Ketogenic Diet in the Treatment of Epilepsy.

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

Telemedicine for Ketogenic Dietary Treatment in Refractory Epilepsy and Inherited Metabolic Disease: State of Play and Future Perspectives.

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

Ketogenic Diet: Parental Experiences and Expectations.

BACKGROUND: The ketogenic diet may be difficult for some patients and their families to implement and can impact physical, emotional, and social well-being. METHODS: Through principles of fundamental qualitative description, we completed an exploratory study on parents' experiences and expectations on the use and efficacy of the ketogenic diet for children with medically refractory epilepsy. RESULTS: Seventeen parents (10 mothers and 7 fathers) of 12 children with epilepsy participated. At the time of the interview, parents had experienced an average of 25 months of ketogenic diet treatment for their child (range 2 months to 98 months). Half of the caregivers learned about the ketogenic diet from their neurologist, whereas the remainder had heard about it from another source (ie, the internet). Most caregivers' (n = 13) diet expectations were related to seizure control. However, child development (n = 5) and quality of life (n = 5) were also crucial to some. Physical impacts of the diet were most commonly gastrointestinal for children (n = 9). Social and emotional effects were noted in some older children with typical development. Most caregivers described negative impacts on finances (n = 15), relationships (n = 14), and emotional well-being (ie, stress) (n = 12). Caregivers benefited from the ketogenic diet team's regular communication, close follow-up, and family-centered care. CONCLUSIONS: Despite the impacts that the ketogenic diet may have on caregivers' emotional and social well-being, the positive impacts of the diet were felt to outweigh any perceived risks. Effects (both positive and negative) on quality of life and child development (eg, social, emotional, cognitive) are essential for caregivers and require additional investigation.

ATN1-related infantile developmental and epileptic encephalopathy responding to Ketogenic diet.

BACKGROUND: Research has shown gene ATN1 to be associated with the nuclear receptor signaling. Its mutations in an evolutionarily conserved histidine-rich motif may cause CHEDDA, short for congenital hypotonia, epilepsy, developmental delay and digital anomalies, a recently identified neurodevelopmental syndrome that could evolve into developmental and epileptic encephalopathy (DEE). Up to date, there have been reported less than 20 cases, whose clinical features and treatment are worth in-depth exploring. METHODS: The clinical characteristics and genetic data of an infant with CHEDDA and further DEE were analyzed, who carried a de novo ATN1 variant identified by trio whole-exome sequencing. The alike patients with such a neurodevelopmental syndrome and epileptic seizures were reviewed on the literature. RESULTS: The infant harboring a de novo missense mutation in ATN1 (c.3155A>C; p.His1052Pro) held almost all features of CHEDDA and presented with drug-resistant epileptic spasms, differing from one case previously reported with the same gene variant exhibiting milder seizures controlled easily. We further reviewed 11 CHEDDA patients with epileptic seizures in the literature and compared the correlation between abnormal cerebral structure and the incidence of intractable epilepsy among CHEDDA patients. Fortunately, this patient's seizures decreased remarkably after administering ketogenic diet (KD). CONCLUSION: CHEDDA patients have significant phenotypic differences, especially in the epilepsy severity and their drug resistance, even if they carry the same mutation hotspot. Ketogenic diet and other treatments like Topiramate should be recommended for ATN1-related refractory epilepsy based on their regulation on expression of cation-chloride cotransporters and cellular hyperpolarization.

The CORE-KDT study: a mixed methods protocol to establish core outcomes for refractory childhood epilepsy treated with ketogenic diet therapy.

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

Clinical implementation of ketogenic diet in children with drug-resistant epilepsy: Advantages, disadvantages, and difficulties.

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

The Effect of the Ketogenic Diet on Adiponectin, Omentin and Vaspin in Children with Drug-Resistant Epilepsy.

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

Transcriptomic profile of epileptic children treated with ketogenic therapies.

