Multiple Sclerosis and the Effects of Ketogenic Diet Therapy

Overview

Multiple sclerosis (MS) is an inflammatory and immune-mediated neurological disease with multifactorial etiology. The specific etiopathogenetic mechanisms of MS are still unknown but it is clear that it results from a combination of genetic and environmental factors. Several studies have reported the possible role of diet as a risk factor for MS and its progression. To date, many dietary patterns and their association with MS have been studied, but data is still limited and inconclusive. Mediterranean Diet (MedDiet) has been associated with a lower risk of developing MS, compared to a Western-style diet. In one of investigators' studies, higher MedDiet adherence was associated with a 6-fold greater likelihood of having lower disease severity than those with low adherence. A significant restriction of carbohydrates (up to ketogenesis) can have beneficial effects on various parameters (inflammatory markers, oxidative stress, altered glucose metabolism) which are altered in subjects with MS. Ketogenic diet therapies (KDTs) have been recommended mainly for children with drug-resistant epilepsy, but in recent years they have been applied to Multiple Sclerosis. Preclinical studies in animal models evaluating the efficacy of KDTs in experimental autoimmune encephalomyelitis (EAE) found a beneficial effect of diet in slowing of disease progression, improvement of motor disability, reduction of inflammatory cytokines and reactive oxygen species. In a randomized study, improvements in health-related quality of life (HRQL) scores and a slight decrease in EDSS scores were found. An open-label, single-arm study of 20 patients with RRMS also reported that, after 6 months of MAD, no subjects had new or enlarging FLAIR/T2 lesions, with a significant improvement in the EDSS score, the Modified Fatigue Impact Scale subscales and arm. A 3-arm parallel-arm randomized controlled pilot study was planned to determine the effectiveness of a modified Atkins diet (MAD) compared to a Mediterranean diet (MedDiet) on quality of life in a population with MS.

Multiple sclerosis (MS) is an inflammatory and immune-mediated neurological disease with multifactorial etiology. MS is one of the most important causes of disability in young adults and affects more women than men (with a male-female incidence ratio between 1.5:1 and 2.5:1). The specific etiopathogenetic mechanisms of MS are still unknown but it is clear that it derives from a combination of genetic and environmental factors. Several studies have reported the possible role of diet as a risk factor for MS and its progression. The possible role of dietary components on neuroinflammation, one of the main pathogenetic mechanisms of MS, has attracted a lot of interest. Diet and dietary components can be beneficial not only on MS symptoms but also on disease progression and disability status. To date, many dietary patterns and their association with MS have been studied, but the data is still limited and inconclusive. Notably, previous observational studies have found that MS patients tend to have a less healthy or more pro-inflammatory diet, compared to controls. Recently, Alfredsson and colleagues evaluated the risk of MS based on adherence to different dietary patterns (Western, Mediterranean and vegan/vegetarian diets). The authors reported that the Mediterranean Diet (MedDiet) was associated with a lower risk of developing MS, compared to a Western-style diet, while no significant associations were described between the vegetarian/vegan diet and the risk of MS. The positive association between MedDiet adherence and improved MS severity was recently confirmed by our study, in which high MedDiet adherence was associated with a 6-fold greater likelihood of having a lower severity of disease compared to those with low adherence to the MedDiet. Over the years, researchers have studied not only the neurological aspects of the disease but also the metabolic characteristics of MS patients. Insulin resistance, inflammatory markers, oxidative stress have been and are currently the main topics of interest. Studies have highlighted that MS is associated with altered glucose and insulin metabolism, which can negatively influence cognitive decline and dysfunction. All of these mechanisms can be modified through significant carbohydrate restriction that decreases glycemia and insulin levels and leads to ketogenesis. Dietary interventions aimed at inducing therapeutic ketosis are called ketogenic diet therapies (KDTs) and include different dietary regimes: the classic ketogenic diet (cKD), the medium chain triglyceride (MCT) diet, the modified Atkins diet (MAD). These protocols have been recommended mainly for children with drug-resistant epilepsy, but in recent years they have been applied to several other neurological pathologies such as Alzheimer's, Parkinson's and, recently, Multiple Sclerosis. Preclinical studies in animal models evaluating the efficacy of KDTs in experimental autoimmune encephalomyelitis (EAE) found a beneficial effect of diet. In particular, KDT slowed disease progression, improved motor disability, reduced inflammatory cytokines and reactive oxygen species. Choi et al. (2016) enrolled 60 patients with relapsing-remitting MS (RRMS) in a randomized, parallel 3-arm study to evaluate the safety and feasibility of a 6-month KDT or fasting-mimicking diets (FMD) on patients' quality of life. The study reported improvements in health-related quality of life (HRQL) scores of both the KDT group and the FMD group, at 3 and 6 months. Furthermore, a slight decrease in EDSS scores was reported in the FMD and KDT groups. An open-label, single-arm study tested a modified Atkins diet (MAD) for 6 months in a group of 20 patients with RRMS with the aim of evaluating the feasibility and safety of the diet. The study reported that, after 6 months of MAD, no subjects had new or enlarging FLAIR/T2 lesions, with significant improvement in EDSS score, Modified Fatigue Impact Scale (MFIS) subscales, and arm function (assessed through the Nine-Hole Peg Test). Similarly, in their phase II study, Brenton and colleagues confirmed their initial findings and described an improvement in depression (Beck Depression Inventory, BDI) and quality of life (Multiple Sclerosis Quality of Life-54, MSQoL -54). Given this context, a 3-arm parallel-arm randomized controlled pilot study was planned to determine the effectiveness of a modified Atkins diet (MAD) compared to a Mediterranean diet (MedDiet) on quality of life, measured by the physical health subscale (CPH ) of MSQoL -54, in a population with MS followed at the Mondino Foundation Institute of Pavia, Italy. Safety, feasibility and general neurological, nutritional, motor and clinical outcomes were also assessed.