Efficacy and Safety of Ketogenic Dietary Therapies in Infancy. A Single-Center Experience in 42 Infants Less Than Two Years of Age

Abstract, originally published in Seizure.

Purpose: Ketogenic dietary therapies (KDT) are high-fat and low-carbohydrate diets that may achieve seizure control and improve cognitive state. We describe our KDT experience in infants (children less than two years of age).

Research methods & procedures: We conducted a retrospective, descriptive and observational study of 42 infants treated with KDT between 2000-2018.

Results: The types of KDT started were: classic ketogenic diet ratio 3:1 (40), ratio 4:1 (1) and modified ketogenic diet with medium-chain triglycerides (1). Four patients switched to a modified Atkins diet. During follow-up, 79%, 57%, 38% and 17% of infants remained on KDT at 3, 6, 12 and 24 months, respectively. Seizure reduction ?50% compared to baseline was achieved in 50%, 45%, 38% and 17% at 3, 6, 12 and 24 months, respectively. Seizure control was excellent (reduction >90%) in 33%, 31%, 26% and 12%, and seizure-free infants were 9, 9, 10 and 4, at different follow-up intervals, respectively. Sixty-three percent of infants with West syndrome were responders to KDT. Mean length of KDT was 390 days (16 days-4.9 years). Ineffectiveness was the reason for withdrawal in 50% of patients. Early adverse effects (during first month) occurred in 40% of infants. The most frequent early side effects were asymptomatic hypoglycemia and gastrointestinal disturbances. Late-onset side effects occurred in 55-14% of infants during therapy, and most frequent were hypercalciuria and dyslipidaemia.

Conclusion: Ketogenic dietary therapies are useful and effective treatments in infancy. Side effects are frequent but mild and easy to manage.

The Relation of Etiology Based on the 2017 ILAE Classification to the Effectiveness of the Ketogenic Diet in Drug-Resistant Epilepsy in Childhood

Abstract, originally published in Epilepsia

Objective: To investigate the effectiveness and safety of the ketogenic diet (KD) in drug-resistant epilepsy in childhood in relation to the new 2017 International League Against Epilepsy (ILAE) classification of etiology.

Methods: A consecutive cohort of patients treated with the KD were categorized according to the ILAE classification into known (structural, genetic, metabolic, infectious, and immune-mediated) and unknown etiology. Primary outcome was the frequency of patients achieving seizure freedom with the KD at 3 months, secondary outcomes were seizure reduction >50% at 3 months, and both seizure freedom and seizure reduction >50% at 6, 12 months, and at last follow-up (LFU), and adverse effects. Outcomes were compared between etiology groups.

Results: Etiology was known in 70% (129/183). Outcomes did not differ at 3 months (known vs unknown: seizure freedom 28% vs 33%, seizure reduction 62 vs 67%), but seizure freedom was significantly less frequent in known etiology at 6 months (26% vs 43%) and beyond (22% vs 37%). Logistic regression identified duration of epilepsy, number of previous antiseizure medications (ASMs), and age-appropriate psychomotor development as positive determinants of outcome. Among individual etiology groups, the effectiveness of KD was relatively best for genetic (33% at LFU) and poorest for metabolic etiology (8% at LFU). The small number of patients with infectious and immune-mediated etiology requires larger numbers in each etiology group to corroborate our results. No differences in type and frequency of adverse effects (in 71%) between etiology groups were observed, requiring medical intervention in 21%.

Significance: The ketogenic diet was most effective in genetic and unknown etiology, many unknowns probably represent yet unidentified genetic causes. We recommend consequent diagnostic and genetic work-up to identify etiologies that respond best to the ketogenic diet. The ketogenic diet should be offered early to infants with genetic epilepsy before deterioration of epileptic symptoms and of psychomotor development.

New Dietary Treatment for Epilepsy Well Tolerated and Reduced Seizures

Article, originally published in Brain Communications

The first clinical trial of a new dietary treatment for children and adults with severe forms of epilepsy, co-developed by UCL researchers and based on the ketogenic diet, has been successfully completed.

