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We aimed to develop a registry ('Keto-Reg') for individuals with epilepsy referred for ketogenic dietary therapy (KDT) and to test feasibility of its implementation. The purpose of the registry is to provide a platform for collaborative research to answer specific research questions regarding long-term clinical and safety outcomes and to identify the most suitable candidates for KDT. Registry data items were determined via an international Delphi survey of KDT healthcare professionals, and then entered into an electronic platform. Three UK and two other European KDT centres entered data for 10 'patients' and reported on its acceptability and feasibility of use via questionnaire. 25 % of data was validated against medical records. A national survey was distributed and 19 parents and four young people were interviewed about a potential future patient/family section to the registry. Healthcare professionals from six continents responded to the Delphi (n = 153 round 1, n = 79 round 2); 70 items reached the agreement threshold. Registry data entry was accurate (0.3 % errors identified) and reported to be feasible and acceptable in the short-term. Lack of time was identified as the main barrier to longer-term implementation, with funded hours required. 87 % of the 53 survey responders and all interviewees viewed a patient/family section to be positive and feasible. We have shown healthcare professional involvement in Keto-Reg to be feasible in the short-term, and have identified what is necessary for the next stage: prospective longitudinal data entry from a larger number of international centres. • Ketogenic dietary therapy for epilepsy registry developed - Keto-Reg, data items determined by international Delphi survey. • Keto-Reg tested in 3 UK and 2 other European centres. • Healthcare professional involvement in Keto-Reg feasible with accurate data entry. • Extra time needed for long term international implementation. • Parent and young people interest in a future family/patient section of Keto-Reg. [ABSTRACT FROM AUTHOR]

Ketogenic diet therapy (KDT) is a safe and effective treatment for epilepsy and glucose transporter type 1 (GLUT1) deficiency syndrome in infancy. Complete weaning from breastfeeding is not required to implement KDT; however, breastfeeding remains uncommon. Barriers include feasibility concerns and lack of referrals to expert centres. Therefore, practical strategies are needed to help mothers and professionals overcome these barriers and facilitate the inclusion of breastfeeding and human milk during KDT. A multidisciplinary expert panel met online to address clinical concerns, systematically reviewed the literature, and conducted two international surveys to develop an expert consensus of practical recommendations for including human milk and breastfeeding in KDT. The need to educate about the nutritional benefits of human milk and to increase breastfeeding rates is emphasized. Prospective real‐world registries could help to collect data on the implementation of breastfeeding and the use of human milk in KDT, while systematically including non‐seizure‐related outcomes, such as quality of life, and social and emotional well‐being, which could improve outcomes for infants and mothers. What this paper adds: Human milk and breastfeeding can be incorporated safely into ketogenic diet therapy.With expert guidance, human milk and breastfeeding do not reduce diet effectiveness.We show two strategies for clinical practice to include human milk.Mothers can be encouraged to continue breastfeeding. [ABSTRACT FROM AUTHOR]

• Families' experiences of ketogenic diet therapy (KDT) are poorly understood. • KDT offers a problem focussed coping strategy to help parents manage epilepsy. • Children experience improvement in seizure and non-seizure related outcomes with KDT. • KDT can be challenging but when successful, parents believe it is worth the effort. • Parents need a support network of friends, family, KD charities, and a keto team. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Objective: Ketogenic diet therapy (KDT) can result in benefits (seizure‐related and non‐seizure‐related) for children with drug‐resistant epilepsy. However, clinical trials report a wide range of outcomes, making synthesis of evidence difficult, and do not adequately reflect parent views on important outcomes for their child. To address this, we established the first international parent, health professional, and researcher consensus to develop a core outcome set, guided by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative (COMET registration #1116). Methods: Ethical approval was granted (London–Surrey REC19/LO/1680). A scoping review and interviews with parents identified a comprehensive list of potentially important outcomes, followed by a two‐round online Delphi survey of parents and health professionals to prioritize outcomes of importance for inclusion in a core outcome set. This informed a stakeholder consensus meeting and consultation process to finalize the core outcome set. Results: In total, 97 outcomes were identified; 90 from the scoping review and seven from parent interviews. These were rationalized to 77 by the study advisory group, then rated in the first Delphi round by 49 parents and 96 health professionals, who suggested 12 new outcomes for rating in Round 2. Sixty‐six percent of participants (30 parents and 66 professionals) completed Round 2, where 22 outcomes met criteria for inclusion. In the consensus meeting (nine parents and 13 professionals), 27 undecided outcomes were discussed and scored; one further outcome reached consensus for inclusion. After consultation and ratification, 14 outcomes across five domains were included in the core outcome set. Significance: A core outcome set for childhood epilepsy treated with KDT has been developed, incorporating the views of international parents and professionals. Implementation in research and clinical settings will standardize outcome selection and reporting, facilitate data synthesis, and ultimately enhance the relevance of outcomes to parents, researchers, and health professionals. [ABSTRACT FROM AUTHOR]

