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In 30% of epileptic individuals, intractable epilepsy represents a problem for the management of seizures and severely affects the patient's quality of life due to pharmacoresistance with commonly used antiseizure drugs (ASDs). Surgery is not the best option for all resistant patients due to its post-surgical consequences. Therefore, several alternative or complementary therapies have scientifically proven significant therapeutic potential for the management of seizures in intractable epilepsy patients with seizure-free occurrences. Various non-pharmacological interventions include metabolic therapy, brain stimulation therapy, and complementary therapy. Metabolic therapy works out by altering the energy metabolites and include the ketogenic diets (KD) (that is restricted in carbohydrates and mimics the metabolic state of the body as produced during fasting and exerts its antiepileptic effect) and anaplerotic diet (which revives the level of TCA cycle intermediates and this is responsible for its effect). Neuromodulation therapy includes vagus nerve stimulation (VNS), responsive neurostimulation therapy (RNS) and transcranial magnetic stimulation therapy (TMS). Complementary therapies such as biofeedback and music therapy have demonstrated promising results in pharmacoresistant epilepsies. The current emphasis of the review article is to explore the different integrated mechanisms of various treatments for adequate seizure control, and their limitations, and supportive pieces of evidence that show the efficacy and tolerability of these non-pharmacological options.

Background and aim Ketogenic diets (KDs) have gained interest as a complementary treatment for cancer patients. Here we present first results of our ongoing KETOCOMP study (NCT02516501) concerning body composition changes among rectal, breast and head & neck cancer (HNC) patients who consumed a KD during curative radiotherapy (RT). Experimental procedure Sixty-one patients eating a non-ketogenic diet were compared to 20 patients on a KD supplemented with 10 g essential amino acids on RT days. Body composition was measured prior to and weekly during RT using 8-electrode bioimpedance analysis. Longitudinal body composition data were analyzed using linear mixed effects models. Results and conclusion Patients on the KD exhibited nutritional ketosis, defined as serum β-hydroxybutyrate levels ≥0.5 mmol/l, in a median of 69.0% of blood measurements (range 0–100%) performed in our clinic. In rectal and breast cancer patients, KD was significantly associated with a loss of 0.5 and 0.4 kg fat mass per week (p = 0.00089 and 8.49 × 10−5, respectively), with no significant changes in fat free and skeletal muscle mass. In HNC patients, concurrent chemotherapy was the strongest predictor of body weight, fat free and skeletal muscle mass loss during RT, while consuming a KD was significantly associated with a gain in these measures. These preliminary results confirm prior reports indicating that KDs are safe to consume during standard-of-care therapy. They also provide an important first indication that KDs with ample amino acid intake could improve body composition during RT in curative cancer patients., Graphical abstract Image 1, Highlights • Consumption of a ketogenic diet (KD) during radio(chemo-)therapy is feasible. • In rectal and breast cancer patients, the KD significantly reduced fat mass. • Fat-free mass and skeletal muscle mass were preserved by the KD. • In head and neck cancer patients a KD influenced body composition opposite to chemotherapy.

