Tolerance, adherence, and acceptability of a ketogenic 2.5:1 ratio, nutritionally complete, medium chain triglyceride-containing liquid feed in children and adults with drug-resistant epilepsy following a ketogenic diet.

OBJECTIVE: To investigate incorporating a ready-to-use 2.5:1 ratio liquid feed into a ketogenic diet (KD) in children and adults with drug-resistant epilepsy. METHODS: Following a three-day baseline, patients (n = 19; age: 19 years [SD 13], range: 8-46 years) followed a KD for 28 days (control period), then incorporated ≥200 mL/day of a ready-to-use liquid feed, made with a ratio of 2.5 g of fat to 1 g of protein plus carbohydrate and including medium chain triglycerides ([MCTs]; 25.6% of total fat/100 mL) for 28 days as part of their KD (intervention period). Outcome measures (control vs intervention period) included gastrointestinal (GI) tolerance, adherence to KD and intervention feed, dietary intake, blood ß-hydroxybutyrate (BHB) concentration, seizure outcomes, health-related quality of life (HRQoL), acceptability and safety. RESULTS: Compared to the control period, during the intervention period, the percentage of patients reporting no GI symptoms increased (+5% [SD 5], p = 0.02); adherence to the KD prescription was similar (p = 0.92) but higher in patients (n = 5) with poor adherence (<50%) to KD during the control period (+33% [SD 26], p = 0.049); total MCT intake increased (+12.1 g/day [SD 14.0], p = 0.002), driven by increases in octanoic (C8; +8.3 g/day [SD 6.4], p < 0.001) and decanoic acid (C10; +5.4 g/day [SD 5.4], p < 0.001); KD ratio decreased (p = 0.047), driven by a nonsignificant increase in protein intake (+11 g/day [SD 44], p = 0.29); seizure outcomes were similar (p ≥ 0.63) but improved in patients (n = 6) with the worst seizure outcomes during the control period (p = 0.04); and HRQoL outcomes were similar. The intervention feed was well adhered to (96% [SD 8]) and accepted (≥88% of patients confirmed). SIGNIFICANCE: These findings provide an evidence-base to support the effective management of children and adults with drug-resistant epilepsy following a KD with the use of a ready-to-use, nutritionally complete, 2.5:1 ratio feed including MCTs. PLAIN LANGUAGE SUMMARY: This study examined the use of a ready-to-use, nutritionally complete, 2.5:1 ratio (2.5 g of fat to 1 g of protein plus carbohydrate) liquid feed, including medium chain triglycerides (MCTs), into a ketogenic diet (KD) in children and adults with drug-resistant epilepsy. The results show that the 2.5:1 ratio feed was well tolerated, adhered to, and accepted in these patients. Increases in MCT intake (particularly C8 and C10) and improvements in seizure outcomes (reduced seizure burden and intensity) and KD adherence also occurred with the 2.5:1 ratio feed in patients with the worst seizures and adherence, respectively.

Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial.

BACKGROUND: Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy. METHODS: In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1-24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6-8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding. FINDINGS: Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6-8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1-16]) and antiseizure medication group (3 [IQR 2-11]; IRR 1·33, 95% CI 0·84-2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee. INTERPRETATION: In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications. FUNDING: National Institute for Health and Care Research.

Patient and carer perspectives on the use of video consultations in the management of the ketogenic diet for epilepsy.