Aim: To investigate the rate of successful withdrawal of antiseizure medication (ASM) after starting the ketogenic diet in children and identify predictive factors. Method: We retrospectively reviewed data of children with epilepsy, who were treated with the ketogenic diet for 6 months or longer at our institution, over a 5‐year period. We defined successful withdrawal of one or more medications as a time period of 3 months or more off this medication without restarting it or starting a new agent. Predictive clinical factors were investigated using binary multivariable logistic regression. Results: Seventy‐one children were included (28 females, 43 males; median age at seizure onset 5 months, median age at diet initiation 58.5 months, median duration of ketogenic diet 27.7 months). Reduction of one or more ASMs was attempted in 54 out of 71 (76%) children and was successful in 34 out of 54 (63%), including discontinuation of all ASMs in 13. Younger age at the start of the ketogenic diet was associated with higher odds of successful ASM withdrawal. ASM withdrawal was successful in 11 out of 19 children with less than 50% seizure reduction at 3 months. Interpretation: Reduction of ASM was achieved in two‐thirds of patients after the start of the ketogenic diet, where attempted, and can be successful even with little or unchanged seizure frequency while on the diet. [ABSTRACT FROM AUTHOR]

Purpose: Clinical trials on childhood epilepsy treated with ketogenic diet (KD) use a wide range of outcomes, however, patients and decision-makers often do not perceive the outcomes used as the most important. We sought parental opinion on outcomes of importance and compared these to outcomes reported in published research.Methods: Ethical approval (London-Surrey-REC19/LO/1680). A scoping review identified outcomes reported in previous studies of childhood epilepsy and KD. Parents were recruited from nine KD centres (UK), charities and social media (international), then interviewed (Jan-April 2020) to explore priority outcomes. Content analysis identified all outcomes in transcripts. Parent identified outcomes were compared with those in the scoping review. Outcomes were collated and grouped into domains according to the COMET Taxonomy.Results: Of 2663 articles;147 met inclusion criteria. 921 verbatim outcomes were sorted into 90 discrete outcomes, reduced to 70 in consultation with the study advisory group, then classified into 21 domains. Parents (n = 21) identified 39 outcomes as important from the scoping review and seven new outcomes. They prioritised both physiological and functional outcomes in contrast to past studies, which prioritised physiological outcomes.Conclusion: Little consistency exists in the outcomes used in childhood epilepsy and KD research. Those traditionally used do not adequately reflect parents' important outcomes for their child. Clinical trials should consider the broader priorities of parents when choosing outcomes, in particular, functional outcomes. Identified outcomes will inform an international two-round Delphi-study with parent, professional and researcher participants to develop a core outcome set for this clinical area (COMET registration #1116). [ABSTRACT FROM AUTHOR]

Ketogenic diet therapies (KDT) are high-fat, low carbohydrate diets used as an effective treatment option for drug-resistant epilepsy. There is limited research on the efficacy of KDT for super-refractory status epilepticus (SRSE). We systematically review evidence for use of KDT in children with SRSE and present a single UK tertiary centre's experience. Thirty one articles were included, of which 24 were "medium" or "low" quality. One hundred and forty seven children with SRSE started KDT, of which 141 (96%) achieved ketosis. KDT was started mean 5.3 days (range 1–420) after status epilepticus (SE) started. SRSE resolved in 85/141 (60%) children after mean 6.3 days (range 0–19) post SE onset, but it is unclear whether further treatments were initiated post-KDT. 13/141 (9%) children died. Response to KDT was more likely when initiated earlier (p = 0.03) and in females (p = 0.01). Adverse side effects were reported in 48/141 (34%), mostly gastrointestinal; potentially serious adverse effects occurred in ≤4%. Eight children with SRSE, all diagnosed with febrile infection-related epilepsy syndrome, were treated with KDT at Great Ormond Street Hospital for Children. KDT was initiated enterally at mean day 13.6+/− 5.1 of admission. Seven of 8 (88%) children reported adverse side effects, which were potentially serious in 4/8 (50%), including metabolic acidosis, hypoglycaemia and raised amylase. SE ceased in 6/8 (75%) children after mean 25+/− 9.4 days post onset, but other treatments were often started concomitantly and all children started other treatments post-KDT. Two of 8 (25%) children died during admission and another died post-admission. Four of the remaining 5 children continue to have drug-resistant seizures, one of whom remains on KDT; seizure burden was unknown for one child. Our findings indicate that KDT is possible and safe in children with SRSE. Cessation of SRSE may occur in almost two-thirds of children initiated with KDT, but a causal effect is difficult to determine due to concomitant treatments, treatments started post-KDT and the variable length of time post-KDT onset when SRSE cessation occurs. Given that serious adverse side effects seem rare and response rates are (cautiously) favorable, KDT should be considered as an early treatment option in this group. [ABSTRACT FROM AUTHOR]

Approximately 25% of children with epilepsy are drug-resistant. Lack of seizure control in infants impacts developmental outcome and places a large burden on NHS services, but there are few data to guide optimal treatment in infants with drug-resistant epilepsy. Ketogenic diet therapy is an effective non-pharmacological treatment option for individuals with drug-resistant epilepsy and reports of its use in infants have increased over the last decade. This article gives an overview of use of ketogenic diet therapy in infants with epilepsy, including a history of dietary treatment, evidence for efficacy in infants, patient selection and clinical and dietetic management. [ABSTRACT FROM AUTHOR]

