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Ketogenic diet (KD) is an excess fat, enough protein, and minimal carbohydrate diet. The high fat content in KD lowers the oesophageal sphincter tone, slows gastric emptying, and decreases intestinal transit time. The primary aim of the current clinical trial was to study the effect of L-carnitine supplementation on gastric emptying in children with drug resistant epilepsy (DRE) on KD. Assessment of the protective effect of L-carnitine on bowel function and habits in those patients was a secondary aim. The current study recruited 30 patients aged 12 months to 18 years newly diagnosed with DRE assigned to start KD who were following up at the Pediatric Clinical Nutrition and Neurology Outpatient Clinics or were admitted due to DRE at the Pediatric Neurology Inpatient Department, Children's Hospital, Ain Shams University (Egypt). Participants were assigned randomly into 2 arms; arm I: received KD with L-carnitine supplementation, arm II: received KD only. Patients were assessed at baseline and after 3 months of starting KD, the assessments of children included: 24-hour dietary recall, Chalfont Seizures Severity Scale, gastrointestinal symptoms score and Bristol stool chart, frequency of defecation per week, anthropometric measurements assessment, fasting serum lipid profile and measurement of the antral length by ultrasound. There was significant increase in antral length in the patients who received KD with L-carnitine supplementation compared to the non-supplemented group. The antral length showed a significant negative correlation with GI symptoms score in all cases and the L-carnitine supplemented group. It also showed a significant positive correlation with Bristol stool score in all patients and a significant positive correlation with stool frequency in the L-carnitine supplemented group only. L-carnitine supplementation to children with DRE on KD has a significant role in improving gastric motility and it increases the frequency of defecation. Further studies are recommended to explore additional benefits, meanwhile it is prudent to advise L-carnitine supplementation for such patients., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The ketogenic diet (KD) is a high fat, sufficient protein, and low carbohydrate dietary therapy for drug-resistant epilepsy. The underlying mechanisms of action of the KD remain unclear. In mice, the microbiota is necessary for the anti-seizure effect and specific microbes influence circulatory levels of metabolites that are linked to seizure reduction. However, it remains unclear which changes are linked to seizure reduction in patients with epilepsy., Methods: We analysed the serum metabolome of children with drug-resistant epilepsy (n = 14) before and after three months on KD. Metabolomic changes were correlated to the gut microbiome and treatment outcome, i.e., seizure reduction., Findings: In this prospective observational study, we uncovered associations between microbial species and serum metabolites that correlated with seizure reduction. Plasmalogens were most strongly linked to seizure reduction and had significant positive correlations with several gut microbes (e.g., Faecalibacterium prausnitzii, Alistipes communis, Alistipes shahii, and Christensenella minuta) while significant negative correlations were found for five strains of Escherichia coli. Infant-type Bifidobacteria correlated negatively with other metabolites associated with seizure reduction., Interpretation: The microbes and metabolites identified here may contribute to the therapeutic effect of the KD in children with drug-resistant epilepsy. Several of these metabolites (e.g., plasmalogens) play important roles in neurobiology and may influence seizures. Based on our findings, anti-seizure therapeutic strategies could be developed involving the targeted manipulation of the gut microbiota and/or its metabolites., Funding: This study was supported by the Swedish Brain Foundation, Margarethahemmet Society, Sunnerdahls Handikappfond, Stockholm County Council Research Funds, and Linnea & Josef Carlssons Foundation., Competing Interests: Declaration of interests None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: The ketogenic diet is a valuable nonpharmacologic therapy for the treatment of refractory epilepsy in children and adults. It can be time-intensive for ketogenic teams, typically comprised of a physician and dietitian at a minimum. Challenges and barriers to providing ketogenic diet services to patients by members of these teams has not been studied extensively., Methods: A survey was created and distributed to attendees at a ketogenic diet training conference (KetoCollegeAdvance™) held 21-23 May 2024 in United Kingdom. Questions included Likert scales and fill-in responses. Surveys were provided by 63 attendees (mostly dietitians) from 17 countries., Results: Respondents were mostly dietitians (45/63, 71 %) and from the United Kingdom. In regards to perceived interest levels in KD in general in their countries, dietitians were perceived as 80 % very or extremely interested, parents (66 %), and neurologists (45 %). The majority of teams included a dietitian (79 %) and physician (78 %). The majority, 43 (68 %) of respondents, assumed care of all aspects of epilepsy care once the KD was started. Common barriers to starting KD services included a long waiting list, lack of adult KD services, funding dietitians, and low referrals. Barriers to continuing KD services included poor patient compliance, a lack of financial resources for some families to afford foods, and a need for more pre-made ketogenic foods including bread, pizza, pasta, potato fries, and chocolates., Conclusions: These results from a conference of international ketogenic dietitians and physicians highlights common difficulties in providing the ketogenic diet successfully. Addressing these barriers may help expand the usage of this therapy for more patients with epilepsy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EK – Consultant to Simply Good Foods, Nutricia, Bloom Science, Cerecin, LivaNova. Data Safety Monitoring Board to NeuroPace, Royalties from Springer, Johns Hopkins University Press, UpToDate, Oxford University Press, and Elsevier. ZS – Honorarium from Nutricia and Vitaflo. Matthews Friends Medical Board Member and British Dietetic Association Professional Committee Member. JF – Director, KetoCollege., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Ketogenic diet is an effective therapy for patients with medically refractory epilepsy. It is generally well tolerated, with the most common side effects being gastrointestinal. Hepatic toxicity has been described as an uncommon side effect of ketogenic diet, usually with long-term use. However, there are limited data to implicate ketogenic diet in acute liver toxicity., Methods and Results: We analyzed all patients who underwent elective inpatient ketogenic diet initiation at our institution from June 2019 to June 2022. Of the 25 patients reviewed, we found 6 patients who showed acute, asymptomatic changes in liver function tests during initiation, in both hepatocellular and cholestatic patterns. Two patients stopped the ketogenic diet acutely and 3 patients continued ketogenic diet with changes in medications and/or addition of choline-all patients had improvement and normalization of liver function tests in the short term. One patient had acute normalization of chronically elevated liver function tests on ketogenic diet initiation., Conclusion: Ketogenic diet can cause acute changes in liver function tests during initiation of ketogenic diet, with both hepatocellular and cholestatic patterns, with and without the concurrent use of hepatotoxic medications. In most patients, ketogenic diet can be continued successfully by making changes to medications or addition of choline., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

