999;45:133-41.

  76. Di Biase A, Salvati S. Exogenous lipids in myelination and myelination. Kaohsiung J Med Sci 1997;13:19-29.

  77. Ford AH, Flicker L, Alfonso H, et al. Vitamins B(12), B(6), and folic acid for cognition in older men. Neurology 2010;75:1540-7.

  78. Bowman GL, Silbert LC, Howieson D, et al. Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. Neurology 2012;78:241-9.

  79. Kotze MJ, van Rensburg SJ. Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of Alzheimer's disease. Metab Brain Dis 2012;27:255-66.

  80. van Rensburg SJ, Kotze MJ, van Toorn R. The conundrum of iron in multiple sclerosis - time for an individualised approach. Metab Brain Dis 2012;27:239-53.

  81. Deng W, Yue Q, Rosenberg PA, Volpe JJ, Jensen FE. Oligodendrocyte excitotoxicity determined by local glutamate accumulation and mitochondrial function. J Neurochem 2006;98:213-22.

  82. Toshniwal PK, Zarling EJ. Evidence for increased lipid peroxidation in multiple sclerosis. Neurochem Res 1992;17:205-7.

  83. Jablonski NG, Chaplin G. Human skin pigmentation, migration and disease susceptibility. Philos Trans R Soc Lond B Biol Sci 2012;367:785-92.

  84. Tyszka AC, Farber RS. Exploring the relation of health-promoting behaviors to role participation and health-related quality of life in women with multiple sclerosis: a pilot study. Am J Occup Ther 2010;64:650-9.

  85. Martinelli-Boneschi F, Esposito F, Brambilla P, et al. A genome-wide association study in progressive multiple sclerosis. Mult Scler 2012.

  86. Alloza I, Otaegui D, de Lapuente AL, et al. ANKRD55 and DHCR7 are novel multiple sclerosis risk loci. Genes Immun 2012;13:253-7.

  87. Kotze MJ, van Rensburg SJ. Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of Alzheimer's disease. Metab Brain Dis 2012.

  88. Marini NJ, Gin J, Ziegle J, et al. The prevalence of folate-remedial MTHFR enzyme variants in humans. Proc Natl Acad Sci U S A 2008;105:8055-60.

  89. Alatab S, Hossein-nezhad A, Mirzaei K, Mokhtari F, Shariati G, Najmafshar A. Inflammatory profile, age of onset, and the MTHFR polymorphism in patients with multiple sclerosis. J Mol Neurosci 2011;44:6-11.

  90. Collins FS. The language of life. New York: HarperCollins; 2010.

  91. Busnello FM, Bodanese LC, Pellanda LC, Santos ZE. Nutritional intervention and the impact on adherence to treatment in patients with metabolic syndrome. Arq Bras Cardiol 2011;97:217-24.

  92. Smiley WH, 3rd. Getting patients to their lipid targets: a practical approach to implementing therapeutic lifestyle changes. J Am Osteopath Assoc 2011;111:eS13-7.

  93. Kontogianni MD, Liatis S, Grammatikou S, Perrea D, Katsilambros N, Makrilakis K. Changes in dietary habits and their association with metabolic markers after a non-intensive, community-based lifestyle intervention to prevent type 2 diabetes, in Greece. The DEPLAN study. Diabetes Res Clin Pract 2012;95:207-14.

  94. Timmerman GM, Stuifbergin AK. Eating patterns in women with multiple sclerosis. J Neurosci Nurs 1999;31:152-8.

  95. Agnello E, Palmo A. [The efficacy of dietetic intervention in multiple sclerosis]. Minerva Gastroenterol Dietol 2004;50:317-23.

  96. Lambert CP, Archer RL, Carrithers JA, Fink WJ, Evans WJ, Trappe TA. Influence of creatine monohydrate ingestion on muscle metabolites and intense exercise capacity in individuals with multiple sclerosis. Arch Phys Med Rehabil 2003;84:1206-10.

  97. Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 2002;21:495-505.

  98. Baranzini SE, Nickles D. Genetics of multiple sclerosis: swimming in an ocean of data. Curr Opin Neurol 2012;25:239-45.

  99. Montgomery SL, Bowers WJ. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol 2012;7:42-59.

 

Dr. Frans J. Cronjé

 

  MBChB  (UP), MSc