Objective: Ketogenic diet therapy (KDT) is a group of high‐fat, low‐carbohydrate diets used as an effective treatment option for children and adults with drug‐resistant epilepsy. There is limited research on the efficacy of KDT in infants, where there is the highest incidence of onset of the epilepsy. We aimed to systematically review studies that have reported on response to KDT in infants with epilepsy. Methods: An online comprehensive literature search was performed, including studies that provided seizure frequency data for at least one infant younger than 2 years of age who was treated with KDT for ≥1 month. The proportions of infants achieving ≥50% seizure reduction, seizure‐freedom rates, retention rates, and reported side effects were extracted from studies. Meta‐analyses were performed using a random‐effects model, and subgroup analyses were performed to investigate possible between‐study heterogeneity. Results: Thirty‐three studies met inclusion criteria and were included in the final analysis, with a total of 534 infants with efficacy data. Two studies were randomized‐controlled trials, and the remainder were uncontrolled cohort studies. All studies were categorized as low quality. Meta‐analyses of uncontrolled studies estimate 59% (95% confidence interval [CI] 53‐65) of infants achieved ≥50% seizure reduction and 33% (95% CI 26‐43) of infants achieved seizure freedom. Retention rates ranged from 84% at 3 months to 27% at 24 months. The most commonly reported side effects were dyslipidemia (20/171, 12%), vomiting (11/171, 6%), constipation (7/171, 4%), gastroesophageal reflux (6/171, 4%), and diarrhea (6/171, 4%). Significance: This review indicates that KDT is safe and tolerable and that it can be an effective treatment option for infants with drug‐resistant epilepsy. However, there are few studies focusing on infants treated with KDT, and high‐quality evidence is lacking. High‐quality randomized‐controlled trials are needed to confirm the effectiveness, safety, and tolerability of dietary treatment in this vulnerable age group. [ABSTRACT FROM AUTHOR]

Over time, with careful delineation of Dravet syndrome, we have gained experience in treatments most likely to lead to improvement in seizures, as well as those that should be avoided. Sodium valproate, clobazam, stiripentol, and topiramate are all medications that may lead to benefit, as well as the ketogenic diet. Bromides may be utilized in resistant cases. However, equally important are outlining prompt rescue treatment for prolonged seizures and avoidance of precipitants. Newer agents including cannabidiol and fenfluramine have been demonstrated to be of benefit in clinical trials. We propose an algorithm for management, but appreciate that the positioning of newer agents is yet to be established. [ABSTRACT FROM AUTHOR]

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Over time, with careful delineation of Dravet syndrome, we have gained experience in treatments most likely to lead to improvement in seizures, as well as those that should be avoided. Sodium valproate, clobazam, stiripentol, and topiramate are all medications that may lead to benefit, as well as the ketogenic diet. Bromides may be utilized in resistant cases. However, equally important are outlining prompt rescue treatment for prolonged seizures and avoidance of precipitants. Newer agents including cannabidiol and fenfluramine have been demonstrated to be of benefit in clinical trials. We propose an algorithm for management, but appreciate that the positioning of newer agents is yet to be established. [ABSTRACT FROM AUTHOR]

Febrile infection-related epilepsy syndrome (FIRES) is a severe epilepsy disorder that affects previously healthy children. It carries high likelihood of unfavourable outcome and putative aetiology relates to an auto-inflammatory process. Standard antiepileptic drug therapies including intravenous anaesthetic agents are largely ineffective in controlling status epilepticus in FIRES. Deep brain stimulation of the centromedian thalamic nuclei (CMN-DBS) has been previously used in refractory status epilepticus in only a few cases. The use of Anakinra (a recombinant version of the human interleukin-1 receptor antagonist) has been reported in one case with FIRES with good outcome. Here we describe two male paediatric patients with FIRES unresponsive to multiple anti-epileptic drugs, first-line immune modulation, ketogenic diet and cannabidiol. They both received Anakinra and underwent CMN-DBS. The primary aim for CMN-DBS therapy was to reduce generalized seizures. CMN-DBS abolished generalized seizures in both cases and Anakinra had a positive effect in one. This patient had a favourable outcome whereas the other did not. These are the first reported cases of FIRES where CMN-DBS has been used. • Centromedian thalamic deep brain stimulation plays a role in FIRES as a treatment for reducing generalized seizure burden. • In view of the proposed autoinflammatory aetiology for FIRES Anakinra should be considered as a possible treatment option. • CMN-DBS did not have a lasting effect on focal seizures burden. [ABSTRACT FROM AUTHOR]