There are many treatment options available for patients with medically refractory epilepsy including antiseizure medications, surgery, devices and ketogenic diet therapy. Ketogenic diet therapy has been shown to be a safe and effective treatment option in adult and pediatric patients. In order to obtain maximal clinical effectiveness and tolerability of any treatment option, adjustments are often necessary. This article outlines the "fine-tuning" options available for antiseizure medications, vagus nerve stimulation and ketogenic diet therapies and demonstrates that ketogenic diet therapies offer a wider array of personalizing and fine-tuning options., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To identify key factors influencing the therapeutic efficacy of the ketogenic diet (KD) for children with drug-resistant epilepsy and elucidate their interconnected relationships to optimize clinical practice., Methods: Participants were selected from children receiving KD treatment at West Second University Hospital of Sichuan University from September 2015 to October 2023. Clinical factors pre-KD and post-KD (at the third month) were analyzed systematically using an analytical framework. Descriptive analyses, univariate analyses, and multivariate regression analyses were performed for the entire cohort and subgroups of genetic and non-genetic (i.e., structural and unknown) etiologies. Thereby, the most significant predictors were identified for each relevant dependent variable. Path analysis diagrams were used for visual representation., Results: Of 156 patients, genetic etiology was prevalent (38.5%). In the genetic subgroup, channelopathies predicted lower baseline seizure frequency and increased chance of seizure freedom with KD. Frequent seizures and complex history of anti-seizure medications (ASMs) predicted severe baseline psychomotor abnormalities. Younger age at KD initiation benefited psychomotor improvement. In the non-genetic subgroup, lower baseline seizure frequency increased the likelihood of seizure freedom post-KD. Concurrent use of multiple ASMs helped achieve ≥50% seizure reduction. Boys were more likely to experience psychomotor improvement. A significant correlation was found between ≥50% seizure reduction and psychomotor improvement in both subgroups. Delayed KD initiation (longer epilepsy duration at KD start) was related to a greater number of ASMs used, infrequent seizures, and older age at epilepsy onset. In addition, patients with channelopathies had delayed initiation of KD., Significance: Children with genetic epilepsy display more pronounced characteristics of epileptic encephalopathy. Early KD intervention is crucial for channelopathies, notably SCN1A variants. For other drug-resistant epilepsy cases, KD alongside diverse ASMs may improve seizure control and developmental outcomes. However, the patient population benefiting most from early KD tends to start the treatment later, urging a re-evaluation of KD decision-making paradigms., (© 2024 International League Against Epilepsy.)

Purpose: There is limited research on the proportion of individuals with epilepsy who maintain response to ketogenic diet therapy (KDT) after discontinuing treatment. We aimed to determine the proportion of individuals who did / did not maintain response post KDT and explore factors that may influence the likelihood of maintaining response., Methods: Retrospective data were collected from 97 individuals from 9 KDT centres. Individuals had achieved ≥50 % seizure reduction on KDT for at least 12 months, with seizure frequency data available at 3 months+ post diet. Outcome 1 was: recurrence of seizures or increase in seizure frequency post diet; outcome 2: recurrence of seizures, increase in seizure frequency or an additional anti-seizure treatment started post diet., Results: 61/97 (62.9 %) individuals maintained response at latest follow-up (mean 2.5[2.0] years since stopping KDT). Approximately one third maintained response without further anti-seizure treatments. One quarter of individuals had an increase in frequency or recurrence of seizures within 6 months (95 %CI 4, 12) for outcome 1 and within 3 months (3, 6) for outcome 2. Individuals who did not achieve seizure freedom on diet were significantly more likely to have an increase in seizures or to require additional anti-seizure treatments post diet compared to those who were seizure-free on diet (hazard ratio 4.02, 95 %CI (1.46, 11.16) p < 0.01)., Conclusion: Our findings should help guide clinical teams with the information they provide patients and their families regarding likelihood of long-term seizure response to KDT. Realistic costings for KDT services may need to be considered., Competing Interests: Declaration of competing interest NES was previously supported for a research post by Vitaflo (International). She has received grants from Nutricia Advanced Medical Nutrition, Vitaflo (International) and Matthew's Friends Charity, and honoraria from Nutricia Advanced Medical Nutrition, Vitaflo (International) Ltd and Dr Schaer. EGN has received consultancy payments and honoraria from Vitaflo (International), Kanso and Cerecin. CTS is a director of FabeSmith Limited (trading as KetoSuite™) and Smith Family Limited (trading as Ketogenic Diet Therapy New Zealand). She has received grants from Callaghan Innovation and The Brydie Lauder Trust and honoraria from Nutricia Limited (NZ) and Cortex Health. EC and PT have received consultancy payments, honroraria and sponsorship from Nutricia Ltd Advanced Medical Nutrition. The remaining authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: The present study was designed to study the efficacy of sequential dietary therapy with a modified Atkins diet (mAD) followed by low glycemic index treatment (LGIT) in treating drug-resistant epilepsy in children., Methods: This interventional study was conducted from February 2021 to February 2022 among children aged 6 months to 5 years who had failed to respond to more than two conventional and correctly chosen antiseizure medications. The primary endpoint was the proportion of good responders, that is, children with more than 50% seizure reduction. Secondary outcome measures were the proportion of children with seizure freedom, > 90% seizure reduction, and the nature of parent-reported adverse events., Results: A total of 45 children were recruited for the study, with 6 children being lost to follow-up at 12 weeks. At 12 weeks, 30 of 39 (76.9%) children were good responders with more than 50% seizure reduction. Of these 30 children, 11 (24.4%) had more than 90% seizure reduction, with 9 (20%) achieving complete spasm freedom. Constipation was the most common side effect of the diet among the enrolled subjects., Conclusion: Clinicians can consider sequential dietary therapy with a mAD in the first month followed by LGIT in the next 2 months for treating children who could not tolerate mAD beyond 1 month., Competing Interests: None declared., (Thieme. All rights reserved.)

Approximately 30% of people with epilepsy will be refractory. This manuscript reviews current evidencebased non-surgical treatment modalities for pediatric refractory epilepsy, including pharmacological and dietary strategies.

Background: Ketogenic diet therapy (KDT) has been recommended as a treatment for drug-resistant epilepsy in children and young people since 2012 in the National Institute for Health and Care Excellence Clinical Guidelines for Epilepsies. The Ketogenic Dietitians Research Network completed a survey in 2017 to assess the impact of these guidelines., Methods: An online survey was circulated to ketogenic dietitians across the UK and Ireland. The results were compared with those of the 2017 survey., Results: The number of individuals following KDT was 854, comprising an increase of 13% since 2017. Service sizes ranged widely, with 1-74 (median 16) patients on the diet. Of 36 services, 30 had a waiting list, ranging from 2 to 67 (median 9) patients. The classical diet continued to be the most common KDT used (58% of patients). Ten services reported use of a new flexible medium chain triglyceride protocol. Some 48% of patients (n = 427) had been following the KDT for over 2 years, comprising an 18% increase since 2017. Of these, 68 (15.9%) had attempted to wean off KDT but had to re-start as a result of a deterioration in seizures., Conclusions: The number of individuals following medical KDT remains stable. Referral numbers and waiting lists remain high, highlighting that KDT is still a well-recognised treatment option for drug-resistant epilepsy. The types of KDT used are similar to previous years, although increasingly flexible protocols are being adopted. Longer-term use of KDT is increasing, with a proportion of patients requiring long-term use to maintain seizure control., (© 2024 The British Dietetic Association Ltd.)

