Decreased Serum Concentrations of Anti-Seizure Medications in Children with Drug Resistant Epilepsy Following Treatment with Ketogenic Diet

Abstract found on Wiley Online Library

Objective: To examine the potential influence of a ketogenic diet on serum concentrations of anti-seizure medications (ASMs) in children with drug-resistant epilepsy.

Methods: We investigated the serum concentrations of ASMs in 25 children with drug-resistant epilepsy, 2 to 13?years of age, treated with a classical ketogenic diet for 12?weeks. The patients were recruited from the National Centre for Epilepsy from August 15th, 2017, to January 24th, 2022. Changes in ASM serum concentrations were analyzed using a mixed-effect model analysis. Significance level was set at P <0.05 for all comparisons.

Results: The participants used 12 different ASMs during the study. The mean number of ASMs was 2.4 (±SD 0.7). None of the participants changed the type or dose of the ASMs during the intervention period. The serum concentrations of clobazam (n =?9, P =?0.002), desmethylclobazam (n =?9, P =?0.010), and lamotrigine (n =?6, P =?0.016) decreased significantly during the dietary treatment. The analytes with the largest reduction in serum concentration after 12?weeks of dietary treatment were clobazam (mean change -38%) and desmethylclobazam (mean change -37%). We found no significant change in the serum concentrations of levetiracetam, topiramate, and valproic acid.

Significance: We identified a significant decrease in the serum concentrations of clobazam, desmethylclobazam, and lamotrigine following a 12-week ketogenic diet intervention in children with drug-resistant epilepsy. An unintended decrease in the serum concentrations of ASMs may render the patient prone to seizures. Measurements of ASM serum concentrations might be useful in patients on a ketogenic diet, especially in patients with lack of efficacy of the dietary treatment.

Health-Related Quality of Life in Adults with Drug-Resistant Focal Epilepsy Treated with Modified Atkins Diet in a Randomized Clinical Trial

Abstract found on PubMed

Ketogenic diet, a high-fat, low-carbohydrate diet, is an established treatment for patients with severe epilepsy. We have previously reported a moderate reduction in seizure frequency after treatment with a modified Atkins diet. This study aimed to see whether dietary therapy impacts the patients’ health-related quality of life (HRQOL). In a randomized controlled design, we compared the change in self-reported HRQOL among adults with difficult-to-treat epilepsy after a 12-week diet intervention. Thirty-nine patients with drug-resistant focal epilepsy (age 16 – 65 years) were randomized to eat a modified Atkins diet with maximum 16 grams of carbohydrate per day (diet group, n=19) or to continue eating habitual diet (control group, n=20). No changes to the other epilepsy treatments were allowed. Patient reported HRQOL was assessed with the Quality of Life in Epilepsy Inventory-89 (QOLIE-89). The diet group experienced a statistically significant improvement in mean total score of QOLIE-89 of 10 points compared to controls (p=0.002). Moreover, although not statistically significant when using a cut-off of 50% seizure reduction, our data suggest an association between diet-induced reduction in seizure frequency and improvement of HRQOL. The improvement in HRQOL was not associated with diet-induced weight reduction.

Efficacy and Safety of Dietary Therapies for Childhood Drug-Resistant Epilepsy

Abstract found on Jama Network

Importance: Despite advances in the understanding of dietary therapies in children with drug-resistant epilepsy, no quantitative comparison exists between different dietary interventions.

Objective: To evaluate the comparative efficacy and safety of various dietary therapies in childhood drug-resistant epilepsy.

Data Sources: Systematic review and network meta-analysis (frequentist) of studies in PubMed, Embase, Cochrane, and Ovid published from inception to April 2022 using the search terms ketogenic diet, medium chain triglyceride diet, modified Atkins diet, low glycemic index therapy, and refractory epilepsy.

Study Selection: Randomized clinical trials comparing different dietary therapies (ketogenic diet, modified Atkins diet, and low glycemic index therapy) with each other or care as usual in childhood drug-resistant epilepsy were included. Abstract, title, and full text were screened independently by 2 reviewers.

Conclusions and Relevance: This study found that all dietary therapies are effective in the short term. However, the modified Atkins diet had better tolerability, a higher probability for 50% or higher seizure reduction, and comparable probability for 90% or higher seizure reduction and may be a sounder option than the ketogenic diet. Direct head-to-head comparison studies are needed to confirm these findings.

