Intensive, Directed Nutrition and Neuromuscular Electrical Stimulation for Secondary Progressive Multiple Sclerosis
Terry Wahls, University of Iowa
Background
Secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) are progressive neurodegenerative diseases with muscle spasm, rigidity, and poor ambulation. Pharmacotherapy, the standard treatment for these diseases, has a goal of arresting, or at least slowing, disease progression. We hypothesize that interventions which increase availability of nerve growth factors and provide nutrients needed to rebuild damaged neurons can restore lost functions and slow/stop disease progression. Patients, therefore, would directly benefit from such interventions which should improve motor function, particularly with respect to ambulation, as well as cognition and mood. We are planning to conduct a feasibility study which is subsequently described.
Hypothesis
Substantial, measurable improvements in mobility, cognition and mood can be achieved within a 6 to 12 month timeframe by combining intensive, directed nutrition ( IDN) (to provide necessary nutrients for optimal nervous system repair and function and to decrease cytokine production), neuromuscular electrical stimulation (NMES) (to provide muscle stimulation), and a progressive exercise program (PEP) which progressively increases exercise rigor.
Rationale
The rationale for the use of Intensive, Directed Nutrition, Neuromuscular Electrical Stimulation and Progressive Exercise is as follows:
1) Most Americans fail to consume the recommended daily allowance for B vitamins, magnesium and trace minerals, essential fatty acids. Many are vitamin D deficient.1
2) Single nucleotide polymorphisms (SNPs) affecting methylenetetrahydrofolate reductase2 and or sulfation have been associated with reduced excretion of toxic compounds and increased risk of neurodegenerative disorders,3;4.
3) The effects of these SNPs may be overcome with dietary supplementation.
4) Exercise is associated with increased generation of NGF, BDNF, IGF, GCF and endorphins,5;6 all of which are critical for maintenance of muscle mass and/or repair of myelin and are diminished in SPMS, PPMS, and PD.
5) A case report of an individual with SPMS suggests that the combination of IDN + NMES-PEP over a period of 9 months may reduce fatigue and improve gait.7
6) In a subsequent case series using NMES-PEP to treat SPMS- and PPMS-related gait disability, patients who received NMES-PEP >100 days achieved a mean improvement in Expanded Disability Status Scale (EDSS) score of 0.98.
Approach
Study design: Our proposed study design is a feasibility study using interindividual comparisons at 6 and 12 months. We will assess primary endpoints at 6 months and 12 months. We will conduct interim analyses of the data after 6-month and 12-month data are collected on 50% and 75% of participants.
Inclusion/exclusion criteria: Initial subjects must have SPMS with some level of gait disability but must still be able to stand and take a minimum of 5 steps (with assistive devices if needed). We will exclude patients who have 1) unstable medical or psychiatric problems requiring a change in medication in the prior three months.
Interventions: Subjects will receive NMES-PEP+IDN for 12 months.
Intensive, directed nutrition We will provide methyl folate and methyl B12 to bypass any SNP-mediated inefficiencies. Sulfur containing amino acids will support sulfation in phase 2 detoxification pathway . Omega thee fatty acids (fish oil) and iodine (kelp) will support myelin generation.9 Allicin (garlic), flavanol (brightly colored vegetables and fruits) and isothiocyanates (cruciferous vegetables) will favorably modulate NRF2, TNFa, TRPA1, NF?ß, and other pro-inflammatory cytokines.10;11
NMES-PEP: NMES is FDA-approved for the treatment of muscle spasm, disuse atrophy, and muscle pain. We will conduct an introductory NMES session with each participant and provide thorough instruction on the proper operation of a portable electrotherapy device for home use. We will conduct a manual motor assessment for each participant and develop individualized PEPs consistent with each participant’s physical capabilities.
Participant support
We will use the following to help retain participant enthusiasm and compliance with interventions. Intensive orientation session and take home DVD summary. Daily food logs coupled with phone based photography will provide prompts to support food choices consistent with IDN. Weekly phone calls for the initial two months. Monthly home visits to assess and support NMES and progression of exercises and nutritional choices.
Assessments:
1) A NutritionQuest Food frequency survey.
2) Vitamin D, B12, folate, homocysteine, fasting lipids, hemoglobin A1C, C-reactive protein, creatinine, CBC, ALT, blood for future analyses.
3) video recording of a “Get Up and Go” test (seconds required and balance scoring), ambulation of 25 feet at comfortable speed (seconds required).
4) a six minute walking test (meters walked).
5) an EDSS score (or the gait and fatigue subscales of the Unified Parkinson's Disease Rating if a PD patient).
Primary Endpoints: Change in an Overall Composite score consisting of following components: Gait (Get Up and Go, 6 Minute Walk, 25 foot Ambulation (combined score - 50%), Cognitive Stability Index (20%), Mood (10%), Fatigue (10%) and SF36 (10%), weighted so that 0=normal function and 45= total disability all spheres.
Acknowledgements: The following individuals have contributed to the development of this study design: Kathryn Chaloner, PhD, Warren Darling, PhD, Susan Lutgendorf, PhD, Linda Snetselaar, PhD, Heidi Wood, Pharm D, Ergun Uc, MD, E.T. Shivapour, MD, Daniel Kaplan, Allison Banwart ,Emily Bradley and Nicole Grogan.
Reference List
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(2) Wiltshire EJ, Mohsin F, Chan A et al. Methylenetetrahydrofolate reductase and methionine synthase reductase gene polymorphisms and protection from microvascular complications in adolescents with type 1 diabetes. Pediatr Diabetes 2008; 9(4 Pt 2):348-353.
(3) Wiltshire EJ, Mohsin F, Chan A et al. Methylenetetrahydrofolate reductase and methionine synthase reductase gene polymorphisms and protection from microvascular complications in adolescents with type 1 diabetes. Pediatr Diabetes 2008; 9(4 Pt 2):348-353.
(4) Kageyama M, Hiraoka M, Kagawa Y. Relationship between genetic polymorphism, serum folate and homocysteine in Alzheimer's disease. Asia Pac J Public Health 2008; 20 Suppl:111-117.
(5) Carro E, Trejo JL, Busiguina S et al. Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. J Neurosci 2001; 21(15):5678-5684.
(6) Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 2007; 30(9):464-472.
(7) Reese D, Shivapour ET, Wahls TL et al. Neuromuscular electrical stimulation and dietary interventions to reduce oxidative stress in a secondary progressive multiple sclerosis patient leads to marked gains in function: a case report. Cases J 2009; 2:7601.
(8) Wahls TL, Reese D, Uc E et al. Neuromusclar electrical stimulation (NMES) improves ambulation in the setting of Multiple Sclerosis. MIdwest Society of General Medicine. 1809.
(9) Kidd PM. Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management. Altern Med Rev 2005; 10(4):268-293.
(10) Zakkar M, Van der HK, Luong lA et al. Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state. Arterioscler Thromb Vasc Biol 2009; 29(11):1851-1857.
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