Background: Ketogenic dietary therapies (KDT) are used as a treatment in childhood epilepsy. However, their mechanism has not yet been established. The main objective of this study was to determine the changes in the transcriptomic profile induced by KDT in children with epilepsy in order to shed light on its possible mechanisms. Methods: Eight children with refractory epilepsy were enrolled in the study. Peripheral blood mononuclear cells were obtained before and after the children were treated with KDT for a minimum of 6 months. RNA was extracted and mRNA and miRNA profiling were performed and analyzed. Results: Our intervention with KDT significantly reduced the seizure number in seven of the eight paediatric patients treated and caused important changes in their gene expression profile. Our study reveals modifications in the transcription of 4630 genes and 230 miRNAs. We found that the genes involved in the protection against epileptic crises were among those mainly changed. These genes collectively encode for ion channels, neurotransmitter receptors, and synapse structural proteins. Conclusions: Together our results explain the possible mechanisms of KDT and reinforce its clinical importance in the treatment of epilepsy.

Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations.

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

Modified Atkins diet for drug-resistant epilepsy and the risk of urolithiasis.

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

Tratamiento de la epilepsia refractaria. Comparación entre la dieta cetogénica clásica y la de Atkins modificada en cuanto a eficacia, adherencia y efectos indeseables / Treatment of refractory epilepsy. A comparison between classic ketogenic diet and modified Atkins diet in terms of efficacy, adherence, and undesirable effects

Introducción: la dieta cetogénica (CD) es un tratamiento no farmacológico efectivo, ya establecido para la epilepsia refractaria en la infancia. Objetivo: el objetivo de este estudio fue comparar la eficacia, la presencia de efectos indeseables y la adherencia entre la dieta cetogénica clásica (DCC) y la dieta de Atkins modificada (DAM).Materiales y métodos: se realizó una investigación retrospectiva y comparativa, evaluando las historias clínicas de todos los pacientes que iniciaron tratamiento con dieta cetogénica a cargo de un mismo equipo de trabajo entre 2008 y 2018. Se incluyeron 57 pacientes que iniciaron una dieta DAM y 19 pacientes con dieta DCC. Resultados: se observó que tanto la dieta Atkins como la clásica fueron igualmente eficaces (80 %, aproximadamente; p = 0,252). En relación a la adherencia, se registró un porcentaje significativamente mayor de adherencia a la dieta Atkins que a la clásica (p = 0,018). Se observaron menos efectos adversos con la DAM que con la dieta CC (p = 0,012). El 21 % de los pacientes con DAM presentaron efectos desfavorables (12/57), mientras que el 52.63 % de los pacientes en DCC tuvieron complicaciones (10/19). Conclusión: se describe una efectividad equiparable en cuanto al control de crisis entre la DAM y la DCC. Sin embargo, la DAM presenta una adherencia mucho mejor que la observada con la DCC y sus efectos indeseables son más leves y más infrecuentes. Es por eso que, de acuerdo con otros trabajos, la DAM probablemente sea la primera elección para los pacientes con epilepsia refractaria en un gran porcentaje de los casos. (AU)

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

[Treatment of refractory epilepsy. A comparison between classic ketogenic diet and modified Atkins diet in terms of efficacy, adherence, and undesirable effects]. / Tratamiento de la epilepsia refractaria. Comparación entre la dieta cetogénica clásica y la de Atkins modificada en cuanto a eficacia, adherencia y efectos indeseables.

