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.


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.

A cute little girl in a yellow shirt holding a tomato in front of a bowl of salad.

Use of Ketogenic Diet Therapy in Infants with Epilepsy: A Review of the Scientific Literature

Abstract, published in Epilepsia

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. This work 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 one month or longer. The proportions of infants achieving at least a 50% reduction in seizures, seizure freedom rates, retention rates, and reported side effects were extracted from studies.

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 group studies. All studies were categorized as low quality. Analyses of uncontrolled studies estimate 59% of infants achieved at least 50% seizure reduction and 33% of infants achieved seizure freedom. Retention rates ranged from 84% at 3 months to 27% at 24 months. The most common side effects were vomiting (6%), constipation (4%), acid reflux (4%), diarrhea (4%), and abnormal blood lipid levels (12%).

Significance: This review indicates that ketogenic diet therapy 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 this diet, 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.

The Ketogenic Diet All Grown Up—Ketogenic Diet Therapies for Adults

The use of ketogenic diet therapies (KDT) in adults has expanded in the last two decades and has been accompanied by a surge of new retrospective as well as prospective studies evaluating its efficacy in adults with epilepsy. In this review article, researchers highlight the recent clinical trials and advances in the use of the ketogenic diet therapy (KDT) in adult patients with epilepsy. The team analyzes the responder rate in regard to the epilepsy syndrome (focal vs generalized) to identify adults who are optimal to consider for KDT.

In addition to its role in treating patients with chronic epilepsy, this study explores the emerging use of the KDT in the critical care setting in adults with refractory and super-refractory status epilepticus as well as other neurologic disorders. Finally, this study  discusses special considerations for the use of KDT in adults with epilepsy including its potential long-term effects on bone and cardiovascular health, and its use in pregnancy.

A blond woman cradles her infant in her arms, trying to soothe them.

Better Seizure Control with Ketogenic Diet in Infants with Genetic Epilepsy

Infants and young children with epilepsy due to a confirmed genetic abnormality had a better response to treatment with ketogenic diet compared to patients with other types of epilepsy, according to a review of 10-year experience at Ann & Robert H. Lurie Children’s Hospital of Chicago. Results were published in Scientific Reports.

“Overall, we observed that ketogenic diet continues to be a safe, effective and well-tolerated treatment for patients under 3 years of age with drug-resistant epilepsy,” says study author John Millichap, MD, an epilepsy specialist at Lurie Children’s and Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “Based on our experience, clinicians could consider offering ketogenic diet earlier to infants diagnosed with genetic epilepsy, perhaps even before it becomes clear that the patient is not responding to anticonvulsant medication.”

Ketogenic diet is a high fat, low carbohydrate and protein restricted diet that is rigorously medically supervised. It is widely recognized as an effective treatment for epilepsy that does not respond to medications.

“The ketogenic diet helps control seizures by reducing fluctuations of blood sugar, which reduces hyper-excitability in the brain,” explains Dr. Millichap. “At Lurie Children’s we have used it since 1963.”