Objectives: To measure and compare the efficacy and tolerability of a classical ketogenic diet (CKD) and a polyunsaturated fatty acids ketogenic diet (PUFAKD) in managing childhood refractory epilepsy. Efficacy was assessed by measuring the change in seizure frequency at 3, 6, 9, and 12 months within and between groups. The percentage reduction in seizures at <50 %, 50-90 %, >90 %, and 100 % was also measured. Tolerability was assessed and compared by recording adverse events - vomiting, nausea, lethargy, and constipation., Methods: 52 children, aged 2-10 years, were randomized, 25 in the CKD group and 27 in the PUFAKD group. Fat: carbohydrate + protein ratio of 2.2:1-4:1 was maintained in both diets; the PUFAKD group only used unsaturated fats with an omega 3: omega 6 ratio of 1:2.8. Ketone levels were measured using keto-dipsticks, with 4+ and 4++ (80-160 mg/dL) being the most optimal values., Results: A significant decrease (p=0.001) in seizures was observed (n=52), with no significant difference (p=0.537) between the two groups. The mean seizure reduction was 71.1 %, with no significant difference (p=0.488) in both groups. The mean compliance rate was 78.3 % (n=52). A statistically significant linear trend existed between a higher compliance rate and a greater reduction in seizures (p = 0.042, Z=4.039) among all children (n=52). Nausea (p=0.033) and vomiting (p=0.014) occurred more in PUFAKD than in CKD., Conclusion: No significant difference was seen in seizure reduction between the two groups. Compliance correlates with a greater seizure reduction. Despite similar seizure reduction rates, the novel PUFAKD exhibited poorer compliance and more pronounced adverse effects compared to CKD. CKD remained a superior choice over the novel PUFAKD in the management of paediatric refractory epilepsy. More controlled trials with varying PUFA compositions are recommended for long-term evaluations., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The ketogenic diet (KD) is a high fat, moderate protein and very low carbohydrate diet. It can be used as a medical treatment for drug-resistant epilepsy (DRE), glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency. The aim of this scoping review was to map the KD literature, with a focus on epilepsy and associated metabolic conditions, to summarise the current evidence-base and identify any gaps., Methods: This review was conducted using JBI scoping review methodological guidance and the PRISMA extension for scoping reviews reporting guidance. A comprehensive literature search was conducted in September 2021 and updated in February 2024 using MEDLINE, CINAHL, AMED, EmBASE, CAB Abstracts, Scopus and Food Science Source databases., Results: The initial search yielded 2721 studies and ultimately, data were extracted from 320 studies that fulfilled inclusion criteria for the review. There were five qualitative studies, and the remainder were quantitative, including 23 randomised controlled trials (RCTs) and seven quasi-experimental studies. The USA published the highest number of KD studies followed by China, South Korea and the UK. Most studies focused on the classical KD and DRE. The studies key findings suggest that the KD is efficacious, safe and tolerable., Conclusions: There are opportunities available to expand the scope of future KD research, particularly to conduct high-quality RCTs and further qualitative research focused on the child's needs and family support to improve the effectiveness of KDs., (© 2024 The Author(s). Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.)

Sleep problems are common in neurological conditions for which ketogenic dietary therapies (KDTs) are recognised as an effective intervention (drug-resistant epilepsy, autism spectrum disorder, and migraine). Given the composite framework of action of ketogenic dietary therapies, the prevalence of sleep disturbance, and the importance of sleep regulation, the present scoping review aimed at identifying and mapping available evidence of the effects of ketogenic dietary therapies on sleep. A comprehensive web-based literature search was performed retrieving publications published to June 2023 using PubMed and Scopus, yielding to 277 records. Twenty papers were finally selected and included in the review. Data were abstracted by independent coders. High variability was identified in study design and sleep outcome evaluation among the selected studies. Several changes in sleep quality and sleep structure under ketogenic dietary therapies were found, namely an improvement of overall sleep quality, improvement in the difficulty falling asleep and nighttime awakenings, improvement in daytime sleepiness and an increase of REM sleep. The relevance and possible physiological explanations of these changes, clinical recommendations, and future directions in the field are discussed., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

In response to the evolving treatment landscape for new-onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy-seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second-line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second-line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1-1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3-2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second-line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3-8.9)-particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3-21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5-20.1)-than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second-line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes., (© 2024 International League Against Epilepsy.)

Aims: This study aimed to evaluate the safety of reducing or withdrawing anti-seizure medications (ASMs) in a cohort comprising both adults and children with drug-resistant epilepsy (DRE) undergoing ketogenic diet therapy (KDT)., Methods: We conducted a comprehensive analysis of clinical profiles in adults and children with DRE who had adhered to KDT for at least 6 months. Successful withdrawal or reduction of an ASM was defined as discontinuation or dose reduction without subsequent resumption or increase and without initiation of any new ASM throughout the entire follow-up period. Changes in the ASM load were calculated specifically for adult patients., Results: The study enrolled 56 participants (34 children and 22 adults) with DRE, with 64.3% achieving successful withdrawal of at least one ASM. The probability of ASM withdrawal remained consistent for children (64.7%) versus adults (63.6%), as well as for responders (62.5%) versus non-responders (68.8%), and it was not associated with other clinical factors. Early ASM reduction (including withdrawal) after diet initiation occurred in 15 patients (26.8%), with treatment outcomes comparable to those of the remaining participants. Among the 22 adults, the mean values of ASM load reduced by 24.5%, with a similar magnitude observed for responders (24.2%) versus non-responders (25.1%). In addition, adults tend to have a slower elevation in serum ketone levels compared to children., Conclusion: This study demonstrates the safe achievability of ASM withdrawal through KDT in most patients with DRE, irrespective of age or seizure frequency reduction., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Introduction: Drug-resistant epilepsy presents high worldwide prevalence and is difficult to control despite the wide variety of available antiepileptic drugs (AED). The modified Atkins diet (MAD) is an additional treatment alternative. Several studies have addressed the use of the ketogenic diet and MAD in children with drug-resistant epilepsy, but insufficient research has been conducted into adults with the same condition., Objective: To evaluate the effectiveness and tolerability of, and adherence to, the MAD in adults with drug-resistant epilepsy., Material and Methods: We conducted a 6-month pre-post prospective study at a reference hospital. Patients were prescribed the MAD with limited carbohydrate intake and unlimited fat intake. We conducted clinical and electroencephalographic follow-up according to the relevant guidelines, and assessed adverse effects changes in laboratory findings, and adherence., Results: Thirty-two patients with drug-resistant epilepsy were included in the study. Patients' mean age was 30 years, mean disease progression time was 22 years, and all patients had focal or multifocal epilepsy. Thirty-four percent of patients presented > 50% decreases in overall seizure frequency (P =  .001); seizure control was greater in the first month and subsequently declined. These patients presented weight loss (RR: 7.2; 95% CI, 1.3-39.5; P = .02), good to fair adherence only in the first and third months (RR: 9.4; 95% CI, 0.9-93.6; P = .04 and RR: 0.4; 95% CI, 0.30-0.69; P = .02, respectively). Tolerability data showed that the MAD is safe: adverse effects were minor and short-lived in most cases, with the exception of mild to moderate hyperlipidaemia in one-third of patients. The adherence rate was 50% at the end of the study., Conclusions: In adults with drug-resistant focal epilepsy, the MAD showed adequate tolerability and moderate but decreasing effectiveness and adherence, probably due to a preference for a carbohydrate-based diet., (Copyright © 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

The ketogenic diet (KD), characterized by high-fat and low-carbohydrate intake, is currently gaining widespread popularity as a treatment for drug-resistant epilepsy (DRE). In addition to the traditional ketogenic diet, several variants have been introduced to enhance compliance and flexibility, such as the modified Atkins diet (MAD) and the low glycemic index diet (LGID). These adaptations aim to provide patients with more manageable and sustainable options while harnessing the potential therapeutic benefits of DRE. The objective of this study is to evaluate the efficacy and safety of the KD in pediatric patients who exhibit DRE. In this study, we conducted a thorough review of existing literature by searching Cochrane, Embase, Medline, and PubMed. Our approach involved predefined criteria for data extraction and the assessment of study quality. Eleven RCTs with 788 participants were included in this study. The pooled effect estimates revealed a significant association between dietary interventions and seizure frequency reduction of > 50% (OR 6.68, 96% CI 3.52, 12.67) and > 90% (OR 4.37, 95% CI 2.04, 9.37). Dietary interventions also increased the odds of achieving seizure freedom (OR 4.13, 95% CI 1.61, 10.60). The common adverse effects included constipation (39.07%) and vomiting (10%). In conclusion, dietary interventions, notably the KD, hold promise for pediatric DRE, reducing seizures and achieving freedom. These non-pharmacological options improve the quality of life of non-responsive and non-surgical patients. The KD has emerged as a potential therapeutic approach. Further research is needed to address the limitations and investigate their long-term effects., (© 2024. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