Summary: Objective: With the exception of specific metabolic disorders, predictors of response to ketogenic dietary therapies (KDTs) are unknown. We aimed to determine whether common variation across the genome influences the response to KDT for epilepsy. Methods: We genotyped individuals who were negative for glucose transporter type 1 deficiency syndrome or other metabolic disorders, who received KDT for epilepsy. Genotyping was performed with the Infinium HumanOmniExpressExome Beadchip. Hospital records were used to obtain demographic and clinical data. KDT response (≥50% seizure reduction) at 3‐month follow‐up was used to dissect out nonresponders and responders. We then performed a genome‐wide association study (GWAS) in nonresponders vs responders, using a linear mixed model and correcting for population stratification. Variants with minor allele frequency <0.05 and those that did not pass quality control filtering were excluded. Results: After quality control filtering, the GWAS of 112 nonresponders vs 123 responders revealed an association locus at 6p25.1, 61 kb upstream of CDYL (rs12204701, P = 3.83 × 10−8, odds ratio [A] = 13.5, 95% confidence interval [CI] 4.07‐44.8). Although analysis of regional linkage disequilibrium around rs12204701 did not strengthen the likelihood of CDYL being the candidate gene, additional bioinformatic analyses suggest it is the most likely candidate. Significance: CDYL deficiency has been shown to disrupt neuronal migration and to influence susceptibility to epilepsy in mice. Further exploration with a larger replication cohort is warranted to clarify whether CDYL is the causal gene underlying the association signal. [ABSTRACT FROM AUTHOR]

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Hypothalamic hamartoma may present with epilepsy, specifically gelastic or dacrystic seizures, or endocrine dysfunction, commonly precocious puberty. The epilepsy in many patients is drug resistant, and has a high association with progressive cognitive, learning and behavioral difficulty. Medical treatment of seizures remains problematic, with many resistant to drug treatment. Surgical resection, or disconnection of the hamartoma provides the optimal chance of seizure control but with a relatively high risk of endocrine dysfunction, the result of interference with the hypothalamic-pituitary axis in many. Careful assessment and monitoring by specialist centers with discussion of optimal intervention is required for individual cases. [ABSTRACT FROM AUTHOR]

Objective In the absence of specific metabolic disorders, accurate predictors of response to ketogenic dietary therapies ( KDTs) for treating epilepsy are largely unknown. We hypothesized that specific biochemical parameters would be associated with the effectiveness of KDT in humans with epilepsy. The parameters tested were β-hydroxybutyrate, acetoacetate, nonesterified fatty acids, free and acylcarnitine profile, glucose, and glucose-ketone index ( GKI). Methods Biochemical results from routine blood tests conducted at baseline prior to initiation of KDT and at 3-month follow-up were obtained from 13 adults and 215 children with KDT response data from participating centers. One hundred thirty-two (57%) of 228 participants had some data at both baseline and 3 months; 52 (23%) of 228 had data only at baseline; 22 (10%) of 228 had data only at 3 months; and 22 (10%) of 228 had no data. KDT response was defined as ≥50% seizure reduction at 3-month follow-up. Results Acetyl carnitine at baseline was significantly higher in responders (p < 0.007). It was not associated with response at 3-month follow-up. There was a trend for higher levels of free carnitine and other acylcarnitine esters at baseline and at 3-month follow-up in KDT responders. There was also a trend for greater differences in levels of propionyl carnitine and in β-hydroxybutyrate measured at baseline and 3-month follow-up in KDT responders. No other biochemical parameters were associated with response at any time point. Significance Our finding that certain carnitine fractions, in particular baseline acetyl carnitine, are positively associated with greater efficacy of KDT is consistent with the theory that alterations in energy metabolism may play a role in the mechanisms of action of KDT. [ABSTRACT FROM AUTHOR]

Background: The incidence of epilepsy is greatest in the first 2 years of life, an age group where there is generally a poor prognosis for both seizure control and neurodevelopmental outcome. Early control of seizures can be associated with better developmental outcome but many of the epilepsies presenting in infancy are poorly responsive to antiepileptic medication. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet designed to mimic the effects of starvation on the body. Dietary fat is converted into ketones in the body and used as an energy source by the brain. The KD has been shown to be successful in controlling seizures in many observational studies, and in two randomised controlled trials (RCTs) in older children. However, little evidence is available in the very young.Methods/design: An open-label RCT where eligible children (age 3 months to 2 years with epilepsy who have failed two antiepileptic drugs (AEDs)) undergo baseline assessment, including medical and seizure history. Participants then start an observation period (7 or 14 days) with documentation of seizure frequency. Randomisation will occur on day 8 or day 15 to receive the KD or a further AED; the allocated treatment will commence on day 15, with instruction and training. A second assessment (4 weeks after start of treatment) will include a clinical review and tolerability questionnaire (modified Hague Scale of Side Effects - for those allocated to the KD group). Assessments will be repeated at 8 weeks after the start of treatment including biochemical investigations, after which, according to patient response, KD (diet group) or AED (standard AED group) will then be continued or changed. Those in the AED group who have failed to achieve seizure control at the 8-week assessment will then be offered KD outside the context of the trial. Those in the KD arm who fail to achieve seizure control will be changed to standard clinical management. All patients will be followed up for 12 months from randomisation for retention, seizure outcome, quality of life and neurodevelopmental status.Discussion: The slow rate of recruitment is an ongoing practical issue. There is a limitation to the number of eligible patients compared to what was predicted, mainly due to the nature of this patient group. After a substantial amendment to widen inclusion criteria and reduce the baseline period to 7 days for patients with a high seizure burden, the rate of recruitment steadily increased. A number of operational concerns regarding dietetic time were also highlighted impacting on the recruitment rate. However, the combination of a low dropout rate and the opening of further centres, the trial should successfully meet the final recruitment target. All nine centres are now recruiting and we hope to open further centres within the UK.Trial Registration: ClinicalTrials.gov, identifier: NCT02205931 . Registered on 16 December 2013. [ABSTRACT FROM AUTHOR]

