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Ketogenic Dietary Therapies in Neurological Disorders

A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Nutrition and Public Health".

Deadline for manuscript submissions: closed (20 September 2021) | Viewed by 45333

Special Issue Editors

Human Nutrition and Eating Disorders Research Centre, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia PV, Italy
Interests: ketogenic dietary treatments; gut microbiota; obesity and eating disorders; assessment of nutritional status; body composition and energy expenditure
Special Issues, Collections and Topics in MDPI journals
Laboratory of Food Education and Sport Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, PV, Italy
Interests: ketogenic diet; sport nutrition; nutrition knowledge; dietary habits; eating disorders

Special Issue Information

Dear Collegues,

Ketogenic dietary therapies (KDT) are established, effective nonpharmacologic treatments for intractable childhood epilepsy and some neurometabolic disorders. Today there are several ketogenic dietary therapies (KDTs) used in neurology: the classic ketogenic diet, the medium-chain triglyceride diet (MCT), the modified Atkins diet (MAD), and the low glycemic index treatment (LGIT).  In a few studies a very low calorie ketogenic diet (VLCKD)  has also been used. These dietary protocols differ greatly in their ketogenic potential and blood levels of ketosis. The mechanisms by which KDTs exert their antiseizure effects are likely multiple, may be different for various epilepsy conditions. There is a growing interest in using KDTs for several conditions other than epilepsy. KDTs may be efficacious in improving brain cancer survival and slowing progression. Ketogenesis may be a useful therapeutic strategy for migraines. In Alzheimer’s disease medium-chain triglyceride supplements have been shown to improve short-term cognitive performance in clinical studies. In autism, metabolic or mitochondrial dysfunction has been implicated as an underlying pathophysiology, with KDTs being used to target this dysfunction. Preclinical data suggest that KDTs may modulate immunity, reduce disease severity and promote remyelination in the mouse model of Multiple Sclerosis. Although KDTs use in several neurological conditions is promising, understanding mechanisms underlying its efficacy and larger studies are needed for these diverse disorders. While ketosis remain a feasible indicator of dietary compliance, its relationship with clinical efficacy has not been completely clarified.  This issue is aimed at collecting studies on a) emerging applications of KDTs in neurology and b) definition of the best dietary protocol and level of ketosis to implement in the different clinical conditions.

Prof. Dr. Anna Tagliabue
Dr. Cinzia Ferraris
Guest Editors

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Keywords

  • ketogenic dietary therapies
  • ketogenic potential, ketosis
  • classic ketogenic diet
  • modified Atkins diet
  • low-glycemic diet
  • medium chain triglycerides
  • epilepsy
  • Alzheimer’s disease
  • brain cancer
  • multiple sclerosis, migraine
  • autism
  • gut microbiota

Published Papers (8 papers)