Pharmacotherapy is the therapeutic mainstay in epilepsy; however, in about 30% of patients, epileptic seizures are drug-resistant. A ketogenic diet (KD) is an alternative therapeutic option. The mechanisms underlying the anti-seizure effect of a KD are not fully understood. Epileptic seizures lead to an increased energy demand of neurons. An improvement in energy provisions may have a protective effect. C8 and C10 fatty acids have been previously shown to activate mitochondrial function in vitro. This could involve sirtuins (SIRTs) as regulatory elements of energy metabolism. The aim of the present study was to investigate whether ß-hydroxybutyrate (ßHB), C8 fatty acids, C10 fatty acids, or a combination of C8 and C10 (250/250 µM) fatty acids, which all increase under a KD, could up-regulate SIRT1, -3, -4, and -5 in HT22 hippocampal murine neurons in vitro. Cells were incubated for 1 week in the presence of these metabolites. The sirtuins were measured at the enzyme (fluorometrically), protein (Western blot), and gene expression (PCR) levels. In hippocampal cells, the C8, C10, and C8 and C10 incubations led to increases in the sirtuin levels, which were not inferior to a ßHB incubation as the 'gold standard'. This may indicate that both C8 and C10 fatty acids are important for the antiepileptic effect of a KD. A KD may be replaced by nutritional supplements of C8 and C10 fatty acids, which could facilitate the diet.

The classic ketogenic diet is an effective treatment option for drug-resistant epilepsy, but its high fat content challenges patient compliance. Optimizing liver ketone production guided by a method comparing substrates for their ketogenic potential may help to reduce the fat content of the diet without loss in ketosis induction. Here, we present a liver cell assay measuring the β-hydroxybutyrate (βHB) yield from fatty acid substrates. Even chain albumin-conjugated fatty acids comprising between 4 and 18 carbon atoms showed a sigmoidal concentration-βHB response curve (CRC) whereas acetate and omega-3 PUFAs produced no CRC. While CRCs were not distinguished by their half-maximal effective concentration (EC50), they differed by maximum response, which related inversely to the carbon chain length and was highest for butyrate. The assay also suitably assessed the βHB yield from fatty acid blends detecting shifts in maximum response from exchanging medium chain fatty acids for long chain fatty acids. The assay further detected a dual role for butyrate and hexanoic acid as ketogenic substrate at high concentration and ketogenic enhancer at low concentration, augmenting the βHB yield from oleic acid and a fatty acid blend. The assay also found propionate to inhibit ketogenesis from oleic acid and a fatty acid blend at low physiological concentration. Although the in vitro assay shows promise as a tool to optimize the ketogenic yield of a fat blend, its predictive value requires human validation., (© 2024. The Author(s).)

Background: A diagnosis of drug-resistant epilepsy is life changing for a family. Ketogenic diet therapy (KDT) can offer hope when other treatments have failed. However, it often requires a significant change in daily routine and dietary habits. This qualitative descriptive study aimed to explore families' experiences of epilepsy and KDT., Methods: Parents of a child aged ≤18 years with epilepsy, currently or recently treated with KDT, were recruited from the UK and internationally via UK Ketogenic Diet (KD) centres, charities, and social media. Semi-structured interviews were audio recorded, transcribed verbatim, anonymised, coded using Nvivo (V12), and inductive thematic analysis undertaken., Results: Twenty-one parents participated. Four themes and 12 subthemes emerged: 1. 'Epilepsy is all consuming' explored the impact of epilepsy on the family. 2. 'KD provides a window to new opportunities' explores the motivators for KDT and positive outcomes. 3. 'The reality of KD' explores day to day life and how families adapt to KD. 4. 'Looking to the future' explores the factors that may make KD easier for families. All were glad their child trialled KD, even when less successful. The importance of a support network including family, friends, charity organisations and the KD team was evident across all themes., Conclusions: We conclude with five recommendations to help support families in their management of KDT; Improved access to KDT and transition to adult services, access to quality education and support, enhanced variety of KD foods, regular social education and finally consideration of peer mentoring., Competing Interests: Declaration of competing interest The funders had no involvement in the study design, conduct, analysis or write up., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Ketogenic dietary therapies (KDT) are diets that induce a metabolic condition comparable to fasting. All types of KDT comprise a reduction in carbohydrates whilst dietary fat is increased up to 90% of daily energy expenditure. The amount of protein is normal or slightly increased. KDT are effective, well studied and established as non-pharmacological treatments for pediatric patients with refractory epilepsy and specific inherited metabolic diseases such as Glucose Transporter Type 1 Deficiency Syndrome. Patients and caregivers have to contribute actively to their day-to-day care especially in terms of (self-) calculation and (self-) provision of dietary treatment as well as (self-) measurement of blood glucose and ketones for therapy monitoring. In addition, patients often have to deal with ever-changing drug treatment plans and need to document occurring seizures on a regular basis. With this review, we aim to identify existing tools and features of telemedicine used in the KDT context and further aim to derive implications for further research and development.

Epilepsy is one of the most disabling neurological diseases. Despite proper pharmacotherapy and the availability of 2nd and 3rd generation antiepileptic drugs, deep brain stimulation, and surgery, up to 30-40% of epilepsy patients remain drug-resistant. Consequences of this phenomenon include not only decreased a quality of life, and cognitive, behavioral, and personal disorders, but also an increased risk of death, i.e., in the mechanism of sudden unexpected death in epilepsy patients (SUDEP). The main goals of epilepsy treatment include three basic issues: achieving the best possible seizure control, avoiding the undesired effects of treatment, and maintaining/improving the quality of patients' lives. Therefore, numerous attempts are made to offer alternative treatments for drug-resistant seizures, an example of which is the ketogenic diet. It is a long-known but rarely used dietary therapy for intractable seizures. One of the reasons for this is the unpalatability of the classic ketogenic diet, which reduces patient compliance and adherence rates. However, its antiseizure effects are often considered to be worth the effort. Until recently, the diet was considered the last-resort treatment. Currently, it is believed that a ketogenic diet should be used much earlier in patients with well-defined indications. In correctly qualified patients, seizure activity may be reduced by over 90% or even abolished for long periods after the diet is stopped. A ketogenic diet can be used in all age groups, although most of the available literature addresses pediatric epilepsy. In this article, we focus on the mechanisms of action, effectiveness, and adverse effects of different variants of the ketogenic diet, including its classic version, a medium-chain triglyceride diet, a modified Atkins diet, and a low glycemic index treatment.