Background The ketogenic diet (KD) is an established, effective non-pharmacologic treatment for drug resistant childhood epilepsy. For a long time, the KD was not recommended for use in infancy (under the age of 2 years) because this is such a crucial period in development and the perceived high risk of nutritional inadequacies. Indeed, infants are a vulnerable population with specific nutritional requirements. But current research shows that the KD is highly effective and well tolerated in infants with epilepsy. Seizure freedom is often achieved and maintained in this specific patient group. There is a need for standardised protocols and management recommendations for clinical use. Method In April 2015, a project group of 5 experts was established in order to create a consensus statement regarding the clinical management of the KD in infants. The manuscript was reviewed and amended by a larger group of 10 international experts in the KD field. Consensus was reached with regard to guidance on how the diet should be administered and in whom. Results The resulting recommendations include patient selection, pre-KD counseling and evaluation, specific nutritional requirements, preferred initiation, monitoring of adverse effects at initiation and follow-up, evaluation and KD discontinuation. Conclusion This paper highlights recommendations based on best evidence, combined with expert opinions and gives directions for future research. [ABSTRACT FROM AUTHOR]

Our inability to adequately treat many patients with refractory epilepsy caused by focal cortical dysplasia ( FCD), surgical inaccessibility and failures are significant clinical drawbacks. The targeting of physiologic features of epileptogenesis in FCD and colocalizing functionality has enhanced completeness of surgical resection, the main determinant of outcome. Electroencephalography ( EEG)-functional magnetic resonance imaging ( fMRI) and magnetoencephalography are helpful in guiding electrode implantation and surgical treatment, and high-frequency oscillations help defining the extent of the epileptogenic dysplasia. Ultra high-field MRI has a role in understanding the laminar organization of the cortex, and fluorodeoxyglucose-positron emission tomography ( FDG- PET) is highly sensitive for detecting FCD in MRI-negative cases. Multimodal imaging is clinically valuable, either by improving the rate of postoperative seizure freedom or by reducing postoperative deficits. However, there is no level 1 evidence that it improves outcomes. Proof for a specific effect of antiepileptic drugs (AEDs) in FCD is lacking. Pathogenic mutations recently described in mammalian target of rapamycin ( mTOR) genes in FCD have yielded important insights into novel treatment options with mTOR inhibitors, which might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease. The ketogenic diet ( KD) has been demonstrated to be particularly effective in children with epilepsy caused by structural abnormalities, especially FCD. It attenuates epigenetic chromatin modifications, a master regulator for gene expression and functional adaptation of the cell, thereby modifying disease progression. This could imply lasting benefit of dietary manipulation. Neurostimulation techniques have produced variable clinical outcomes in FCD. In widespread dysplasias, vagus nerve stimulation ( VNS) has achieved responder rates >50%; however, the efficacy of noninvasive cranial nerve stimulation modalities such as transcutaneous VNS (tVNS) and noninvasive (nVNS) requires further study. Although review of current strategies underscores the serious shortcomings of treatment-resistant cases, initial evidence from novel approaches suggests that future success is possible. [ABSTRACT FROM AUTHOR]

The Ketogenic diet ( KD) is an effective treatment with regards to treating pharmaco-resistant epilepsy. However, there are difficulties around compliance and tolerability. Consequently, there is a need for refined/simpler formulations that could replicate the efficacy of the KD. One of the proposed hypotheses is that the KD increases cellular mitochondrial content which results in elevation of the seizure threshold. Here, we have focussed on the medium-chain triglyceride form of the diet and the observation that plasma octanoic acid (C8) and decanoic acid (C10) levels are elevated in patients on the medium-chain triglyceride KD. Using a neuronal cell line ( SH- SY5Y), we demonstrated that 250-μM C10, but not C8, caused, over a 6-day period, a marked increase in the mitochondrial enzyme, citrate synthase along with complex I activity and catalase activity. Increased mitochondrial number was also indicated by electron microscopy. C10 is a reported peroxisome proliferator activator receptor γ agonist, and the use of a peroxisome proliferator activator receptor γ antagonist was shown to prevent the C10-mediated increase in mitochondrial content and catalase. C10 may mimic the mitochondrial proliferation associated with the KD and raises the possibility that formulations based on this fatty acid could replace a more complex diet. [ABSTRACT FROM AUTHOR]

Highlights: [•] We searched for putative predictors of response to Ketogenic Diet Therapies (KDT) for epilepsy. [•] No specific factors appear to affect response to KDT in humans – evidence is inconsistent. [•] Gender and intellectual status do not seem to affect response to KDT. [•] More studies are needed to improve understanding of the mechanisms behind KDT. [Copyright &y& Elsevier]

The ketogenic diet is not a new treatment for the treatment of epilepsy, but the degree of literature now available seems to have given it a new lease of life. Over the past 12 years, there has been more scientific data on both benefits and effect of the ketogenic diet. Data demonstrate a clear benefit in efficacy. We also have a clearer idea in utilization, type of diet to use, and in whom. Questions however remain and further work is required, not least in recognizing likely candidates and in simplifying administration. [ABSTRACT FROM AUTHOR]