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Research

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13 pages, 1637 KiB  
Article
Effects of Classic Ketogenic Diet in Children with Refractory Epilepsy: A Retrospective Cohort Study in Kingdom of Bahrain
Nutrients 2022, 14(9), 1744; https://doi.org/10.3390/nu14091744 - 22 Apr 2022
Cited by 8 | Viewed by 2922
Abstract
Background: The classic ketogenic diet (cKD) has been used worldwide as an effective therapy for children with drug-resistant epilepsy. However, there have been no studies performed in Middle Eastern countries in order to assess the efficacy, side effects, predictors of cKD response [...] Read more.
Background: The classic ketogenic diet (cKD) has been used worldwide as an effective therapy for children with drug-resistant epilepsy. However, there have been no studies performed in Middle Eastern countries in order to assess the efficacy, side effects, predictors of cKD response and factors mostly associated with diet adherence. This study aims to assess the efficacy of cKD ratios of 4:1 and 3:1 and their influence on growth and biochemical parameters, particularly lipid profile and liver function tests (LFTs), and the factors most associated with diet adherence in a cohort of children with drug-resistant epilepsy in Bahrain. Methods: Baseline and follow-up data related to patients’ demographic and biochemical variables, epilepsy episodes, diet history and anthropometric measurements were retrieved for a total of 24 children treated with cKD in Bahrain. Results: After 6 months cKD initiation, 58.3% were positive responders with >50% seizure rate reduction, and 33.3% became seizure-free at 12 months. After 6 months of intervention with cKD, the level of triglycerides and albumin had a significant (p < 0.05) average increase over time of +1.47 mmol/L and 4.3 g/L, respectively. Although the median values of total cholesterol and alanine transaminase increased, respectively, following cKD initiation, the difference over time was not statistically significant. The mean z-scores for weight, height, and body mass index (or weight-for-length) did not change significantly at 12 months follow-up. cKD duration was the highest correlated variable with cKD efficacy (r = 0.76), which was followed by age at cKD initiation (r = 0.47). The cKD was discontinued by 14 patients (58.3%) during the first follow-up period (6 months), which was mainly due to inefficacy (n = 8), poor compliance (n = 3), food refusal (n = 1), achieved required efficacy (n = 1) and death (n = 1). Conclusions: cKD is an effective treatment for patients with drug-resistant epilepsy, and positive response to cKD was the main factor that increased adherence to the diet. Although long-term cKD could increase the risk of dyslipidemia and hepatic problems, it appears safe for children. Consequently, close monitoring and emphasis on healthy fats is of high priority. Full article
(This article belongs to the Special Issue Ketogenic Dietary Therapies in Neurological Disorders)
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11 pages, 572 KiB  
Article
Keto-on-the-Clock: A Survey of Dietetic Care Contact Time Taken to Provide Ketogenic Diets for Drug-Resistant Epilepsy in the UK
Nutrients 2021, 13(8), 2484; https://doi.org/10.3390/nu13082484 - 21 Jul 2021
Cited by 2 | Viewed by 3181
Abstract
Medical ketogenic diets (KDs) are effective yet resource-intensive treatment options for drug-resistant epilepsy (DRE). We investigated dietetic care contact time, as no recent data exist. An online survey was circulated to ketogenic dietitians in the UK and Ireland. Data were collected considering feeding [...] Read more.
Medical ketogenic diets (KDs) are effective yet resource-intensive treatment options for drug-resistant epilepsy (DRE). We investigated dietetic care contact time, as no recent data exist. An online survey was circulated to ketogenic dietitians in the UK and Ireland. Data were collected considering feeding route, KD variant and type of ketogenic enteral feed (KEF), and the estimated number of hours spent on patient-related activities during the patient journey. Fifteen dietitians representing nine KD centres responded. Of 335 patients, 267 (80%) were 18 years old or under. Dietitians spent a median of 162 h (IQR 54) of care contact time per patient of which a median of 48% (IQR 6) was direct contact. Most time was required for the classical KD taken orally (median 193 h; IQR 213) as a combined tube and oral intake (median 211 h; IQR 172) or a blended food KEF (median 189 h; IQR 148). Care contact time per month was higher for all KDs during the three-month initial trial compared to the two-year follow-up stage. Patients and caregivers with characteristics such as learning or language difficulties were identified as taking longer. Twelve out of fifteen (80%) respondents managed patients following the KD for more than two years, requiring an estimated median contact care time of 2 h (IQR 2) per patient per month. Ten out of fifteen (67%) reported insufficient official hours for dietetic activities. Our small survey gives insight into estimated dietetic care contact time, with potential application for KD provision and service delivery Full article
(This article belongs to the Special Issue Ketogenic Dietary Therapies in Neurological Disorders)
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10 pages, 238 KiB  
Article
The Feasibility and Tolerability of Medium Chain Triglycerides in Women with a Catamenial Seizure Pattern on the Modified Atkins Diet
Nutrients 2021, 13(7), 2261; https://doi.org/10.3390/nu13072261 - 30 Jun 2021
Cited by 1 | Viewed by 2295
Abstract
Ketogenic diet therapy (KDT), particularly modified Atkins diet (MAD), is increasingly recognized as a treatment for adults with epilepsy. Women with epilepsy (WWE) comprise 50% of people with epilepsy and approximately one in three have catamenial epilepsy. The purpose of this study was [...] Read more.
Ketogenic diet therapy (KDT), particularly modified Atkins diet (MAD), is increasingly recognized as a treatment for adults with epilepsy. Women with epilepsy (WWE) comprise 50% of people with epilepsy and approximately one in three have catamenial epilepsy. The purpose of this study was to determine whether adding a medium chain triglyceride emulsion to MAD to target catamenial seizures was feasible and well-tolerated. This was a prospective two-center study of pre-menopausal WWE with a catamenial seizure pattern on MAD. After a 1-month baseline interval with no changes in treatment, participants consumed betaquik® (Vitaflo International Ltd.) for 10 days each menstrual cycle starting 2 days prior to and encompassing the primary catamenial seizure pattern for five cycles. Participants recorded seizures, ketones, and menses, and completed surveys measuring tolerability. Sixteen women aged 20–50 years (mean 32) were enrolled and 13 (81.2%) completed the study. There was 100% adherence for consuming betaquik® in the women who completed the study and overall intervention adherence rate including the participants that dropped out was 81.2%. The most common side effects attributed to MAD alone prior to starting betaquik® were constipation and nausea, whereas abdominal pain, diarrhea, and nausea were reported after adding betaquik®. The high adherence rate and acceptable tolerability of betaquik® shows feasibility for future studies evaluating KDT-based treatments for catamenial seizures. Full article