Background: Research has shown gene ATN1 to be associated with the nuclear receptor signaling. Its mutations in an evolutionarily conserved histidine-rich motif may cause CHEDDA, short for congenital hypotonia, epilepsy, developmental delay and digital anomalies, a recently identified neurodevelopmental syndrome that could evolve into developmental and epileptic encephalopathy (DEE). Up to date, there have been reported less than 20 cases, whose clinical features and treatment are worth in-depth exploring., Methods: The clinical characteristics and genetic data of an infant with CHEDDA and further DEE were analyzed, who carried a de novo ATN1 variant identified by trio whole-exome sequencing. The alike patients with such a neurodevelopmental syndrome and epileptic seizures were reviewed on the literature., Results: The infant harboring a de novo missense mutation in ATN1 (c.3155A>C; p.His1052Pro) held almost all features of CHEDDA and presented with drug-resistant epileptic spasms, differing from one case previously reported with the same gene variant exhibiting milder seizures controlled easily. We further reviewed 11 CHEDDA patients with epileptic seizures in the literature and compared the correlation between abnormal cerebral structure and the incidence of intractable epilepsy among CHEDDA patients. Fortunately, this patient's seizures decreased remarkably after administering ketogenic diet (KD)., Conclusion: CHEDDA patients have significant phenotypic differences, especially in the epilepsy severity and their drug resistance, even if they carry the same mutation hotspot. Ketogenic diet and other treatments like Topiramate should be recommended for ATN1-related refractory epilepsy based on their regulation on expression of cation-chloride cotransporters and cellular hyperpolarization., Competing Interests: Declaration of competing interest We declare that there is no conflict of interest associated with this Research., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Context: Epilepsy is one of the most prevalent neurological disorders in childhood. Antiepileptic drugs are the preferred treatment. However, 30% of children continue suffering seizures. A ketogenic diet (KD) is one of the emerging alternative treatments., Objective: This review aims to analyze the current evidence regarding the use of a KD for the treatment of refractory epilepsy (RE) in childhood., Data Sources: A systematic review of reviews was performed, based on MEDLINE (PubMed) as at January 2021., Data Extraction: The data extracted included the first author's last name; the year of publication; the country; the study design; the population; the diagnosis, concept, and description of KD types; and major outcome., Results: Twenty-one reviews were included, 8 with systematic methodology (2 of them included a meta-analysis) and 13 with unsystematic methodology. The main difference between the 2 types of reviews is the reproducibility of their methodology. Therefore, the results of each type of review were analyzed separately. Each type of review described 4 categories of KD: classic KD, modified Atkins diet (MAD), use of medium-chain triglycerides (MCTs), and low glycemic index treatment (LGIT). In terms of effectiveness, the considered systematic reviews reported reductions in the frequency of seizures greater than 50% in about half of the patients. Reviews without systematic methodology reported that 30%-60% of the children showed a 50% or greater reduction in seizures. The most frequently described adverse effects in the 8 systematic reviews were: vomiting (6/8), constipation (6/8), and diarrhea (6/8); and in the unsystematic reviews: vomiting and nausea (10/13), constipation (10/13), and acidosis (9/13)., Conclusion: KD can be an effective treatment for RE, with a more than 50% reduction in the frequency of seizures and cognitive improvement being achieved in half of the pediatric patients. The effectiveness of the various types of KD is comparable, and the KD can be adapted to the needs of the patient., Systematic Review Registration: PROSPERO registration no. CRD42021244142., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The ketogenic diet may be difficult for some patients and their families to implement and can impact physical, emotional, and social well-being., Methods: Through principles of fundamental qualitative description, we completed an exploratory study on parents' experiences and expectations on the use and efficacy of the ketogenic diet for children with medically refractory epilepsy., Results: Seventeen parents (10 mothers and 7 fathers) of 12 children with epilepsy participated. At the time of the interview, parents had experienced an average of 25 months of ketogenic diet treatment for their child (range 2 months to 98 months). Half of the caregivers learned about the ketogenic diet from their neurologist, whereas the remainder had heard about it from another source (ie, the internet). Most caregivers' (n = 13) diet expectations were related to seizure control. However, child development (n = 5) and quality of life (n = 5) were also crucial to some. Physical impacts of the diet were most commonly gastrointestinal for children (n = 9). Social and emotional effects were noted in some older children with typical development. Most caregivers described negative impacts on finances (n = 15), relationships (n = 14), and emotional well-being (ie, stress) (n = 12). Caregivers benefited from the ketogenic diet team's regular communication, close follow-up, and family-centered care., Conclusions: Despite the impacts that the ketogenic diet may have on caregivers' emotional and social well-being, the positive impacts of the diet were felt to outweigh any perceived risks. Effects (both positive and negative) on quality of life and child development (eg, social, emotional, cognitive) are essential for caregivers and require additional investigation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Rajesh RamachandranNair received a research grant from the Ontario Brain Institute and served as a paid consultant to UCB Canada Inc and Sunovion Pharmaceuticals Canada Inc. Eric Kossoff has served as a paid consultant for Simply Good Foods Inc, Nutricia, Inc, Bloom Science, Cerecin, and LivaNova, and has received royalties from Springer Medical Publishing, UpToDate, and the Oxford University Press. The remaining authors have no conflicts of interest.

Background: A core outcome set defines the minimum outcomes that should be included in clinical trials, audit or practice. The aim being to increase the quality and relevance of research by ensuring consistency in the measurement and reporting of outcomes. Core outcome sets have been developed for a variety of disease states and treatments. However, there is no established set of core outcomes for refractory childhood epilepsy treated with ketogenic diet therapy. This should be developed using a patient-centred approach to ensure the outcomes measured are relevant to patients and clinical practice., Methods: This is a mixed methods study of four phases to develop a core outcome set for refractory childhood epilepsy treated with ketogenic diet therapy. In phase 1, a systematic scoping review of the literature will establish which outcomes are measured in trials of refractory epilepsy treated with ketogenic diet therapy. In phase 2, qualitative interviews with parents and carers will aim to identify the outcomes of importance to these stakeholders. Phase 3 will see a comprehensive list of outcomes collated from the first two phases, grouped into domains according to an outcome taxonomy. Phase 4 will invite parents, health care professionals and researchers to participate in a two-round Delphi study to rate the importance of the presented outcomes. Following which, the core outcome set will be ratified at a face to face consensus meeting., Discussion: This study will guide outcome measurement in future studies of childhood epilepsy treated with ketogenic diet therapy and clinical practice through audit and service evaluation., (© 2022. The Author(s).)

Purpose: Ketogenic diet (KD) is a well-established nonpharmacologic treatment for drug-resistant epilepsy. However, although KD has a long history of clinical use, there are still many difficulties with its real-world practice. This study retrospectively described the situation of KD practice in two children's hospitals in Southwest China., Methods: We reviewed and analyzed clinical data collected at the baseline, and during follow ups at 1, 3, 6, 12, 18, and 24 months. The patient retention, the efficacy, side effects of KD, and the reasons for discontinuation were focused., Results: There was increasing availability of KD for children with epilepsy in Southwest China and its effectiveness in controlling seizures was reconfirmed. Nonetheless, less than half of the patients adhered to KD for one year and about 1/5 of the patients for two years. Unsatisfactory seizure control was the most common reason for discontinuation, followed by patient/caregiver preference, acute infection, and loss to follow up. Adverse effects were mostly tolerable and not the main reason for discontinuation. Meanwhile, KD showed negative impacts on linear growth, and our cohort seemed to have more infections and deaths., Conclusions: Despite increasing availability and good efficacy, long-term adherence to KD was difficult. Compliance issues appeared to be prominent. Enhancing food taste and patient support can help to improve the retention rate., (Copyright © 2022. Published by Elsevier Ltd.)

