Abstract Objective Ketogenic dietary therapies (KDTs) are the treatment of choice for Glut1 Deficiency Syndrome (Glut1DS), providing dietary ketones as an alternative fuel to the brain and effectively controlling seizures. Recent evidence indicates insufficient seizure control in Glut1DS patients despite adequate KDT and ketosis. Methods Fifty‐three patients, diagnosed with Glut1DS and treated by KDT, were followed in a single‐center outpatient clinic from 2000 to 2023. Epilepsy, present in 44 patients, was analyzed for seizure control, EEG changes, and potential correlations to clinical and genetic features. Epilepsy response to KDT was defined as a >90% seizure reduction on KDT monotherapy. Results On KDT monotherapy 27/44 (61%) patients became >90% seizure free, rated as responders. 17/44 were non‐responders. Within this group, 10/17 patients responded to KDT plus antiseizure comedication. In 7 patients, KDT plus antiseizure comedication failed to control seizures. No correlations of seizure control to gender, age at start or type of KDT, or SLC2A1 variants were observed. In responders (n = 27), EEG epileptic activity, evident in 15/27 patients, improved on KDT in 5 patients. In non‐responders (n = 17), EEG epileptic activity was evident in 14/17 and improved on KDT in 9 patients. EEG background slowing prior to KDT normalized in KDT in all responders (4/27), but in none of the non‐responders (4/17). Significance Epilepsy is a dominant feature of Glut1DS. KDT provides efficient seizure control, but failure to control epilepsy is more common than expected. KDT epilepsy response did not correlate with seizure type, clinical, or genetic features, emphasizing the complexity of this entity. Add‐on antiseizure medication can be effective in some patients, without individual drug superiority. Epileptic activity on EEG did not prove a good marker for outcome, but reversible EEG background slowing on KDT might be predictive for favorable seizure control. Plain Language Summary Impaired glucose transport into the brain causes a brain energy crisis termed Glut1 Deficiency. Ketogenic diets mimic fasting, provide ketones as an alternative fuel, and effectively restore brain function. In our study, this worked for ca. 60% of patients. To our surprise, epilepsy persisted in about 40% of patients despite ketogenic diets for reasons unknown. Additional medication against epilepsy randomly helped in some patients. We analyzed many parameters without finding obvious explanations. Electrical brain activity improvement on ketogenic diets might be a future marker for efficient seizure control.

This retrospective study on X-linked PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency combined a systematic literature review with a multicentre survey exploring genotypes, phenotypes and survival. Data from 891 individuals (45% unpublished) were included. Of note, 53% of cases were females. Median age at last assessment was 6 years (range 0-80 years, n = 622). We detected 331 different (118 unpublished) PDHA1 variants, of which 75% (305/405) had occurred de novo. Variants in this study were uploaded to ClinVar (SCV006297015-SCV006297345). The 10 most frequent variants accounted for 36% of the diagnoses. Sixty-nine per cent of the variants were private; missense (50%) and frameshift (20%) variants were most common. Frameshift/nonsense (FS/N) variants in males (44/401, 11%) were confined to regions escaping nonsense-mediated decay (NMD) and were significantly less frequent than in females (151/461, 33%). Neonatal or infantile (405/529, 77%) presentations were most frequent, with pre/perinatal abnormalities reported in 47% (159/342). FS/N variants in the NMD-predicted region 3.9 [95% confidence interval (CI) 1.54-11.04] times increased the odds of fetal findings. Females presented significantly earlier [2 months, interquartile range (IQR) 7.0, n = 224] than males (8 months, IQR 16.6, n = 233), with increased risk of neonatal presentation [odds ratio (OR) 3.01 (95% CI 1.279-7.616)] when harbouring FS/N variants in the NMD-predicted region. The overall (n = 242) mean survival time was 10.9 (95% CI 9.9-11.9) years. On average, females survived 4.5 (95% CI 2.62-6.40) years longer than males despite presenting more severe phenotypes. Poor survival was associated with male sex [hazard ratio (HR) 3.3 (95% CI 1.95-5.62)], neonatal presentation [HR 5.5 (95% CI 2.17-14.09)], FS/N variants in the NMD-predicted region [HR 4.0 (95% CI 1.78, 9.16)] and splice variants [HR 2.3 (95% CI 1.15, 4.59)]. More severe clinical phenotypes were predicted by neonatal or infantile presentations and by female sex. Developmental delay (DD), intellectual disability (ID), muscle hypotonia, abnormal movements, seizures, feeding difficulties and microcephaly were the most frequent phenotypes, all occurring in more than half. Corpus callosum or basal ganglia alterations and cerebral atrophy were common. Four per cent (36/891) were reported to have mild phenotypes with no DD nor ID (25/36 males). This is the largest dataset on a nuclear-encoded defect of mitochondrial energy metabolism. The genotypic and phenotypic details further defines the disease landscape and can be used for variant interpretation. The correlations between genotypes, sex, phenotypes and survival, adds substantial improvement to counselling.