Background: Alzheimer's disease (AD) prevalence is increasing, but its etiology remains elusive. Gut microbes can contribute to AD pathology and may help identifying novel markers and therapies against AD. Methods: A randomized crossover pilot study of modified Mediterranean-ketogenic diet (MMKD) and American Heart Association Diet (AHAD) intervention is performed on 17 subjects (age: 63.4±3.7yr), of which 11 have mild cognitive impairment (MCI), while 6 are cognitively normal (CN). Subjects undergo MMKD and AHAD intervention for 6-weeks separated by 6-weeks washout periods. Gut microbiome, fecal short-chain fatty acids (SCFAs), and markers of AD in cerebrospinal fluid (CSF) including amyloid β (Aβ)-40 and As-42, total tau, and phosphorylated tau-181 (tau-p181) are measured at before and after diet interventions. Findings: At baseline, MCI and CN subjects show no notable difference in microbiome diversity but several unique microbial signatures are detected in MCI subjects. Proteobacteria correlate positively with Aβ-42: Aβ-40 while fecal propionate and butyrate correlates negatively with Aβ-42 in MCI subjects. Several bacteria are differently affected by the two diets with distinct patterns between CN and MCI subjects. Notably, the abundance of Enterobacteriaceae, Akkermansia, Slackia, Christensenellaceae and Erysipelotriaceae increases while that of Bifidobacterium and Lachnobacterium reduces on MMKD, while AHAD increases Mollicutes. MMKD slightly reduces fecal lactate and acetate while increasing propionate and butyrate. Conversely, AHAD increases acetate and propionate while reducing butyrate. Interpretation: The data suggest that specific gut microbial signatures may predict the MCI and that the MMKD can modulate the gut microbiome and metabolites in association with improved AD biomarkers. Funding Statement: The work was supported by National Institutes of Health grant P30AG049638; R01AG055122 (SC), the Department of Defense funding W81XWH-18-1-0118 (HY), as well as the funds and services provided from Center for Diabetes, Obesity and Metabolism, Wake Forest Baptist Medical Center and National Center for Advancing Translational Sciences (NCATS), National Institutes of Health funded Wake Forest Clinical and Translational Science Institute (WF CTSI) through Grant Award Number UL1TR001420. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study was approved by the Institutional Review Boards of the Wake Forest School of Medicine and was conducted in the Wake Forest Clinical Research Units. All protocols related to the cohorts involved in the study have been reviewed and approved by the Institutional Review Board of the Wake Forest School of Medicine. All experiments and samplings were carried out in accordance with ethical and biosafety protocols approved by the Institutional guidelines.

Diet therapy is an option for managing patients with drug-resistant epilepsy (DRE). Diet therapies used for patients with epilepsy include the classic ketogenic diet, the modified Atkins diet, the medium chain triglyceride diet, and the low glycemic index diet. The effectiveness of diet therapy is highly dependent on dietary adherence. Coronavirus disease (COVID-19), a novel infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has substantially impacted the lifestyles of people worldwide. Therefore, continuing a specific diet during the COVID-19 pandemic is expected to be difficult in some aspects. Here, based on the available literature, we summarize the perspectives for maintaining diet therapy during the COVID-19 pandemic, as a scoping review. Epileptologists and dieticians need to understand the difficulty of maintaining diet therapy during the COVID-19 pandemic. In addition, the education of patients and all stakeholders to continue diet therapy even during the current COVID-19 pandemic is crucial to control epileptic seizures. In conclusion, continuing diet therapy is not a matter only for patients during the COVID-19 pandemic, but medical staff should also help patients to overcome the problems associated with the pandemic by understanding their situations.

The current coronavirus-19 pandemic has changed dramatically how neurologists care for children and adults with epilepsy. Stay-at-home orders and resistance to hospitalizations by patients have led epileptologists to engage in telemedicine and re-evaluate how to provide elective services. Ketogenic diet therapy is often started in the hospital, with families educated in hospital-based classes, but this is difficult to do in this current pandemic. At our two academic centers, both our pediatric and adult epilepsy diet centers have had to quickly consider alternative methods to both start and maintain ketogenic diet therapy. This paper provides several examples of how ketogenic diet therapy can be provided to patients in unique ways, along with recommendations from other experts and patients learned over the past few months., Highlights • Ketogenic diet therapy can be successfully initiated in the hospital with shorter, focused admissions to minimize exposure. • Similarly, the classic ketogenic diet can be started as an outpatient with telemedicine visits for education and monitoring, a non-fasting approach, and close follow-up. • In adults, starting the modified Atkins diet has been successfully accomplished with live or pre-recording educational sessions and telemedicine as well. • Patients on ketogenic diets in this pandemic should ensure adequate high fat food supplies, medications, a scale for checking their weight, and telemedicine capability.