Background : Ketogenic dietary therapies (KDT) are used as a treatment in childhood epilepsy. However, their mechanism has not yet been established. The main objective of this study was to determine the changes in the transcriptomic profile induced by KDT in children with epilepsy in order to shed light on its possible mechanisms. Methods : Eight children with refractory epilepsy were enrolled in the study. Peripheral blood mononuclear cells were obtained before and after the children were treated with KDT for a minimum of 6 months. RNA was extracted and mRNA and miRNA profiling were performed and analyzed. Results : Our intervention with KDT significantly reduced the seizure number in seven of the eight paediatric patients treated and caused important changes in their gene expression profile. Our study reveals modifications in the transcription of 4630 genes and 230 miRNAs. We found that the genes involved in the protection against epileptic crises were among those mainly changed. These genes collectively encode for ion channels, neurotransmitter receptors, and synapse structural proteins. Conclusions : Together our results explain the possible mechanisms of KDT and reinforce its clinical importance in the treatment of epilepsy., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Background: Changes in adipokine secretion may be involved in the anti-epileptic effect of a ketogenic diet (KD) in drug-resistant epilepsy (DRE)., Objectives: The assessment of the influence of KD on serum adiponectin, omentin-1, and vaspin in children with DRE., Methods: Anthropometric measurements (weight, height, BMI, and waist-to-hip circumference ratio) were performed in 72 children aged 3-9 years, divided into 3 groups: 24 children with DRE treated with KD, 26-treated with valproic acid (VPA), and a control group of 22 children. Biochemical tests included fasting glucose, insulin, beta-hydroxybutyric acid, lipid profile, aminotransferases activities, and blood gasometry. Serum levels of adiponectin, omentin-1 and vaspin were assayed using commercially available ELISA tests., Results: Serum levels of adiponectin and omentin-1 in the KD group were significantly higher and vaspin-lower in comparison to patients receiving VPA and the control group. In all examined children, serum adiponectin and omentin-1 correlated negatively with WHR and serum triglycerides, insulin, fasting glucose, and HOMA-IR. Vaspin levels correlated negatively with serum triglycerides and positively with body weight, BMI, fasting glucose, insulin, and HOMA-IR., Conclusion: One of the potential mechanisms of KD in children with drug-resistant epilepsy may be a modulation of metabolically beneficial and anti-inflammatory adipokine levels.

The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies. The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies. In this review, we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases, and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels. We emphasize that the KD may function through multiple mechanisms, which remain to be further elucidated. The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed. We suggest that, with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action, randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD., (© 2022. The Author(s).)

Background: Ketogenic diet (KD) is widely used for drug-resistant epilepsy (DRE). The study was designed to evaluate one of the risk factors for development of renal calculi with KD., Methods: Twenty patients with DRE on Modified Atkins diet (MAD) were subjected to full history and laboratory investigations, including microscopic urine analysis, urinary calcium after overnight fasting, and calcium/creatinine ratio, as well as pelviabdominal ultrasound. Frequency and severity of seizures assessed by Chalfont severity score were recorded. All assessment measures were repeated after 3 and 6 months of KD therapy., Results: There were significant reductions in both frequency and severity of seizures, yet 2 patients (10%) developed renal stones after 6 months on KD. Gross hematuria was reported in 1 of those 2 patients (50%), but microscopic hematuria was detected in both patients. The urine calcium and the urine calcium/creatinine ratio were elevated in both patients having renal calculi after 6 months., Conclusions: KD increases the risk of renal stones with hypercalciuria among the causes. We recommend initiation of prophylactic measures once KD is commenced by maximizing fluid intake and urine alkalinization with regular urinary studies including calcium/creatinine ratio and renal ultrasound for patients with symptoms., Impact: KD has been increasingly used in epilepsy management and beyond. The potential side effects of such diet should be highlighted while valuing the merits. KD increases the risk of renal stones because of hypercalciuria among other causes. We recommend initiation of prophylactic measures once KD is commenced by maximizing fluid intake and urine alkalinization with estimation of urinary calcium/creatinine ratio and renal ultrasound in patients with relevant symptoms., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Introduction: Background: the ketogenic diet (CD) is an established, effective non-pharmacological treatment for refractory epilepsy in childhood. Aim: the objective of this study was to compare the efficacy, the presence of undesirable effects, and adherence between the classic ketogenic diet (DCC) and the modified Atkins diet (DAM). Materials and methods: a retrospective and comparative investigation was carried out to evaluate the medical records of all the patients who started treatment with a ketogenic diet by the same team between 2008 and 2018. In all, 57 patients were started on a DAM diet and 19 patients were given a DCC diet. Results: it was observed that both the Atkins and the classic diets were equally effective (approximately, 80 %; p = 0.252). Regarding adherence, there was a significantly higher percentage of adherence to the Atkins diet than to the classic diet (p = 0.018). Fewer adverse effects were observed with DAM than with DCC (p = 0.012). In all, 21 % of patients under DAM had unfavorable effects (12/57), while 52.63 % of patients on DCC had complications (10/19). Conclusion: a comparable effectiveness in terms of crisis control was found between DAM and DCC. However, DAM exhibits a much better adherence than DCC, and its undesirable effects are milder, less common. That is why, according to other works, it is likely that DAM should be first-choice for patients with refractory epilepsy in a large percentage of cases.

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.

Background: Neurological manifestations are commonly reported in patients with celiac disease (CD). We aimed to characterize epilepsy features in a pediatric population with CD and the effect of a gluten-free diet (GFD) on seizure burden., Methods: A retrospective chart review was performed on pediatric patients treated at the University of Utah and Primary Children's Hospital in Salt Lake City, Utah, with both epilepsy and CD and compared with a control group with epilepsy only., Results: We identified 56 patients with epilepsy and biopsy-confirmed CD (n = 36, 64%) or elevated tissue transglutaminase antibodies (tTG-Ab) without biopsy-confirmed CD (n = 20, 36%). Age- and gender-matched controls were selected from patients with epilepsy only (n = 168). Patients with biopsy-proven CD or positive tTG-Ab had high percentage of drug-resistant epilepsy (DRE) compared with the control group (P < 0.05). Age at seizure onset preceded the diagnosis of CD on average by 5.9 years for patients with DRE (P < 0.01) compared with 2.2 years for those with drug-responsive epilepsy. Adhering to a GFD reduced seizure frequency or resulted in weaning dosage or weaning off of one or more antiseizure medications in a majority of patients with DRE., Conclusions: DRE was more prevalent in pediatric patients with biopsy-confirmed CD and positive tTG-Ab compared with the control group (which included childhood epilepsy syndromes), but comparable with the prevalence of DRE in the general population. Adherence to a GFD in combination with antiseizure medications appears to reduce seizure burden for those with CD and DRE., (Copyright © 2021 Elsevier Inc. All rights reserved.)