Abstract:Glucose transporter type I (Glut1) deficiency syndrome (Glut1DS) is associated with paroxysmal exertion-induced dystonia (PED). Episodes are published as brief, lasting 20 to 30 minutes. Increasingly, Glut1DS patients report prolonged PED of more than 1 hour duration. In a cohort of 60 Glut1DS patients seen in our institution within a 4-year period, a total of 26/60 patients (43%) on ketogenic dietary therapy (KDT) experienced PED. In 18/26 patients (30%), episodes lasted less than 1 hour as previously described. In 8/26 patients (13%), prolonged episodes lasted more than 1 hour up to 1 day despite adequate dietary treatment. We conclude that PED is common in Glut1DS starting in late childhood despite adequate treatment with KDT. Prolonged PED in Glut1DS occurs in a subset of patients, also unresponsive to KDT, and represents a substantial burden to patients and families.

Glut1 Deficiency Syndrome (Glut1DS) has emerged as a treatable, but complex entity. Increasing data on pathogenic mechanisms, phenotype, genotype, and ketogenic dietary therapies (KDT) are available, as summarized in this review. Many challenges remain: novel symptoms emerge and vary with age. In Glut1DS, KDT in pregnancy and the clinical features in neonates and adults are poorly understood. KDT are ineffective in some patients for reasons yet unknown. Research reaches beyond the concept of brain energy depletion by impaired GLUT1-mediated glucose transfer across the blood-brain barrier. Novel concepts investigate alternative substrates, transport mechanisms, and metabolic interactions of different brain cell types. Future, yet currently unavailable prospects are neonatal screening for Glut1DS, reliable biomarkers, predictors for outcome, and alternative therapies, along with and beyond KDT.

OBJECTIVE:The ketogenic diet (KD) is the standard treatment for glucose transporter type 1 deficiency syndrome (GLUT1-DS), typically yielding seizure reduction and cognitive/motor gains. However, a small subset of patients shows limited or no clinical benefit. This phenomenon, referred to as "KD resistance," remains poorly understood and inconsistently defined. We propose a working definition, outline evaluation domains, summarize candidate mechanisms, and indicate management steps. METHODS:Narrative review of published evidence and expert opinion across clinical, biochemical, EEG, and adherence domains. RESULTS:KD resistance may be considered when all are present: (1) confirmed therapeutic ketosis (serial blood β-hydroxybutyrate ≥2.0-2.5 mmol/L on repeated measurements); (2) adequate dietary adherence verified by dietetic assessment and, when available, validated tools; (3) sufficient trial duration (≥3 months; longer for primarily cognitive/motor goals); and (4) lack of meaningful improvement on symptom-relevant standardized measures. EEG interictal epileptiform discharge burden can be used as an adjunct marker but is not required. KD resistance may involve several dimensions: failure to achieve therapeutic ketosis, lack of symptom improvement despite confirmed ketosis, or challenges with adherence that limit efficacy. Possible contributing factors include genotypic variability in SLC2A1, mitochondrial dysfunction, impaired blood-brain barrier transport, hormonal influences, and epigenetic regulation. We outline a multidomain evaluation framework with suggested metrics, summarize candidate mechanisms (ketone transport/utilization, mitochondrial function, neurotransmission, ion channels/neuromodulators, inflammation/oxidative stress, epigenetic regulation), and indicate when to introduce a KD-compatible anti-seizure medication. SIGNIFICANCE:The proposed definition and framework standardize terminology and reporting, guide decisions for suboptimal responders, and set priorities for multicenter validation.