Now 15-year-old girl with glycogen storage disease (GSD) type IIIa (OMIM 232400 ) developed severe left ventricular obstructive hypertrophy and hepatomegaly while treated with frequent cornstarch meals. Subsequently, she was introduced the ketogenic diet; continuous ketosis has been maintained for over the last 4 years. After the introduction of ketogenic diet, a normalization of the cardiomyopathy and improvement of hepatopathy was achieved, with enhanced overall quality of life.

Liver coordinates a series of metabolic adaptations to maintain systemic energy balance and provide adequate nutrients for critical organs, tissues and cells during starvation. However, the mediator(s) implicated in orchestrating these fasting-induced adaptive responses and the underlying molecular mechanisms are still obscure. Here we show that hepatic growth differentiation factor 15 (GDF15) is regulated by IRE1α-XBP1s branch and promotes hepatic fatty acids β-oxidation and ketogenesis upon fasting. GDF15 expression was exacerbated in liver of mice subjected to long-term fasted or ketogenic diet feeding. Abrogation of hepatic Gdf15 dramatically attenuated hepatic β-oxidation and ketogenesis in fasted mice or mice with STZ-initiated type I diabetes. Further study revealed that XBP1s activated Gdf15 transcription via binding to its promoter. Elevated GDF15 in liver reduced lipid accumulation and impaired NALFD development in obese mice through enhancing fatty acids oxidation in liver. Therefore, our results demonstrate a novel and critical role of hepatic GDF15 activated by IRE1α-XBP1s branch in regulating adaptive responses of liver upon starvation stress., Highlights • GDF15 is augmented in livers of mice subjected to fasting or ketogenic diet feeding. • XBP1s activates the transcription of Gdf15 via binding to its promoter. • Abrogation of hepatic Gdf15 impairs fatty acid β-oxidation and ketogenesis. • Inhibition of hepatic Gdf15 attenuates ketoacidosis of diabetic mice. • Ectopic expression of hepatic GDF15 alleviates obese-induced NAFLD development.

Objective Fibroblast growth factor 21 (FGF21), a key regulator of the metabolic response to fasting, is highly induced by endoplasmic reticulum (ER) stress. The X-box binding protein 1 (Xbp1) is one of several ER stress proteins that has been shown to directly activate the FGF21 promoter. We aimed to determine whether hepatic Xbp1 is required for induction of hepatic FGF21 in vivo. Methods Mice bearing a hepatocyte-specific deletion of Xbp1 (Xbp1LKO) were subjected to fasting, pharmacologic ER stress, or a ketogenic diet, all potent stimuli of Fgf21 expression. Results Hepatocyte-specific Xbp1 knockout mice demonstrated normal induction of FGF21 in response to fasting or pharmacologic ER stress and enhanced induction of FGF21 in response to a ketogenic diet. Consistent with preserved induction of FGF21, Xbp1LKO mice exhibited normal induction of FGF21 target genes and normal ketogenesis in response to fasting or a ketogenic diet. Conclusion Hepatic Xbp1 is not required for induction of FGF21 under physiologic or pathophysiologic conditions in vivo., Highlights • Deletion of hepatic Xbp1 in mice allows for normal induction of FGF21 upon fasting. • ER stress induces FGF21 independently of hepatic Xbp1. • Mice lacking hepatic Xbp1 show enhanced FGF21 induction when fed a ketogenic diet. • Hepatic Xbp1 is not required for induction of FGF21 in vivo.