For the study, published in Brain Communications, clinicians evaluated the use of K.Vita®, (also known as Betashot), an oral liquid dietary supplement developed by UCL in collaboration with Royal Holloway, University of London, and Vitaflo International Ltd.

The ketogenic diet (KD) consists of high-fat, low-carbohydrate, and adequate protein consumption and mimics the fasting state, altering the metabolism to use body fat as the primary fuel source. This switch from carbohydrates to fat for body fuel is known as ketosis.

It is widely used to treat drug-resistant epilepsies. However, the highly restrictive diet, which can cause constipation, low blood sugar, and stomach problems, can have poor compliance and is not suitable for everyone. Some KD supplements are also known to be unappetizing.

K.Vita is based on novel findings by UCL researchers*, who discovered a different underlying mechanism to explain why the KD is effective against epilepsy; in developing a new treatment, researchers also sought to reduce the adverse side effects caused by KD.

Corresponding author Professor Matthew Walker (UCL Queen Square Institute of Neurology) said: “The ketogenic diet has been used for 100 years to treat epilepsy, helping reduce seizures in both children and adults.

“It has long been thought the diet was effective due to its production of ketones**, however, we now believe the increase in levels of the fatty acid, decanoic acid, also produced by the diet, may provide the powerful antiseizure effects.

“In this study, we evaluated a newly developed medium-chain triglyceride (type of dietary fat) supplement, designed to increase levels of decanoic acid, while also reducing the adverse side effects, and to be more palatable.”

For the feasibility trial, researchers wanted to establish participants’ tolerance (side effects such as bloating or cramps) to the treatment, acceptability (flavor, texture, taste), and compliance (how easy it is to use K.Vita at the advised quantity, as part of their daily diet).

As secondary outcomes, they also monitored the frequency of epileptic seizures or paroxysmal events (fits, attacks, convulsions) and whether ketone production was decreased.

In total, 35 children (aged 3 to 18) with genetically caused epilepsy and known to be unresponsive to drugs, and 26 adults with drug-resistant epilepsy*** (DRE), were given K.Vita liquid supplements (a drink), to be taken with meals. They were also asked to limit high-refined sugary food and beverages from their diets.

The trial lasted 12 weeks with K.Vita treatments increasing incrementally over time, taking into account individuals’ tolerance to the treatment.

In total, 23/35 (66%) children and 18/26 (69%) adults completed the trial i.e they were continuing to take K.Vita at 12 weeks. Gastrointestinal disturbances were the primary reason for discontinuation, and their incidence decreased over time

Over three-quarters of participants/caregivers reported favorably on sensory attributes, such as taste, texture and appearance, and ease of use.

In regards to the secondary outcomes, there was a mean 50% reduction in seizures or paroxysmal events, and fewer than 10% of people on the diet produced significant ketones.

Commenting on the findings, Professor Walker, who is also a consultant neurologist at the National Hospital for Neurology and Neurosurgery, said: “Our study provides early evidence of the tolerability and effectiveness of a new dietary supplement in severe drug-resistant epilepsies in adults and children and provides a further treatment option in these devastating conditions.

“It also offers an alternative, more liberal, diet for those who cannot tolerate or do not have access to ketogenic diets.”

He added: “While this study was not designed to include enough patients to fully assess the supplement’s effects on seizures, it is exciting to report that there was a statistically significant reduction in the number of seizures in the group overall after three months of treatment.

“Furthermore, high ketone levels were not observed in over 90% of the participants. This indicates that the effect of the diet was independent from ketosis; this is important because high ketone levels in the ketogenic diets contribute to both short- and longer-term side effects.”

First author, Dr. Natasha Schoeler, Research Dietitian at UCL Great Ormond Street Institute of Child Health, commented: “This novel dietary approach for epilepsy management involves following the principles of a healthy balanced diet alongside use of K.Vita, allowing greater dietary freedom compared to ketogenic diets. Our approach also requires much less input from a specialist dietician than is required by traditional ketogenic diets, and so may allow more widespread access to people with drug-resistant epilepsy.”

Researchers say larger, controlled studies of K.Vita are now needed to determine the precise epilepsies and conditions in which the supplement is most effective.