(This article belongs to the Special Issue Ketogenic Dietary Therapies in Neurological Disorders)
15 pages, 3016 KiB  
Article
Graph Theory-Based Electroencephalographic Connectivity and Its Association with Ketogenic Diet Effectiveness in Epileptic Children
Nutrients 2021, 13(7), 2186; https://doi.org/10.3390/nu13072186 - 25 Jun 2021
Cited by 4 | Viewed by 3734
Abstract
Ketogenic diet therapies (KDTs) are widely used treatments for epilepsy, but the factors influencing their responsiveness remain unknown. This study aimed to explore the predictors or associated factors for KDTs effectiveness by evaluating the subtle changes in brain functional connectivity (FC) before and [...] Read more.
Ketogenic diet therapies (KDTs) are widely used treatments for epilepsy, but the factors influencing their responsiveness remain unknown. This study aimed to explore the predictors or associated factors for KDTs effectiveness by evaluating the subtle changes in brain functional connectivity (FC) before and after KDTs. Segments of interictal sleep electroencephalography (EEG) were acquired before and after six months of KDTs. Analyses of FC were based on network-based statistics and graph theory, with a focus on different frequency bands. Seventeen responders and 14 non-responders were enrolled. After six months of KDTs, the responders exhibited a significant functional connectivity strength decrease compared with the non-responders; reductions in global efficiency, clustering coefficient, and nodal strength in the beta frequency band for a consecutive range of weighted proportional thresholds were observed in the responders. The alteration of betweenness centrality was significantly and positively correlated with seizure reduction rate in alpha, beta, and theta frequency bands in weighted adjacency matrices with densities of 90%. We conclude that KDTs tended to modify minor-to-moderate-intensity brain connections; the reduction of global connectivity and the increment of betweenness centrality after six months of KDTs were associated with better KD effectiveness. Full article
(This article belongs to the Special Issue Ketogenic Dietary Therapies in Neurological Disorders)
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16 pages, 1976 KiB  
Article
Ketogenic Diet Decreases Alcohol Intake in Adult Male Mice
Nutrients 2021, 13(7), 2167; https://doi.org/10.3390/nu13072167 - 24 Jun 2021
Cited by 12 | Viewed by 4634
Abstract
The classic ketogenic diet is a diet high in fat, low in carbohydrates, and well-adjusted proteins. The reduction in glucose levels induces changes in the body’s metabolism, since the main energy source happens to be ketone bodies. Recent studies have suggested that nutritional [...] Read more.
The classic ketogenic diet is a diet high in fat, low in carbohydrates, and well-adjusted proteins. The reduction in glucose levels induces changes in the body’s metabolism, since the main energy source happens to be ketone bodies. Recent studies have suggested that nutritional interventions may modulate drug addiction. The present work aimed to study the potential effects of a classic ketogenic diet in modulating alcohol consumption and its rewarding effects. Two groups of adult male mice were employed in this study, one exposed to a standard diet (SD, n = 15) and the other to a ketogenic diet (KD, n = 16). When a ketotic state was stable for 7 days, animals were exposed to the oral self-administration paradigm to evaluate the reinforcing and motivating effects of ethanol. Rt-PCR analyses were performed evaluating dopamine, adenosine, CB1, and Oprm gene expression. Our results showed that animals in a ketotic state displayed an overall decrease in ethanol consumption without changes in their motivation to drink. Gene expression analyses point to several alterations in the dopamine, adenosine, and cannabinoid systems. Our results suggest that nutritional interventions may be a useful complementary tool in treating alcohol-use disorders. Full article
(This article belongs to the Special Issue Ketogenic Dietary Therapies in Neurological Disorders)
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9 pages, 1195 KiB  
Article
Ketogenic Diet: Impact on Cellular Lipids in Hippocampal Murine Neurons
Nutrients 2020, 12(12), 3870; https://doi.org/10.3390/nu12123870 - 18 Dec 2020
Cited by 7 | Viewed by 2891
Abstract
Background: The mechanism of action of the ketogenic diet (KD), an effective treatment for pharmacotherapy refractory epilepsy, is not fully elucidated. The present study examined the effects of two metabolites accumulating under KD—beta-hydroxybutyrate (ßHB) and decanoic acid (C10) in hippocampal murine (HT22) neurons. [...] Read more.
Background: The mechanism of action of the ketogenic diet (KD), an effective treatment for pharmacotherapy refractory epilepsy, is not fully elucidated. The present study examined the effects of two metabolites accumulating under KD—beta-hydroxybutyrate (ßHB) and decanoic acid (C10) in hippocampal murine (HT22) neurons. Methods: A mouse HT22 hippocampal neuronal cell line was used in the present study. Cellular lipids were analyzed in cell cultures incubated with high (standard) versus low glucose supplemented with ßHB or C10. Cellular cholesterol was analyzed using HPLC, while phospholipids and sphingomyelin (SM) were analyzed using HPTLC. Results: HT22 cells showed higher cholesterol, but lower SM levels in the low glucose group without supplements as compared to the high glucose groups. While cellular cholesterol was reduced in both ßHB- and C10-incubated cells, phospholipids were significantly higher in C10-incubated neurons. Ratios of individual phospholipids to cholesterol were significantly higher in ßHB- and C10-incubated neurons as compared to controls. Conclusion: Changes in the ratios of individual phospholipids to cholesterol in HT22 neurons suggest a possible alteration in the composition of the plasma membrane and organelle membranes, which may provide insight into the working mechanism of KD metabolites ßHB and C10. Full article
(This article belongs to the Special Issue Ketogenic Dietary Therapies in Neurological Disorders)
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Review