Background: The risk of nutritional deficiency in children on restrictive dietary treatments and a lack of ketogenic diet (KD)-specific UK supplements raises concerns about micronutrient status. Vitamin A, E, zinc, selenium and magnesium levels were therefore examined in children with intractable epilepsy treated with the KD. Methods: Plasma vitamins A and E, zinc, selenium and magnesium levels were measured at baseline and after 3, 6 and 12 months on the classical ( n = 46) or medium chain triglyceride (MCT) ( n = 45) KD in children aged 2-16 years, as part of a randomised trial, and pairwise comparisons with baseline were performed. Results: Data were available from 91 children. From baseline to 12 months, mean plasma vitamin A decreased from 1.41 μmol L−1 to 1.13 μmol L−1 in the classical group ( P < 0.001) but increased from 1.52 μmol L−1 to 1.81 μmol L−1 in the MCT group ( P < 0.001). Mean plasma vitamin E increased from 22.7 μmol L−1 to 33.2 μmol L−1 in the classical group ( P < 0.001) and from 22.3 μmol L−1 to 23.3 μmol L−1 in the MCT group ( P < 0.05). No significant change in plasma zinc was seen at 12 months, although mean plasma selenium decreased from 0.95 μmol L−1 to 0.88 μmol L−1 in the group as a whole ( P < 0.05). Mean plasma magnesium decreased from 0.87 mmol L−1 to 0.83 mmol L−1 in the group as a whole ( P < 0.001); when subdivided by KD type, this was limited to the classical group. Conclusions: Changes in plasma vitamins A and E and the decline in magnesium status after 12 months of KD treatment suggest that micronutrient status may be suboptimal in this group and that available formulations for KD supplementation may need reviewing. [ABSTRACT FROM AUTHOR]

The ketogenic diet (KD) has been used to treat children with epilepsy who are resistant to antiepileptic drugs (AEDs) since the 1920s, and has undergone a resurgence in popularity over the last 15 years Its use in adolescents and adults has been more restrained. During the past few decades, more liberal regimens have emerged that may seem more attractive to older people while still proving effective, often independent of ketone levels. The KD and its variants may lead to similar reductions in seizure frequency in adolescents and adults as seen in children, although studies are limited and of poor quality. A total of only 122 adults and 82 adolescents have been included in open-label studies on the KD, and only 56 adults and 10 adolescents on the Modified Atkins Diet. Side effects appear similar to those encountered in children. Noncompliance may be higher in adolescents and adults than in children, but the main reason for discontinuation is lack of efficacy. A better understanding of the mechanisms underlying the effects of the KD might allow the same treatment effects to be achieved using novel, better-tolerated, nondietary approaches. [ABSTRACT FROM AUTHOR]

Abstract: The ketogenic diet has been used for the treatment of epilepsy in childhood for almost 100 years. Although initial use was wide, the advent of antiepileptic drugs led to reduced utilisation. However, an apparently ‘forgotten treatment’ gained further popularity in the early 1990s when significant individuals gained benefit. This aside, although there are many open label trials to suggest benefit can be gained in children with drug resistant epilepsy it is only recently that definitive evidence from randomised controlled trials has become available. There continues to be a constant struggle with the demand for the resources required, and therefore availability and apparent management choice is limited. [ABSTRACT FROM AUTHOR]

The ketogenic diet (KD) is a high fat, restricted carbohydrate regime that has been used as a treatment for seizures since the 1920s, when it was designed to induce a similar metabolic response to fasting. A modification of this early classical version of the KD was introduced in the 1970s using medium chain triglycerides as an alternative fat source. More recently, two alternative, less-restrictive dietary treatments have been developed: the modified Atkins diet and the low glycaemic index diet. There are many case reports and observational studies reporting successful use of the KD, and a growing number of studies reporting similar success with the modified Atkins protocol. A recent randomised controlled trial has shown a significant benefit of the KD compared to no change in treatment. The use of these dietary therapies in the UK is supported by literature evidence, although often is limited by a lack of resources; increasing awareness and knowledge is fundamental to ensure availability for those individuals with intractable epilepsy who may benefit from them. [ABSTRACT FROM AUTHOR]

To conduct the first randomized trial on classical and medium-chain triglyceride (MCT) versions of the ketogenic diet, examining efficacy and tolerability after 3, 6, and 12 months. One hundred forty-five children with intractable epilepsy were randomized to receive a classical or an MCT diet. Seizure frequency was assessed after 3, 6, and 12 months. Treatment withdrawals were documented. Tolerability was assessed by questionnaire, and blood ketone levels were measured. Of the 61 children who started a classical diet and the 64 who started an MCT diet, data from 94 were available for analysis: 45 classical and 49 MCT. After 3, 6, and 12 months there were no statistically significant differences in mean percentage of baseline seizures between the two groups (3 months: classical 66.5%, MCT 68.9%; 6 months: classical 48.5%, MCT 67.6%; 12 months: classical 40.8%, MCT 53.2%; all p > 0.05). There were no significant differences between groups in numbers achieving greater than 50% or 90% seizure reduction. Serum acetoacetate and β-hydroxybutyrate levels at 3 and 6 months were significantly higher in children on the classical diet (p < 0.01); this was the case at 12 months for acetoacetate. There were no significant differences in tolerability except increased reports in the classical group of lack of energy after 3 months and vomiting after 12 months. This study has shown classical and MCT ketogenic diet protocols to be comparable in efficacy and tolerability; both ways of implementing the diet have their place in the treatment of childhood epilepsy. [ABSTRACT FROM AUTHOR]