Review: Practical Considerations for Ketogenic Diet in Adults With Super Refractory Status Epilepticus

Abstract, originally published in Neurology Clinical Practice

PURPOSE OF REVIEW: Ketogenic diet therapy can be utilized as an adjuvant treatment of super refractory status epilepticus (SRSE). However, the drug and metabolic interactions with concomitant treatments present a challenge for clinicians. In this review we focus on the practical considerations of implementing ketogenic dietary therapy in the acute setting, including the dietary composition, potential drug-diet interactions, and monitoring during ketogenic treatment.

RECENT FINDINGS: This report describes the ketogenic diet therapy protocol implemented for the treatment of SRSE and a review of the current evidence to support clinical practice.

SUMMARY: The control of super refractory status epilepticus is critical in reducing morbidity and mortality. There is emerging evidence that ketogenic diet may be a safe and effective treatment option for these patients.

Incidence of Potential Adverse Events During Hospital-Based Ketogenic Diet Initiation Among Children with Drug-Resistant Epilepsy

Abstract, originally published in Epilepsia

Objective: Due to the possibility of serious adverse events (AE), patients are commonly admitted to hospital for 3–5 days for ketogenic diet (KD) initiation. This study examined the incidence of potential AE during admission for KD initiation to investigate the possibility of safely initiating a KD at home.

Methods: Children with drug-resistant epilepsy (DRE) who were admitted to hospital for five days for KD initiation were retrospectively studied.

Results: A total of 66 children (59% female) were analyzed. The mean age at the initiation of the KD was 48.0±38.4 months and the mean weight was 14.6±6.3 kilograms. The median number of anticonvulsant medications used at the time of KD initiation was 3. The etiology of the DRE was structural in 4.5%, hypoxic ischemic encephalopathy in 10.6%, genetic/metabolic in 31.8%, acquired in 10.6% and unknown in 42.2%. The potential AE occurred in 28.7% of patients, including hypoglycemia (20%), hypoactivity (6.1%), somnolence (3%), and vomiting (7.6%). A univariate analysis of the clinical characteristics of the AE and no AE groups showed a statistically significant difference in weight (P = 0.003) and age (P = 0.033). The concurrent use of topiramate was found to have a near significant association (P = 0.097) between the groups. The groups’ urine ketone levels on all five days were compared and a statistically significant difference was found on day three (P = 0.026). A statistically significant difference in the serum bicarbonate levels (P = 0.038) was found between the patients taking topiramate and those not taking it.

Significance: The incidence of adverse events during admission for ketogenic diet initiation was found to be low. The adverse events either required no intervention or were easily managed with simple interventions. Thus, it may be possible to initiate a ketogenic diet at home if the parents are adequately prepared and monitored.

Review: Cross Talk Between Drug-Resistant Epilepsy and the Gut Microbiome

Abstract, originally published in Epilepsia

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

Can Changes in Gut Microbiota Composition Be Used as a Marker of How Well the Ketogenic Diet Works in Patients With Drug-Resistant Epilepsy?

Abstract, originally published in Epilepsy Behav.

To answer the question posed in the title of the manuscript, we critically examined the connection between ketogenic diet (KD), gut microbiota (GM), and epilepsy. We conclude that although the evidence for a KD-GM-epilepsy link is fairly robust in rodent epilepsy models, it is very hard to draw meaningful conclusions in humans. The limitations of human studies that have investigated the KD-microbiota-epilepsy relationship include small sample size, a heterogeneous patient population with regard to age and epilepsy type, failure to account for the effect of dietary habits, antiseizure drugs (ASDs) and comedications on GM composition, variability in the KD administered and in the duration of the intervention, and different approaches used in sequencing the microbiome. Although alteration in the GM composition may be a potential indicator of responsiveness/resistance to a KD, we need well-designed randomized case-control and cohort studies involving a large number of a fairly homogenous population of patients with epilepsy adjusted to their habitual dietary habits and region of residence before labeling it as a surrogate marker. Research in this direction may also help us to unravel the mysteries of GM-brain axis not only concerning epilepsy but also in other neurological diseases.