BACKGROUND: The COVID-19 pandemic resulted in a significant change in the way healthcare was delivered worldwide. During this time, a survey of Ketogenic Dietitians Research Network (KDRN) members found that all respondents expected digital platforms for clinics and/or education to continue post-pandemic. As a follow-up to this, we surveyed views about video consultations (VCs) of patients and carers of those following the ketogenic diet for drug-resistant epilepsy. METHODS: The SurveymonkeyTM survey was distributed on Matthews' Friends and KDRN social media platforms and emailed from five United Kingdom ketogenic diet centers to their patients/carers. RESULTS: Forty eligible responses were received. More than half of the respondents (23, 57.5%) had attended a VC. Eighteen respondents (45%) would like to have VCs for most (categorized as approximately 75%) or all of their consultations. Half as many (9, 22.5%) would not like video consultations. The most common benefits selected were saving travel time (32, 80%), less stress of finding somewhere to park and not having to take time off work (22, 55% each). Twelve (30%) responded that VCs lessened environmental impact. The most common disadvantages selected were not being able to get blood tests/having to make a separate consultation for blood tests (22, 55% overall), not being able to get weight or height checked/having to make a separate consultation for this and it is less personal/preferring face-to-face (17, 42.5% each). Three-quarters (30 respondents) felt it would be very easy or easy to accurately weigh the patient when not attending an in-person consultation. CONCLUSION: Our results suggest that many patients and carers would welcome the option of VCs as well as face-to-face consultations. Where possible and appropriate patients and their families should be offered both options. This is in line with the NHS Long-Term Plan and the NHS response to climate change.

Impact of ketogenic diet therapy on growth in children with epilepsy.

RATIONALE: Ketogenic diet therapy (KDT) is an effective treatment for drug-resistant epilepsy in children. There is conflicting evidence regarding the impact of KDT on growth. We aimed to determine whether linear growth and weight were affected in children who followed KDT in the UK, and to explore potential associations with clinical or demographic factors with impacted growth. METHODS: A retrospective review of medical records of children with epilepsy following KDT at 3 UK centres was conducted. Height and weight measurements taken as part of routine clinical management were recorded at baseline, 1-8 years on diet, and 1-year post-diet. Measurements were converted into z-scores, and the differences from baseline analysed using Wilcoxon Signed Rank tests. Potential associations of impacted growth with feeding method, ambulatory status, diet type, age at diet onset and average daily protein intake were investigated using Mann-Whitney, Kruskal-Wallis tests or Spearman's Rank correlation. RESULTS: 265 individuals were included, of which 84 had post-diet data available. Median height z-score significantly decreased at 1- (n = 139, p = .018), 2- (n = 86, p < .0005) and 3 years (n = 27, p = .001) on diet. There was no significant change to height or weight z-score 1-year post-diet discontinuation. Median weight z-score significantly decreased from baseline at 4 years (n = 15, p = .020), and 6 years (n = 8, p = .025) on diet, but not at other time points. There was greater height z-score decrease in non-ambulatory children at 2 years (p = .009), in those following a classical diet compared with the modified ketogenic diet at 2 years (p = .006) and amongst younger children at 2 years (n = 86, p < .005) and 3 years (n = 27, p = .008) on diet. No significant differences were found in weight z-score change across any subgroup, following Bonferroni correction for multiple testing. CONCLUSIONS: Median linear growth was significantly adversely affected for the first 3 years on KDT but catch-up growth post diet discontinuation was observed. Non-ambulatory children, younger children, and individuals following a classical diet may be more vulnerable to impacted growth when on KDT, although this was not consistent across all time points. The potential short-term impact on linear growth should be discussed with individuals considering KDT, and monitored closely.

Antiseizure medication reduction and withdrawal in children with drug-resistant epilepsy after starting the ketogenic diet.

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.

K.Vita: a feasibility study of a blend of medium chain triglycerides to manage drug-resistant epilepsy.