E-health technologies improve healthcare quality and disease management. The aim of this study was to develop a ketogenic diet management app as well as a website about this dietary treatment and to evaluate the benefits of giving caregivers access to various web materials designed for paediatric patients with refractory epilepsy. Forty families participated in the questionnaire survey, from January 2016 to March 2016. All caregivers were exposed to paper-based materials about the ketogenic diet, whereas only 22 received the app, called KetApp, and videos produced by dieticians. Caregivers with free access to web materials were more satisfied than the others with the informative material provided by the centre ( p ≤ 0.001, Mann-Whitney test). Indeed, they showed a better attitude towards treatment, and they became more aware of dietary management in comparison to the control group ( p ≤ 0.001). Moreover, caregivers provided with web materials were stimulated to pursue the treatment ( p = 0.002) and to introduce it to their children and other people ( p = 0.001). Additionally, caregivers supplied with web materials were more willing to help other families in choosing the ketogenic diet ( p = 0.004). Overall, these findings indicate that web materials are beneficial for caregivers of paediatric patients with refractory epilepsy in our centres. Thus, the use of e-health applications could be a promising tool in the daily aspects of ketogenic diet management, and it is especially of value in the attempt to start or maintain the diet during the ongoing COVID-19 pandemic crisis.

Dietary therapy has an important role in the therapeutic process in children suffering refractory epilepsy. There are two kinds of dietary therapy which are the most common in children with refractory epilepsy: The classic ketogenic diet (KD) and the modified Atkins diet (MAD). The purpose of the present study was to compare the efficacy, tolerability, and compliance of these two dietary therapies in the children who have refractory epilepsy during 6 months of treatment. From March 2017 to November 2018, 45 children aged 2-15 years who had refractory epilepsy were randomly allocated in KD or MAD group. The intervention period was 6 months in both groups. The frequencies of seizures were determined from parental reports and were compared between the groups. The patients with upper than 50% reduction in seizure frequency were deemed as responders to the diets. Twenty-four patients were assigned to the KD and 11 patients to the MAD. Overall, 45.8% of children treated with the KD and 45.5% of children treated with MAD had over than 50% response to the diet therapies. The difference was not statistically significant (P = 0.437). The MAD was more advantageous regarding better tolerability and fewer side effects. There is not much difference regarding the efficacy between the MAD and classic KD. The MAD with fewer side effects may be more suitable as the first line of dietary therapy in children with refractory epilepsy.

Background: A classic ketogenic diet, even though effective in children with drug-resistant epilepsy is not tolerated well by them and cumbersome to prepare. Low glycemic index therapy (LGIT), the least restrictive with minimal adverse effects among ketogenic dietary therapies has been proven effective in uncontrolled trials, but a placebo-controlled trial in this regard is still lacking., Methods: In this open-label randomized controlled study, we randomized children above age two years with drug-resistant epilepsy into two groups (LGIT and control groups). Patients in the LGIT group received an add-on low glycemic index diet for 3 months along with the ongoing antiepileptic drugs and the patients in the control group did not receive any dietary intervention. Seizure frequency was assessed from the seizure diary maintained by the parents. Diet compliance was assessed using the diet diary that was maintained by the parents for three days just before the scheduled monthly visits of the patients., Results: Forty children with drug-refractory epilepsy (20 in each group) were enrolled. While 6/20 children in the LGIT arm have >50 % reduction in seizure frequency, none achieved this in the control arm (p = 0.02). The overall compliance with the low glycemic diet in the intervention group was 88.5 %. Out of six responders to LGIT, one child achieved seizure freedom and one achieved >90 % seizure reduction. Five continued LGIT further for a median duration of 8 months (range-4-12 months) successfully. The number needed to treat for more than 50 % seizure reduction was 3 and for more than 90 % seizure reduction was 10. The mean frequency of seizures for the intervention and control groups at three months of follow-up was not significantly different (p = 0.16), but the change in seizure frequency as compared to baseline was better in the intervention arm (p = 0.01). Three patients in the LGIT arm had non-serious adverse events (lethargy in two, vomiting in one)., Conclusion: In children aged 2-8 years with drug-refractory epilepsy, the administration of LGIT along with ongoing anti-seizure medications (ASM) is more efficacious in reducing seizure frequency as compared to ASM alone., (Copyright © 2021. Published by Elsevier B.V.)

In infantile Alexander disease (iAxD), one of the serious symptoms is intractable epilepsy, and some reports have suggested that neuroinflammation may be involved in the pathophysiology of the disease. Drug-resistant seizures adversely affect not only the quality of life of the caregivers and patients, but also patients' lifespan. Thus, controlling epilepsy is clinically important. For intractable childhood epilepsy, ketogenic diet therapy (KDT) is well-established, but its effects on iAxD have not been characterized. Here, we describe the use of KDT in three iAxD patients experiencing drug-resistant seizures. In all three cases, the formerly intractable epilepsies were well controlled by KDT. However, the brain magnetic resonance imaging findings deteriorated even after the epilepsy was controlled. In addition, the concentrations of monocyte chemotactic protein-1 and proinflammatory cytokines in the cerebrospinal fluid of the patients remained still high. KDT is effective in controlling epilepsy in iAxD. Our results clinically support previous reports arguing the involvement of neuroinflammation in the pathophysiology of iAxD.　Although KDT cannot prevent disease progression, earlier initiation might contribute to a better prognosis., (Copyright © 2020. Published by Elsevier B.V.)