The ketogenic diet (KD) is an established, effective nonpharmacologic treatment for intractable childhood epilepsy. The KD is provided differently throughout the world, with occasionally significant variations in its administration. There exists a need for more standardized protocols and management recommendations for clinical and research use. In December 2006, The Charlie Foundation commissioned a panel comprised of 26 pediatric epileptologists and dietitians from nine countries with particular expertise using the KD. This group was created in order to create a consensus statement regarding the clinical management of the KD. Subsequently endorsed by the Practice Committee of the Child Neurology Society, this resultant manuscript addresses issues such as patient selection, pre-KD counseling and evaluation, specific dietary therapy selection, implementation, supplementation, follow-up management, adverse event monitoring, and eventual KD discontinuation. This paper highlights recommendations based on best evidence, including areas of agreement and controversy, unanswered questions, and future research. [ABSTRACT FROM AUTHOR]

The ketogenic diet (KD) has been used in the treatment of epilepsy for almost 100 years. Several cohort studies have emphasized its possible benefit, although use became less at the introduction of anticonvulsant medication. However, the KD has regained recognition over the past 15 years. Resources remain scarce and its availability for children may be limited. One argument has been the lack of evidence from suitably designed trials. Systematic reviews and meta-analyses have revealed that studies are limited to class 3 and 4 data. A recently published randomized controlled trial has shown that the benefit of the KD is equivalent to any of the new anticonvulsant medications, emphasizing the need for more resources to ensure greater diet availability. [ABSTRACT FROM AUTHOR]

Summary: In 2012, the third biannual international symposium focused on dietary treatments for neurologic disorders will be held. Over the next two years between this current meeting in Edinburgh and the next (Chicago, USA), it is important to keep strong momentum going in order to advance the field. To summarize all the discussions and focus efforts, group meetings were held towards the end of the 4-day symposium to address the critical issues that needed attention in the immediate future. Clinical researchers, basic scientists, dietitians, and parents discussed their goals and the results are presented in this article. [ABSTRACT FROM AUTHOR]

Summary: The ketogenic diet is now an established treatment in children for drug resistant epilepsy. Although in use for almost 100 years, it has taken time for us to determine an evidence base to verify its use in these children. However, increasing research both from a clinical and basic science perspective as well as a wide clinical interest has now enabled its use throughout the world. This aside, there remains lack of resources to guarantee its availability to all those who may be suitable. It is also now quite clear that it may have benefit in wider areas of neurology beyond epilepsy, specifically in metabolic disorders where glucose cannot be used as a primary energy source. [ABSTRACT FROM AUTHOR]

The author gives opinion on the effectiveness of the ketogenic diet in treating epilepsy in children. According to her, the diet has been used in the management of childhood epilepsy for nearly a century. She cites the publication of the first randomized controlled trial of the diet in 2008. She also provides an overview of a study published in the same issue which puts emphasis on how to carry out successfully administration of such a form of diet with cultural adaptation.

The article focuses on the use of ketogenic diet in treating epilepsy. The ketogenic diet has been in the treatment of epilepsy for almost a century and its popularity and use has been variable over the years. The argument against wide acceptance has often been the lack of appropriate efficacy data. Blinding family and professionals to the treatment was thought to be impossible although a randomized controlled trial of the effect of the ketogenic diet has been performed.

The author discusses a study by M. E. Lemmon et al on the efficacy of the ketogenic diet in Lennox-Gastaut syndrome (LGS). The syndrome was first described in 1996 and initially proposed as Lennox syndrome. The author notes that problem remains in the optimal management and treatment of patients with LGS. It is also illustrated in the Lemmon study that the ketogenic diet may succeed and should be considered in the overall management of children with LGS.

High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for refractory epilepsy. A key mechanism of this treatment is thought to be the generation of ketones, which provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control. However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as preventing neurodegeneration in Alzheimer's disease, the proliferation and spread of cancer, and insulin resistance in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the development of new pharmacological and dietary therapies for epilepsy and other disorders. [ABSTRACT FROM AUTHOR]

Ketogenic dietary therapies are an effective treatment for children with drug-resistant epilepsy. There is currently no high-quality evidence regarding ketogenic dietary therapies in adults, and further research has been recommended. This audit aimed to provide further evidence for the feasibility of dietary treatment for adults and to consider factors that may aid response classification in this population. We evaluated the effectiveness and tolerability of ketogenic dietary therapies in 23 adults with epilepsy attending specialist clinics. Medical notes were used to obtain seizure frequency information and other effects associated with dietary treatment. Individuals who achieved ≥ 50% seizure reduction at all follow-up points were classified as responders. Response rates, in terms of seizure frequency, were similar to those commonly reported in pediatric cohorts: 9/23 (39%) adults were classified as responders. These responders remained on the diet for at least one year (follow-up: 1–10 years). Other benefits reported by patients, but not quantified, included a reduction in seizure severity and increased alertness and concentration. Such factors often favor continuation of ketogenic dietary therapies despite a < 50% seizure reduction. One individual experienced psychosis while following dietary treatment; most commonly reported adverse events were gastrointestinal. Adverse events did not lead to discontinuation of treatment in any cases. Our findings suggest that adults with epilepsy are able to follow ketogenic dietary therapies long-term, and such treatment can lead to seizure reduction. Other aspects besides seizure frequency may be relevant when classifying response in adults, and appropriate ways to quantify these factors should be considered for use in future studies. [ABSTRACT FROM AUTHOR]