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26 pages, 1685 KiB  
Review
Applications of Ketogenic Diets in Patients with Headache: Clinical Recommendations
Nutrients 2021, 13(7), 2307; https://doi.org/10.3390/nu13072307 - 05 Jul 2021
Cited by 20 | Viewed by 17731
Abstract
Headaches are among the most prevalent and disabling neurologic disorders and there are several unmet needs as current pharmacological options are inadequate in treating patients with chronic headache, and a growing interest focuses on nutritional approaches as non-pharmacological treatments. Among these, the largest [...] Read more.
Headaches are among the most prevalent and disabling neurologic disorders and there are several unmet needs as current pharmacological options are inadequate in treating patients with chronic headache, and a growing interest focuses on nutritional approaches as non-pharmacological treatments. Among these, the largest body of evidence supports the use of the ketogenic diet (KD). Exactly 100 years ago, KD was first used to treat drug-resistant epilepsy, but subsequent applications of this diet also involved other neurological disorders. Evidence of KD effectiveness in migraine emerged in 1928, but in the last several year’s different groups of researchers and clinicians began utilizing this therapeutic option to treat patients with drug-resistant migraine, cluster headache, and/or headache comorbid with metabolic syndrome. Here we describe the existing evidence supporting the potential benefits of KDs in the management of headaches, explore the potential mechanisms of action involved in the efficacy in-depth, and synthesize results of working meetings of an Italian panel of experts on this topic. The aim of the working group was to create a clinical recommendation on indications and optimal clinical practice to treat patients with headaches using KDs. The results we present here are designed to advance the knowledge and application of KDs in the treatment of headaches. Full article
(This article belongs to the Special Issue Ketogenic Dietary Therapies in Neurological Disorders)
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14 pages, 1106 KiB  
Review
Ketogenic Dietary Therapies in Patients with Autism Spectrum Disorder: Facts or Fads? A Scoping Review and a Proposal for a Shared Protocol
Nutrients 2021, 13(6), 2057; https://doi.org/10.3390/nu13062057 - 16 Jun 2021
Cited by 15 | Viewed by 5780
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with increasing incidence. An expanding body of literature is examining connections between ASD and dietary interventions. Existing reports suggest a beneficial effect of ketogenic dietary therapies (KDTs) in improving behavioral symptoms in ASD. In this [...] Read more.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with increasing incidence. An expanding body of literature is examining connections between ASD and dietary interventions. Existing reports suggest a beneficial effect of ketogenic dietary therapies (KDTs) in improving behavioral symptoms in ASD. In this context, the purpose of this scoping review was to identify and map available evidence in the literature about the feasibility and potential efficacy of KDTs in pediatric patients with ASD and to inform clinical practice in the field. Moreover, based on the resulting data from the literature review, we aimed to provide a shared protocol to develop a personalized KDT intervention in patients with ASD. A comprehensive and structured web-based literature search was performed using PubMed and Scopus and it yielded 203 records. Seven papers were finally selected and included in the review. Data were abstracted by independent coders. High variability was identified in study designs and dietary aspects emerged among selected studies. Results supported the effectiveness of KDTs in promoting behavioral improvements. Clinical recommendations on which patients may benefit most from KDTs implementation and difficulties in dietary adherence were discussed. Full article
(This article belongs to the Special Issue Ketogenic Dietary Therapies in Neurological Disorders)
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