Objective We have previously shown that the consumption of a low-carbohydrate ketogenic diet (KD) by mice leads to a distinct physiologic state associated with weight loss, increased metabolic rate, and improved insulin sensitivity [1]. Furthermore, we identified fibroblast growth factor 21 (FGF21) as a necessary mediator of the changes, as mice lacking FGF21 fed KD gain rather than lose weight [2]. FGF21 activates the sympathetic nervous system (SNS) [3], which is a key regulator of metabolic rate. Thus, we considered that the SNS may play a role in mediating the metabolic adaption to ketosis. Methods To test this hypothesis, we measured the response of mice lacking all three β-adrenergic receptors (β-less mice) to KD feeding. Results In contrast to wild-type (WT) controls, β-less mice gained weight, increased adipose tissue depots mass, and did not increase energy expenditure when consuming KD. Remarkably, despite weight-gain, β-less mice were insulin sensitive. KD-induced changes in hepatic gene expression of β-less mice were similar to those seen in WT controls eating KD. Expression of FGF21 mRNA rose over 60-fold in both WT and β-less mice fed KD, and corresponding circulating FGF21 levels were 12.5 ng/ml in KD-fed wild type controls and 35.5 ng/ml in KD-fed β-less mice. Conclusions The response of β-less mice distinguishes at least two distinct categories of physiologic effects in mice consuming KD. In the liver, KD regulates peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways through an action of FGF21 independent of the SNS and beta-adrenergic receptors. In sharp contrast, induction of interscapular brown adipose tissue (BAT) and increased energy expenditure absolutely require SNS signals involving action on one or more β-adrenergic receptors. In this way, the key metabolic actions of FGF21 in response to KD have diverse effector mechanisms., Highlights • Ketogenic diets lead to rapid increases in energy expenditure via increased sympathetic outflow to BAT. Long term the diet leads to weight loss. • β-adrenergic receptors mediate these effects; in mice lacking all three β-receptors the effects of the ketogenic diet are not observed. • Browning of subcutaneous fat by the diet is partially activated by presumed peripheral mechanisms in the absence of β-adrenergic receptors. • Sympathetic nervous system activity not required for improved insulin sensitivity and activation of fatty acid oxidation in the liver.

Globally, drug-resistant epilepsy affects one third of people living with epilepsy. With limitations in treatment options for refractory epilepsy in resource-limited regions, ketogenic diet therapy is an important option to consider. Utilizing the 2015 International League Against Epilepsy recommended minimum requirements for ketogenic diet therapy, three male children with refractory epilepsy, aged 2.5, 6.5 and 10 years, were initiated on the classical ketogenic diet using locally available food in August 2017 at University Teaching Hospitals-Children's Hospital in Lusaka, Zambia, through partnership with the Epilepsy Program at Boston Children's Hospital in the United States. Following successful initiation in all three children, the diet was discontinued in the 10-year-old due to difficulties complying with the diet. The youngest child demonstrated an over 50% seizure reduction and gained developmental milestones. The third child achieved seizure freedom and showed marked improvement in behaviour. This pilot demonstrates the feasibility of ketogenic diet as an important therapeutic option for refractory epilepsy in Zambia. Given the limitations in treatment choices and medication accessibility, dietary therapy offers an alternative management strategy in our setting. Collaboration with an established ketogenic diet centre contributes to a successful program., Highlights • Ketogenic diet is a feasible and safe therapeutic option for managing paediatric refractory epilepsy. • Despite widespread use in developed countries, it is not routinely offered in resource limited settings. • We describe the successful use of ketogenic diet therapy in Zambia for the management of paediatric refractory epilepsy.

Circadian rhythms are 24-hour oscillations affecting an organism at multiple levels from gene expression all the way to tissues and organs. They have been observed in organisms across the kingdom of life, spanning from cyanobacteria to humans. In mammals, the master circadian pacemaker is located in the hypothalamic suprachiasmatic nuclei (SCN) in the brain where it synchronizes the peripheral oscillators that exist in other tissues. This system regulates the circadian activity of a large part of the transcriptome and recent findings indicate that almost every cell in the body has this clock at the molecular level. In this review, we briefly summarize the different factors that can influence the circadian transcriptome, including light, temperature, and food intake. We then summarize recently identified general principles governing genome-scale circadian regulation, as well as future lines of research. Genome-scale circadian activity represents a fascinating study model for computational biology. For this purpose, systems biology methods are promising exploratory tools to decode the global regulatory principles of circadian regulation.