AbstractThe ketogenic diet (KD) can have a negative impact on the linear growth and body composition of children. The aims of this study were to review two centers' experience with children who developed height deceleration on the KD and determine if the height deceleration was secondary to growth hormone deficiency (GHD), and if growth hormone therapy (GHT) would be effective and safe (not altering ketosis or seizure frequency). Retrospective chart reviews were performed on patients with KD referred to Endocrinology between 2013 and 2018. Seventeen children were identified. Data reviewed included: demographics, growth velocity, KD ratio, protein/calorie intake, lab results, GH dosage, Tanner stage, and seizure frequency, and endocrine recommendations. Descriptive statistics were performed. Of the 17 children referred to the Endocrine Division, seven children were growth hormone deficient and began GHT. Data were provided for six patients (2 males, 4 females; age 2–7 years at the start of KD) on the KD for >6 years and on GHT for >4 years. Growth for all patients stabilized or increased. IGF‐1 z‐scores normalized. GHT did not affect seizure frequency or ketosis. GHT in those with GHD can be an appropriate option allowing better growth while still maintaining ketogenic therapy and seizure control.Plain Language SummaryThe KD can be an effective treatment for difficult‐to‐control epilepsy and some disorders of carbohydrate metabolism. The KD can adversely affect the linear growth (height) of children. This case series reviewed six patients who had slow linear growth. It was found that all six children had growth hormone deficiency, grew better with growth hormone treatments, and that their seizures and ketone levels were not affected.

Background Variants in GABRB2 , encoding the 0 2 subunit of the gamma-aminobutyric acid type A (GABA(A) ) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype - phenotype correlation analysis in a cohort of individuals with GABRB2 variants. Methods Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. Findings Electrophysiological assessments of alpha 1 0 2 gamma 2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. Interpretation The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic fl owchart that aids in predicting the pathogenicity of recently identi fi ed variants by considering clinical phenotypes.

The aim of this research was to characterize cognitive abilities in patients with Glut1-Deficiency syndrome (Glut1DS) following ketogenic diet therapy (KDT). Methods: The cognitive profiles of eight children were assessed using the Wechsler Intelligence Scale (WISC-IV). The effect of ketogenic diet therapy (KDT) on individual subareas of intelligence was analyzed considering the potential influence of speech motor impairments. Results: Patients with Glut1DS showed a wide range of cognitive performance levels. Some participants showed statistically and clinically significant discrepancies between individual subdomains of intelligence. Both variables, KDT initiation as well as duration, had a positive effect on the overall IQ score. Significant correlations were partially found between the time of KDT initiation and the level of IQ scores, depending on the presence of expressive language test demands of the respective subtests of the WISC-IV. Accordingly, the participants benefited les in the linguistic cognitive domain. The discrepancies in cognitive performance profiles of patients with Glut1DS can be attributed to the possibility of a negative distortion of the results due to the influence of speech motor impairments. Conclusions: The individual access skills of test persons should be more strongly considered in test procedures for the assessment of intelligence to reduce the negative influence of motor deficits on test performance. Specific characterization and systematization of the speech disorder are indispensable for determining the severity of speech motor impairment in Glut1DS. Therefore, a stronger focus on dysarthria during diagnosis and therapy is necessary.

Febrile seizures (FS) are usually self-limiting and cause no morbidity. Nevertheless they represent very traumatic events for families. There is a need to identify key messages that reassure carers and help to prevent inappropriate, anxiety-driven behaviors associated with “fever phobia.” No recommendations have been proposed to date regarding the content of such messages. Using a Delphi process, we have established a consensus regarding the information to be shared with families following a FS. Twenty physicians (child neurologists and pediatricians) from five European countries participated in a three-step Delphi process between May 2018 and October 2019. In the first step, each expert was asked to give 10 to 15 free statements about FS. In the second and third steps, statements were scored and selected according to the expert ranking of importance. A list of key messages for families has emerged from this process, which offer reassurance about FS based on epidemiology, underlying mechanisms, and the emergency management of FS should they recur. Interestingly, there was a high level of agreement between child neurologists and general pediatricians. Conclusion: We propose key messages to be communicated with families in the post-FS clinic setting.