Summary: Background: The ketogenic diet has been widely and successfully used to treat children with drug-resistant epilepsy since the 1920s. The aim of this study was to test the efficacy of the ketogenic diet in a randomised controlled trial. Methods: 145 children aged between 2 and 16 years who had at least daily seizures (or more than seven seizures per week), had failed to respond to at least two antiepileptic drugs, and had not been treated previously with the ketogenic diet participated in a randomised controlled trial of its efficacy to control seizures. Enrolment for the trial ran between December, 2001, and July, 2006. Children were seen at one of two hospital centres or a residential centre for young people with epilepsy. Children were randomly assigned to receive a ketogenic diet, either immediately or after a 3-month delay, with no other changes to treatment (control group). Neither the family nor investigators were blinded to the group assignment. Early withdrawals were recorded, and seizure frequency on the diet was assessed after 3 months and compared with that of the controls. The primary endpoint was a reduction in seizures; analysis was intention to treat. Tolerability of the diet was assessed by questionnaire at 3 months. The trial is registered with ClinicalTrials.gov, number NCT00564915. Findings: 73 children were assigned to the ketogenic diet and 72 children to the control group. Data from 103 children were available for analysis: 54 on the ketogenic diet and 49 controls. Of those who did not complete the trial, 16 children did not receive their intervention, 16 did not provide adequate data, and ten withdrew from the treatment before the 3-month review, six because of intolerance. After 3 months, the mean percentage of baseline seizures was significantly lower in the diet group than in the controls (62·0%vs 136·9%, 75% decrease, 95% CI 42.4–107.4%; p<0·0001). 28 children (38%) in the diet group had greater than 50% seizure reduction compared with four (6%) controls (p<0·0001), and five children (7%) in the diet group had greater than 90% seizure reduction compared with no controls (p=0·0582). There was no significant difference in the efficacy of the treatment between symptomatic generalised or symptomatic focal syndromes. The most frequent side-effects reported at 3-month review were constipation, vomiting, lack of energy, and hunger. Interpretation: The results from this trial of the ketogenic diet support its use in children with treatment-intractable epilepsy. Funding: HSA Charitable Trust; Smiths Charity; Scientific Hospital Supplies; Milk Development Council. [Copyright &y& Elsevier]

Background: The ketogenic diet has been widely and successfully used to treat children with drug-resistant epilepsy since the 1920s. The aim of this study was to test the efficacy of the ketogenic diet in a randomised controlled trial.Methods: 145 children aged between 2 and 16 years who had at least daily seizures (or more than seven seizures per week), had failed to respond to at least two antiepileptic drugs, and had not been treated previously with the ketogenic diet participated in a randomised controlled trial of its efficacy to control seizures. Enrolment for the trial ran between December, 2001, and July, 2006. Children were seen at one of two hospital centres or a residential centre for young people with epilepsy. Children were randomly assigned to receive a ketogenic diet, either immediately or after a 3-month delay, with no other changes to treatment (control group). Neither the family nor investigators were blinded to the group assignment. Early withdrawals were recorded, and seizure frequency on the diet was assessed after 3 months and compared with that of the controls. The primary endpoint was a reduction in seizures; analysis was intention to treat. Tolerability of the diet was assessed by questionnaire at 3 months. The trial is registered with ClinicalTrials.gov, number NCT00564915.Findings: 73 children were assigned to the ketogenic diet and 72 children to the control group. Data from 103 children were available for analysis: 54 on the ketogenic diet and 49 controls. Of those who did not complete the trial, 16 children did not receive their intervention, 16 did not provide adequate data, and ten withdrew from the treatment before the 3-month review, six because of intolerance. After 3 months, the mean percentage of baseline seizures was significantly lower in the diet group than in the controls (62.0%vs 136.9%, 75% decrease, 95% CI 42.4-107.4%; p<0.0001). 28 children (38%) in the diet group had greater than 50% seizure reduction compared with four (6%) controls (p<0.0001), and five children (7%) in the diet group had greater than 90% seizure reduction compared with no controls (p=0.0582). There was no significant difference in the efficacy of the treatment between symptomatic generalised or symptomatic focal syndromes. The most frequent side-effects reported at 3-month review were constipation, vomiting, lack of energy, and hunger.Interpretation: The results from this trial of the ketogenic diet support its use in children with treatment-intractable epilepsy.Funding: HSA Charitable Trust; Smiths Charity; Scientific Hospital Supplies; Milk Development Council. [ABSTRACT FROM AUTHOR]