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

INTRODUCCIÓN: Introducción: la dieta cetogénica (CD) es un tratamiento no farmacológico efectivo, ya establecido para la epilepsia refractaria en la infancia. Objetivo: el objetivo de este estudio fue comparar la eficacia, la presencia de efectos indeseables y la adherencia entre la dieta cetogénica clásica (DCC) y la dieta de Atkins modificada (DAM). Materiales y métodos: se realizó una investigación retrospectiva y comparativa, evaluando las historias clínicas de todos los pacientes que iniciaron tratamiento con dieta cetogénica a cargo de un mismo equipo de trabajo entre 2008 y 2018. Se incluyeron 57 pacientes que iniciaron una dieta DAM y 19 pacientes con dieta DCC. Resultados: se observó que tanto la dieta Atkins como la clásica fueron igualmente eficaces (80 %, aproximadamente; p = 0,252). En relación a la adherencia, se registró un porcentaje significativamente mayor de adherencia a la dieta Atkins que a la clásica (p = 0,018). Se observaron menos efectos adversos con la DAM que con la dieta CC (p = 0,012). El 21 % de los pacientes con DAM presentaron efectos desfavorables (12/57), mientras que el 52.63 % de los pacientes en DCC tuvieron complicaciones (10/19). Conclusión: se describe una efectividad equiparable en cuanto al control de crisis entre la DAM y la DCC. Sin embargo, la DAM presenta una adherencia mucho mejor que la observada con la DCC y sus efectos indeseables son más leves y más infrecuentes. Es por eso que, de acuerdo con otros trabajos, la DAM probablemente sea la primera elección para los pacientes con epilepsia refractaria en un gran porcentaje de los casos.

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.

Celiac Disease in Children: An Association With Drug-Resistant Epilepsy.

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

Evaluation of E-Health Applications for Paediatric Patients with Refractory Epilepsy and Maintained on Ketogenic Diet.

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

The gut microbiome in drug-resistant epilepsy.

Drug-resistant epileptic patients make up approximately one-third of the global epilepsy population. The pathophysiology of drug resistance has not been fully elucidated; however, current evidence suggests intestinal dysbiosis, as a possible etiopathogenic factor. Ketogenic diet, whose effect is considered to be mediated by alteration of gut microbiota synthesis, has long been administered in patients with medically refractory seizures, with positive outcomes. In this review, we present data derived from clinical studies regarding alterations of gut microbiome profile in drug-resistant epileptic patients. We further attempt to describe the mechanisms through which the gut microbiome modification methods (including ketogenic diet, pre- or probiotic administration) improve drug-resistant epilepsy, by reporting findings from preclinical and clinical studies. A comprehensive search of the published literature on the PubMed, Embase, and Web of science databases was performed. Overall, the role of gut microbiome in drug-resistant epilepsy is an area which shows promise for the development of targeted therapeutic interventions. More research is required to confirm the results from preliminary studies, as well as safety and effectiveness of altering gut bacterial composition, through the above-mentioned methods.

Combined use of the ketogenic diet and vagus nerve stimulation in pediatric drug-resistant epilepsy.

Objective: Patients with drug-resistant epilepsy (DRE) pose considerable management challenges for patients, their families, and providers. Both the vagus nerve stimulator (VNS) and the ketogenic diet (KD) have been shown to be safe and effective in treating DRE. Nevertheless, information is lacking regarding treatment with combination of both modalities. This study reports the efficacy and tolerability of combining VNS and KD in a pediatric cohort with intractable epilepsy. Methods: This is a retrospective review of 33 patients (0-17 years) with DRE treated with VNS and KD at a single pediatric level IV epilepsy center. We compared seizure reduction rates for each patient at baseline and at every clinic visit for 24 months after adding the second nonpharmacological therapy. The frequency of adverse events on the combined therapy was collected to assess safety and tolerability. Results: There were a total of 170 visits for all patients while on the combined therapy. At 88% (95% CI: 83%-93%) of the visits, patients reported some reduction in seizure frequency. The proportion of patients reporting a greater than 50% seizure reduction over all visits was 62% (95% CI: 55%-69%). The proportion of a patient's visits with at least a greater than 50% reduction in seizure frequency had a median of 71% (IQR 33%-100%). Continued improvement was seen over time of combined treatment; for every one-unit time unit change (one month), there was a 6% increase in the odds of having a reduction in seizure frequency of >50% (OR = 1.06, 95% CI: 1.01-1.11). Significance: This study shows that combining the VNS and KD in patients with drug-resistant epilepsy is well tolerated and reduces seizure frequency more than either one modality used alone and that the benefits in terms of seizure reduction continue to increase with the length of treatment.