This prospective open-label feasibility study aimed to evaluate acceptability, tolerability and compliance with dietary intervention with K.Vita, a medical food containing a unique ratio of decanoic acid to octanoic acid, in individuals with drug-resistant epilepsy. Adults and children aged 3-18 years with drug-resistant epilepsy took K.Vita daily whilst limiting high-refined sugar food and beverages. K.Vita was introduced incrementally with the aim of achieving ≤35% energy requirements for children or 240 ml for adults. Primary outcome measures were assessed by study completion, participant diary, acceptability questionnaire and K.Vita intake. Reduction in seizures or paroxysmal events was a secondary outcome. 23/35 (66%) children and 18/26 (69%) adults completed the study; completion rates were higher when K.Vita was introduced more gradually. Gastrointestinal disturbances were the primary reason for discontinuation, but symptoms were similar to those reported from ketogenic diets and incidence decreased over time. At least three-quarters of participants/caregivers reported favourably on sensory attributes of K.Vita, such as taste, texture and appearance, and ease of use. Adults achieved a median intake of 240 ml K.Vita, and children 120 ml (19% daily energy). Three children and one adult had ß-hydroxybutyrate >1 mmol/l. There was 50% (95% CI 39-61%) reduction in mean frequency of seizures/events. Reduction in seizures or paroxysmal events correlated significantly with blood concentrations of medium chain fatty acids (C10 and C8) but not ß-hydroxybutyrate. K.Vita was well accepted and tolerated. Side effects were mild and resolved with dietetic support. Individuals who completed the study complied with K.Vita and additional dietary modifications. Dietary intervention had a beneficial effect on frequency of seizures or paroxysmal events, despite absent or very low levels of ketosis. We suggest that K.Vita may be valuable to those with drug-resistant epilepsy, particularly those who cannot tolerate or do not have access to ketogenic diets, and may allow for more liberal dietary intake compared to ketogenic diets, with mechanisms of action perhaps unrelated to ketosis. Further studies of effectiveness of K.Vita are warranted.

Keto-on-the-Clock: A Survey of Dietetic Care Contact Time Taken to Provide Ketogenic Diets for Drug-Resistant Epilepsy in the UK.

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.

Dietary Management of Children With Super-Refractory Status Epilepticus: A Systematic Review and Experience in a Single UK Tertiary Centre.

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.

Use of ketogenic diet therapy in infants with epilepsy: A systematic review and meta-analysis.

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.

Biochemical assessment of patients following ketogenic diets for epilepsy: Current practice in the UK and Ireland.

OBJECTIVE: Biochemical assessment is recommended for patients prior to initiating and following a ketogenic diet (KD). There is no published literature regarding current practice in the UK and Ireland. We aimed to explore practice in comparison with international guidelines, determine approximate costs of biochemical testing in KD patients across the UK and Ireland, and promote greater consistency in KD services nationally. METHODS: A survey was designed to determine the biochemical tests requested for patients at baseline, 3, 6, 12, 18, and 24 months + on KD. The survey was circulated to 39 centers across the UK and Ireland. RESULTS: Sixteen centers completed the survey. Full blood count, electrolytes, calcium, liver function tests (LFTs), lipid profile, and vitamin D were requested at all centers at baseline, in keeping with international guidelines. Bicarbonate, total protein, and urinalysis were less consistently requested. Magnesium and zinc were requested by all centers, despite not being specifically recommended for pre-diet evaluation in guidelines. Urea and electrolyte profiles and some LFTs were consistently requested at follow-up, in accordance with guidelines. Other LFTs and renal tests, full blood count, lipid profile, acylcarnitine profile, selenium, vitamin D, and urinalysis were less consistently requested at follow-up. The mean costs of the lowest and highest number of tests requested at baseline in our participating centers were £167.54 and £501.93; the mean costs of the lowest and highest number of tests requested at 3-month follow-up were £19.17 and £450.06. SIGNIFICANCE: Biochemical monitoring of KD patients varies widely across the UK and Ireland and does not fully correspond to international best practice guidelines. With an ongoing drive for cost-effectiveness within health care, further work is needed to streamline practice while ensuring patient safety.

Correction to: The landscape of epilepsy-related GATOR1 variants.

The original version of this Article contained an error in the author list where the corresponding author Stéphanie Baulac was repeated twice. This has now been corrected in the HTML, the PDF was correct at the time of publication.

The landscape of epilepsy-related GATOR1 variants.

PURPOSE: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. RESULTS: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. CONCLUSION: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

Correction: The landscape of epilepsy-related GATOR1 variants.

The original version of this article contained an error in the spelling of the author Erik H. Niks, which was incorrectly given as Erik Niks. This has now been corrected in both the PDF and HTML versions of the article.