Context: The ketogenic diet is associated with progressive skeletal demineralization, hypercalciuria, and nephrolithiasis. Acute hypercalcemia has been described as a newly recognized complication of this treatment., Objective: To describe the clinical characteristics of acute hypercalcemia in children on the ketogenic diet through analysis of the presentation, response to treatment, and natural history in a large cohort of patients., Design: A multicenter case series was performed including children who developed acute hypercalcemia while treated with the ketogenic diet. Information on clinical presentation, treatment, and course of this complication was collated centrally., Results: There were 14 patients (median (range) age 6.3 (0.9 to 18) years) who developed hypercalcemia 2.1 (range, 0.2-12) years after starting the ketogenic diet. All had low levels of parathyroid hormone and levels of 1,25-dihydroxyvitamin D were low in all except one. Seven (50%) had impaired renal function at presentation. All except the 2 oldest had low alkaline phosphatase levels for age. Once normocalcemia was achieved, hypercalcemia recurred in only 2 of these patients over observation of up to 9.8 years. One patient discontinued the ketogenic diet prior to achieving normocalcemia while 4 more stopped the diet during follow-up after resolution of hypercalcemia., Conclusions: Ketotic hypercalcemia can occur years after starting the ketogenic diet, especially in the setting of renal impairment. The mechanism is unknown but appears to be due to reduced osteoblast activity and impaired bone formation. We recommend close attention to optimizing bone health in these children, and screening for the development of ketotic hypercalcemia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Patients with drug-resistant epilepsy (DRE) pose considerable management challenges for patients, their families, and providers. Both the vagus nerve stimulator (VNS) and the ketogenic diet (KD) have been shown to be safe and effective in treating DRE. Nevertheless, information is lacking regarding treatment with combination of both modalities. This study reports the efficacy and tolerability of combining VNS and KD in a pediatric cohort with intractable epilepsy., Methods: This is a retrospective review of 33 patients (0-17 years) with DRE treated with VNS and KD at a single pediatric level IV epilepsy center. We compared seizure reduction rates for each patient at baseline and at every clinic visit for 24 months after adding the second nonpharmacological therapy. The frequency of adverse events on the combined therapy was collected to assess safety and tolerability., Results: There were a total of 170 visits for all patients while on the combined therapy. At 88% (95% CI: 83%-93%) of the visits, patients reported some reduction in seizure frequency. The proportion of patients reporting a greater than 50% seizure reduction over all visits was 62% (95% CI: 55%-69%). The proportion of a patient's visits with at least a greater than 50% reduction in seizure frequency had a median of 71% (IQR 33%-100%). Continued improvement was seen over time of combined treatment; for every one-unit time unit change (one month), there was a 6% increase in the odds of having a reduction in seizure frequency of >50% (OR = 1.06, 95% CI: 1.01-1.11)., Significance: This study shows that combining the VNS and KD in patients with drug-resistant epilepsy is well tolerated and reduces seizure frequency more than either one modality used alone and that the benefits in terms of seizure reduction continue to increase with the length of treatment., Competing Interests: Ahmed Abdelmoity received honoraria for consulting or serving on the speaker bureau for Livanova, UCB, and Greenwich. The remaining authors have no conflicts of interest. No external funding received for the work presented. All coauthors have been substantially involved in the study and the preparation of the manuscript; no undisclosed groups or persons have had a primary role in the study and/or preparation of the manuscript; all coauthors have seen and approved the submitted version of the paper and accept responsibility for its content. The work described herein is consistent with the Journal's guidelines for ethical publication., (© 2020 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Drug-resistant epileptic patients make up approximately one-third of the global epilepsy population. The pathophysiology of drug resistance has not been fully elucidated; however, current evidence suggests intestinal dysbiosis, as a possible etiopathogenic factor. Ketogenic diet, whose effect is considered to be mediated by alteration of gut microbiota synthesis, has long been administered in patients with medically refractory seizures, with positive outcomes. In this review, we present data derived from clinical studies regarding alterations of gut microbiome profile in drug-resistant epileptic patients. We further attempt to describe the mechanisms through which the gut microbiome modification methods (including ketogenic diet, pre- or probiotic administration) improve drug-resistant epilepsy, by reporting findings from preclinical and clinical studies. A comprehensive search of the published literature on the PubMed, Embase, and Web of science databases was performed. Overall, the role of gut microbiome in drug-resistant epilepsy is an area which shows promise for the development of targeted therapeutic interventions. More research is required to confirm the results from preliminary studies, as well as safety and effectiveness of altering gut bacterial composition, through the above-mentioned methods., Competing Interests: None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (© 2020 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objectives: To study the role of the ketogenic diet (KD) in controlling seizures in children with medically resistant epilepsy in Saudi Arabia., Methods: This retrospective study was conducted in the Pediatric Neurology Clinic at a tertiary care epilepsy center. Thirty-one patients with medically resistant epilepsy were enrolled from 2013 to 2018. The seizure reduction variables were evaluated at 6, 12, 18 and 24 months after enrollment., Results: Of the 31 patients, 14 (45.2%) were males and 17 (54.8%) were females. The most common types of seizures were myoclonic seizures and mixed seizures, both of which occurred in 9 (29%) of the participants. Of the participants, 15 (48.4%) had seizures one to 5 times per day. Six months after starting a KD, 2 (6.45%) of participants were seizure-free; 6 (19.35%) were seizure-free after 12 months of treatment., Conclusion: The present study highlighted the effectiveness of KD in medically resistant epilepsy children to local population. A larger cohort is warrant to confirm these findings., (Copyright: © Neurosciences.)

Background: This study aimed to identify metabolic parameters at different time points of ketogenic diet therapy (KDT) and investigate their association with response to KDT in pediatric drug-resistant epilepsy (DRE)., Methods: Prospectively, twenty-nine patients (0.67~20 years old) with DRE received classic ketogenic diet with non-fasting, gradual KD initiation protocol (GRAD-KD) for 1 year were enrolled. A total of 22 patients remaining in study received blood examinations at baseline, 3rd, 6th, 9th, and 12th months of KDT. β-hydroxybutyrate, free carnitine, acylcarnitines, and amino acids were compared between responders (seizure reduction rate ≥ 50%) and non-responders (seizure reduction rate < 50%) to identify the effectiveness of KDT., Results: The 12-month retention rate was 76%. The responders after 12 months of KDT were 59% (13/22). The free carnitine level decreased significantly at 9th months ( p < 0.001) but increased toward baseline without symptoms. Propionyl carnitine (C3), Isovaleryl carnitine (C5), 3-Hydroxyisovalerylcarnitine (C5:OH) and methylmalonyl carnitine (C4-DC) decreased but 3-hydroxybutyrylcarnitine (C4:OH) increased significantly at 12th months of KDT. The glycine level was persistently higher than baseline after KDT. KDT responders had lower baseline C3 and long-chain acylcarnitines, C14 and C18, as well as lower C5, C18, and leucine/isoleucine., Conclusions: KDT should be avoided in patients with non-ketotic hyperglycemia. Routine carnitine supplementation is not recommended because hypocarnitinemia was transient and asymptomatic during KDT. Better mitochondrial βoxidation function associates with greater KDT response.

One-third of epilepsy patients have drug-resistant epilepsy (DRE), which is often complicated by polydrug toxicity and psychiatric and cognitive comorbidities. Advances in understanding the microbiome and gut-brain-axis are likely to shed light on epilepsy pathogenesis, anti-seizure medication (ASM) resistance, and potential therapeutic targets. Gut dysbiosis is associated with inflammation, blood-brain barrier disruption, and altered neuromodulators. High-throughput and metagenomic sequencing has advanced the characterization of microbial species and functional pathways. DRE patients show altered gut microbiome composition compared to drug-sensitive patients and healthy controls. The ketogenic and modified Atkins diets can reduce seizures in some patients with DRE. These low-carbohydrate dietary therapies alter the taxonomic and functional composition of the gut microbiome, and composition varies between diet responders and nonresponders. Murine models suggest that specific phyla are necessary to confer efficacy from the diet, and antibiotic treatment may eliminate efficacy. The impact of diet might involve alterations in microbiota, promotion of select microbial interactions, and variance in brain neurotransmitter levels that then influence seizures. Understanding the mechanics of how diet manipulates seizures may suggest novel therapies. Most ASMs act on neuronal transmission via effects on ion channels and neurotransmitters. However, ASMs may also assert their effects via the gut microbiota. In animal models, the microbiota composition (eg, abundance of certain phyla) can vary with ASM active drug metabolites. Given the developing understanding of the gut microbiome in DRE, probiotics are another potential therapy. Probiotics alter the microbiota composition, and small studies suggest that these supplements can reduce seizures in some patients. DRE has enormous consequences to patients and society, and the gut microbiome holds promise as a potential therapeutic target. However, the exact mechanism and recognition of which patients are likely to be responders remain elusive. Further studies are warranted., (© 2020 International League Against Epilepsy.)

Hygienic and sanitary measures and social distancing policies implemented during the new coronavirus disease - COVID-19 - pandemic have altered the care and follow-up provided by healthcare professionals for patients with chronic diseases, including patients with epilepsy (PWEs). Telemedicine has become a solution for the healthcare of PWEs in many developed countries. In this short communication, we trace a particular perspective for the application of telemedicine for PWEs undergoing ketogenic diet (KD) treatment, considering the social and economic difficulties faced by healthcare teams in resource-poor countries, such as Brazil. During the pandemic, financial strain was the main impediment to following KD. The pandemic increased socioeconomic insecurity and access to KD-related products, as well as increasing anxiety in 71% of PWE, impacting their KD treatment follow-up. The challenges of telemedicine in Brazil include not only social and economic issues but also access to food, healthcare services, and education for the population, in addition to digital inclusion., (Copyright © 2020 Elsevier Inc. All rights reserved.)