Comparison of the Ketogenic Diet, Modified Atkins Diet, and Low Glycemic Index Therapy Diet Among Children with Drug-Resistant Epilepsy

Abstract, published in JAMA Pediatrics

Objectives: The ketogenic diet (KD) has been used successfully to treat children with drug-resistant epilepsy. Data assessing the efficacy of the modified Atkins diet (MAD) and low glycemic index therapy (LGIT) diet, compared with the KD are scarce. The purpose of this study was to determine whether the MAD and LGIT diets, which are often easier to follow, are as effective as the KD among children with drug-resistant epilepsy.

Design, setting, and participants: One hundred seventy children aged between 1 and 15 years who had 4 or more seizures per month, had not responded to 2 or more antiseizure drugs, and had not been treated previously with the KD, MAD, or LGIT diet were enrolled between April 1, 2016 and August 20, 2017 at a tertiary care referral center in India. Children were randomly assigned to receive the KD, MAD, or LGIT diet as additions to ongoing therapy with antiseizure drugs.

Results: One hundred fifty-eight children completed the trial: KD (n = 52), MAD (n = 52), and LGIT diet (n = 54). Analysis showed that, after 24 weeks of the interventions, the proportion of children with greater than 50% seizure reduction was 67.3% with the KD, 51.9% with the MAD, and 59.3% with the LGIT diet. Treatment-related adverse events were similar between the KD and MAD but were significantly less in the LGIT diet.

Conclusions: Data from this study showed that all 3 dietary regimens – KD, MAD, and the LGIT diet – significantly reduce seizure burden. Importantly, the LGIT diet showed a balance between seizure reduction and relatively fewer adverse events compared with the KD and MAD. These potential benefits suggest that the risk-benefit decision regarding the 3 diets needs to be individualized.

A Gut Geeling about the Ketogenic Diet in Epilepsy

Abstract, published in Epilepsy Research

The ketogenic diet has been used to treat intractable epilepsy for many years, yet the mechanism(s) underlying its effectiveness have not been completely explained. Emerging evidence indicates that the ketogenic diet may correct or otherwise alter a gut microbiota whose fecal microbial composition is different from that in healthy individuals.

Recent studies in animal seizure models also reveal an altered gut microbiome, and, interestingly, changes in the composition of the microbiota after ingestion of a ketogenic diet. The effectiveness of the ketogenic diet in these animal models appears to be absolutely dependent on the presence of gut microbiota. Further evidence suggests that effectiveness of the ketogenic diet in controlling seizures may rely on the ability of specific bacterial populations to alter a particular chemical modification of amino acids, the building blocks of proteins, and thus alter their movement into the central nervous system. These studies suggest new directions for research in patients with epilepsy.

Ketogenic

Long-Term Outcomes of Ketogenic Diet in Patients with Tuberous Sclerosis Complex-Derived Epilepsy

Abstract, published in Epilepsy Research

OBJECTIVE: For epilepsy with tuberous sclerosis complex (TSC), ketogenic diet (KD) therapy has been consistently reported to be more beneficial than the average KD therapy response. Herein, researchers aimed to investigate the long-term outcomes of a ketogenic diet on patients with TSC and intractable epilepsy.

METHODS: This study included 31 patients with intractable epilepsy and TSC who were treated with the KD, and an intention-to-treat analysis was performed.

RESULTS: Overall, 21 of the 31 patients (67.7%) had >50% reduction in seizures at 3 months after initiating the KD. Thirteen of the 31 patients (41.9%) were seizure-free for at least 3 months, but 10 of these 13 patients (76.9%) experienced seizure recurrence during the 24-month follow-up period. Finally, at 24 months of the KD observational period, there was >50% response in 10 of the 31 patients (32.3%), including seizure-free patients (6 of 31 patients, 19.4%). Most of the patients (12 of 13, 92.3%) who experienced seizure freedom had >50% reduction in seizures within 1 month after initiating the KD, and this result was the only factor associated with seizure freedom in the current study.

CONCLUSION: The ketogenic diet appeared to be an effective therapeutic modality for intractable pediatric epilepsy in TSC, but it did not exhibit guaranteed efficacy over a long-term period.