Abstract Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide‐ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye‐head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS‐specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. Clinical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long‐term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle.

Purpose BECTS (benign childhood epilepsy with centrotemporal spikes) is associated with characteristic EEG findings. This study examines the influence of anti-convulsive treatment on the EEG. Methods In a randomized controlled trial including 43 children with BECTS, EEGs were performed prior to treatment with either Sulthiame or Levetiracetam as well as three times under treatment. Using the spike-wave-index, the degree of EEG pathology was quantified. The EEG before and after initiation of treatment was analyzed. Both treatment arms were compared and the EEG of the children that were to develop recurrent seizures was compared with those that were successfully treated. Results Regardless of the treatment agent, the spike-wave-index was reduced significantly under treatment. There were no differences between the two treatment groups. In an additional analysis, the EEG characteristics of the children with recurrent seizures differed statistically significant from those that did not have any further seizures. Conclusion Both Sulthiame and Levetiracetam influence the EEG of children with BECTS. Persistent EEG pathologies are associated with treatment failures.

Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder that results in defective sulfatase post-translational modification. Sulfatases in the body are activated by a unique protein, formylglycine-generating enzyme (FGE) that is encoded by SUMF1. When FGE is absent or insufficient, all 17 known human sulfatases are affected, including the enzymes associated with metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. As such, individuals demonstrate a complex and severe clinical phenotype that has not been fully characterized to date. In this report, we describe two individuals with distinct clinical presentations of MSD. Also, we detail a comprehensive systems-based approach to the management of individuals with MSD, from the initial diagnostic evaluation to unique multisystem issues and potential management options. As there have been no natural history studies to date, the recommendations within this report are based on published studies and consensus opinion and underscore the need for future research on evidence-based outcomes to improve management of children with MSD.

Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

BACKGROUND AND AIMS:Glut1 Deficiency (Glut1D) is caused by impaired glucose transport into brain. The resulting epileptic encephalopathy and movement disorders can be treated effectively by high-fat carbohydrate-restricted ketogenic diet therapies (KDT) mimicking fasting and providing ketones as an alternative cerebral fuel. Recently 6-24 months follow-ups of epileptic patients reported elevated blood lipids and intima thickening of the carotid artery raising concerns about potential cardiovascular risks by KDT. To clarify potential cardiovascular risks we performed a prospective 10 year follow up of 10 Glut1D patients. METHODS:Between August 2001 and January 2016 we enrolled Glut1D patients on KDT at two hospitals in Germany in this prospective, multicenter case series. The minimal follow up was 10 years. Standard deviation scores (SDS) of body mass index (BMI), total cholesterol (TC), HDL-/LDL cholesterol, and triglycerides (TG) before initiation of KDT were compared with respective values at 6 months, 2, 5 years, and 10 years after initiation. After 10 years on KDT cardiovascular risk, assessed by BMI, carotid intima-media thickness (CIMT) measurement, and blood pressure, was compared to a healthy reference population (n = 550). RESULTS:Baseline and 10 year follow-up investigations were available for 10 individuals with Glut1D on KDT. After two years on KDT BMI increased significantly, while total cholesterol, HDL-cholesterol, and LDL-cholesterol decreased. Within 3-5 years on KDT these differences disappeared, and after 10 years blood lipid parameters reflected the situation at initiation of KDT. Prior to KDT one child had dyslipidaemia, but no child after 10 years on KDT. No significant differences were observed with respect to BMI SDS (p = 0.26), CIMT (p = 0.63) or systolic and diastolic blood pressure (SDS p = 0.11 and p = 0.37, respectively) in Glut1D children treated with KDT for at least 10 years compared to healthy controls. CONCLUSIONS:In contrast to previous short-term reports on adverse effects of KDT, 10-year follow-up did not identify cardiovascular risks of dietary treatment for Glut1D.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a neurometabolic disorder with a complex phenotypic spectrum but simple biomarkers in cerebrospinal fluid. The disorder is caused by impaired glucose transport into the brain resulting from variants in SCL2A1. In 10% of GLUT1DS patients, a genetic diagnosis can not be made. Using whole-genome sequencing, we identified a de novo 5′-UTR variant in SLC2A1, generating a novel translation initiation codon, severely compromising SLC2A1 function. This finding expands our understanding of the disease mechanisms underlying GLUT1DS and encourages further in-depth analysis of SLC2A1 non-coding regions in patients without variants in the coding region.