Genome-wide association study: Exploring the genetic basis for responsiveness to ketogenic dietary therapies for drug-resistant epilepsy.

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.

An examination of biochemical parameters and their association with response to ketogenic dietary therapies.

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 ß-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 ß-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.

Ketogenic diet in the treatment of epilepsy in children under the age of 2 years: study protocol for a randomised controlled trial.

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.

Ketogenic dietary therapies in adults with epilepsy: a practical guide.

Ketogenic dietary therapies are an effective treatment option for children with drug-resistant epilepsy. There is an increasing worldwide interest in using these diets to manage adult epilepsy; uncontrolled studies show similar response rates to those in children. Despite this, there are only a few centres with dedicated services for adults. We clearly need controlled studies of this treatment in adults. Here, we aim to familiarise adult neurologists with the evidence base for these diets and give practical advice on starting and maintaining them in adults.

Variants in KCNJ11 and BAD do not predict response to ketogenic dietary therapies for epilepsy.

In the absence of specific metabolic disorders, predictors of response to ketogenic dietary therapies (KDT) are unknown. We aimed to determine whether variants in established candidate genes KCNJ11 and BAD influence response to KDT. We sequenced KCNJ11 and BAD in individuals without previously-known glucose transporter type 1 deficiency syndrome or other metabolic disorders, who received KDT for epilepsy. Hospital records were used to obtain demographic and clinical data. Two response phenotypes were used: ≥ 50% seizure reduction and seizure-freedom at 3-month follow-up. Case/control association tests were conducted with KCNJ11 and BAD variants with minor allele frequency (MAF)>0.01, using PLINK. Response to KDT in individuals with variants with MAF<0.01 was evaluated. 303 Individuals had KCNJ11 and 246 individuals had BAD sequencing data and diet response data. Six SNPs in KCNJ11 and two in BAD had MAF>0.01. Eight variants in KCNJ11 and seven in BAD (of which three were previously-unreported) had MAF<0.01. No significant results were obtained from association analyses, with either KDT response phenotype. P-values were similar when accounting for ethnicity using a stratified Cochran-Mantel-Haenszel test. There did not seem to be a consistent effect of rare variants on response to KDT, although the cohort size was too small to assess significance. Common variants in KCNJ11 and BAD do not predict response to KDT for epilepsy. We can exclude, with 80% power, association from variants with a MAF of >0.05 and effect size >3. A larger sample size is needed to detect associations from rare variants or those with smaller effect sizes.

Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy.

Sudden unexpected death in epilepsy (SUDEP) represents the most severe degree of the spectrum of epilepsy severity and is the commonest cause of epilepsy-related premature mortality. The precise pathophysiology and the genetic architecture of SUDEP remain elusive. Aiming to elucidate the genetic basis of SUDEP, we analysed rare, protein-changing variants from whole-exome sequences of 18 people who died of SUDEP, 87 living people with epilepsy and 1479 non-epilepsy disease controls. Association analysis revealed a significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy (P = 5.7 × 10(- 3)) and non-epilepsy disease controls (P = 1.2 × 10(- 3)). The polygenic burden was driven both by the number of variants per individual, and over-representation of variants likely to be deleterious in the SUDEP cohort. As determined by this study, more than a thousand genes contribute to the observed polygenic burden within the framework of this study. Subsequent gene-based association analysis revealed five possible candidate genes significantly associated with SUDEP or epilepsy, but no one single gene emerges as common to the SUDEP cases. Our findings provide further evidence for a genetic susceptibility to SUDEP, and suggest an extensive polygenic contribution to SUDEP causation. Thus, an overall increased burden of deleterious variants in a highly polygenic background might be important in rendering a given individual more susceptible to SUDEP. Our findings suggest that exome sequencing in people with epilepsy might eventually contribute to generating SUDEP risk estimates, promoting stratified medicine in epilepsy, with the eventual aim of reducing an individual patient's risk of SUDEP.