BACKGROUND:Although a larger number of antiepileptic drugs became available in the last decades, epilepsy remains drug-resistant in approximately a third of patients. Ketogenic diet (KD), first proposed at the beginning of the last century, is complex and has anticonvulsant effects, yet not completely understood. Over the last decades, different types of ketogenic diets (KDs) have been developed, namely classical KD and modified Atkins diet (MAD). They offer an effective alternative for children and adults with drug-resistant epilepsies.METHODS:We review several papers on KDs as an adjunctive treatment of refractory epilepsy of children and adults, discussing its efficacy and adverse events. Because of the heterogenous, uncontrolled nature of the studies, we analyzed all studies individually, without a meta-analysis.RESULTS:KDs may be considered first choice treatment in some specific metabolic conditions, such as glucosetransporter type 1 and pyruvate dehydrogenase deficiencies, and mitochondrial complex I defects. Preliminary findings indicate that KDs may be specifically effective in some epileptic syndromes, such as West syndrome, severe myoclonic epilepsy of infancy, myoclonic-astatic epilepsy, febrile infection related epileptic syndrome, and drug-resistant idiopathic generalized epilepsies or refractory status epilepticus. Short term adverse events are usually mild in both children and adults, including gastrointestinal symptoms, hyperlipidemia, and hypercalciuria; potential long term adverse effects include nephrolitiasis, decreased bone density, and liver steatosis. Possible atherosclerotic effects remain a concern. Patients on KDs should be carefully monitored in specialized centers during initiation, maintenance and withdrawal periods, in order to minimize such adverse events, and to improve compliance. Although the majority of KD trials on children and adults with drug-resistant epilepsies are openlabel, uncontrolled studies based on small samples, an increasing number of randomized controlled trials have provided better quality evidence on its efficacy in recent years.CONCLUSION:There is a need for future randomized clinical trials aimed to confirm the efficacy of KDs in specific epileptic syndromes, and to provide further information about some practical unsolved problems, i.e. for how long KD treatment should be continued.

View Supplementary Video Movement disorders are a major feature of Glut1 deficiency. As recently identified in adults with paroxysmal exercise-induced dystonia, similar events were reported in pediatric Glut1 deficiency. In a case series, parent videos of regular motor state and paroxysmal events were requested from children with Glut1 deficiency on clinical follow-up. A questionnaire was sent out to 60 families. Videos of nonparoxysmal/paroxysmal states in 3 children illustrated the ataxic-dystonic, choreatiform, and dyskinetic-dystonic nature of paroxysmal events. Fifty-six evaluated questionnaires confirmed this observation in 73% of patients. Events appeared to increase with age, were triggered by low ketosis, sleep deprivation, and physical exercise, and unrelated to sex, hypoglycorrhachia, SLC2A1 mutations, or type of ketogenic diet. We conclude that paroxysmal events are a major clinical feature in Glut1 deficieny, linking the pediatric disease to adult Glut1D-associated exercise-induced paroxysmal dyskinesias.

High-fat ketogenic diets are the only treatment available for Glut1 deficiency (Glut1D). Here, we describe an 8-year-old girl with classical Glut1D responsive to a 3: 1 ketogenic diet and ethosuximide. After 3 years on the diet a gradual increase of blood lipids was followed by rapid, severe asymptomatic hypertriglyceridemia (1,910 mg/dL). Serum lipid apheresis was required to determine liver, renal, and pancreatic function. A combination of medium chain triglyceride-oil and a reduction of the ketogenic diet to 1:1 ratio normalized triglyceride levels within days but triggered severe myoclonic seizures requiring comedication with sultiam. Severe hypertriglyceridemia in children with Glut1D on ketogenic diets may be underdiagnosed and harmful. In contrast to congenital hypertriglyceridemias, children with Glut1D may be treated effectively by dietary adjustments alone.

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.