Epilepsy Research News: February 2023

This issue of Epilepsy Research News includes summaries of articles on:


Combining Diet with Drugs to Reduce Seizures

Following a modified Atkins diet that is high in fat and low in carbohydrates in addition to taking antiseizure medication(s) may reduce seizures in people with tough-to-treat epilepsy, according to a recently published study. The study involved 160 adults and adolescents who had epilepsy for more than 10 years on average and had at least 27 seizures per month, despite trying an average of four antiseizure medications at the maximum tolerated dose. After six months, researchers found that 26% of people who used drug therapy and followed the modified Atkins diet had more than a 50% reduction in seizures, compared to only 3% of the people who had drug therapy alone. Four people in the diet group were seizure free by the end of the study, while no one in the medication-only group was seizure free. A limitation of the study is that seizures were self-reported or reported by caregivers, so some seizures may not have been reported. Despite this important consideration, “for people with drug-resistant epilepsy, or those who have been unable to find effective treatment to reduce seizures, it’s encouraging to see that there are lifestyle changes that can be combined with standard drug therapy to reduce the number of seizures,” stated a study author.

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Parents Need Guidance Managing Sleep Issues in Children with Epilepsy

According to a new qualitative study that included interviews with nine mothers, sleep and epilepsy have a complex and bidirectional relationship. The aim of the study was to capture parental perceptions and experiences related to their child’s sleep habits and management, the impact of sleep difficulties on the child and their family, and available support. According to the study, epilepsy exacerbated the struggle to initiate sleep (settling and falling asleep), maintenance of sleep (experiencing night or early morning wakings), duration of sleep, daytime sleepiness, and sleep anxiety. Study authors noted that mothers were aware of the links between sleep and seizures yet felt that they lacked guidance about how to address or improve their child’s sleep, including from their healthcare teams. The authors also stated that the finding emphasizes the need to ensure adequate help is available to support healthy sleep in children with epilepsy.

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New Understanding of the Cause of Post-Traumatic Epilepsy (PTE)

A research team has uncovered information about changes that occur in the brain following a traumatic brain injury (TBI) that could help advance future preventative treatments for PTE, a type of epilepsy caused by a TBI. The findings show that activation of a subset of neurons within an area of the brain called the hippocampus plays a key role in the changes that occur during the development of PTE. For this study, the team looked at neurons called dentate granule cells, which continuously regenerate in areas of the brain that are crucial for learning and memory and are also commonly impacted by epilepsy. The team found that when the dentate granule cells were activated, the activity of other brain cells involved in epilepsy was inhibited. They also found that the cells that were formed just prior to a were much more likely to activate this circuit than those generated at other points in time. The team noted that being able to get to a point of understanding the changes that occur in the development of epilepsy may lead to the ability to prevent or reverse epilepsy.

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Links Between Parental Factors, Emotional, and Behavioral Issues Found in Pediatric Epilepsy

Adolescents with epilepsy commonly experience emotional and behavioral problems, which vary depending on demographic, clinical, and parental factors, according to a new study. The parental factors included how parents perceived that others treated their child. The study included 289 adolescents aged between 11 and 18 years. The study found 18.3% of adolescents with epilepsy had at least one emotional or behavioral problem in the clinical range. Additionally, consistent with findings of prior studies, this study showed one in four parents of adolescents with epilepsy perceived that other people felt uncomfortable with their child, treated their child as inferior, or preferred to avoid their child because of their epilepsy. Due to these findings, the study’s authors emphasized it is crucial to identify and properly manage these problems early to decrease comorbid psychopathology in adolescents with epilepsy.

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Use of Newer Antiseizure Medications for Epilepsy Differs by Race, Ethnicity

Racial and ethnic minority groups are less likely to be taking newer-generation antiseizure medications for their epilepsy, an analysis of Medicaid data showed. Compared with white patients, Black, Hispanic, and Native Hawaiian/Pacific Islander patients had lower odds of being on newer antiseizure medications, the study found. Of note, taking a second-generation antiseizure medication was associated with better treatment adherence, and those seeing a neurologist had higher odds of being on newer antiseizure medications. The study authors stated that being on a newer, second and third-generation antiseizure medication may represent an important marker of quality of care for people with epilepsy and that differences appear to reflect racial and ethnic inequities in epilepsy care.

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Can Diet Combined with Drugs Reduce Seizures?

Article found on Science Daily

Following a modified Atkins diet high in fat and low in carbohydrates plus taking medication may reduce seizures in people with tough-to-treat epilepsy, according to a study published in the January 4, 2023, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“For people with drug-resistant epilepsy, or those who have been unable to find effective treatment to reduce seizures, it’s encouraging to see that there are lifestyle changes that can be combined with standard drug therapy to reduce the number of seizures,” said study author Manjari Tripathi, MD, DM, of All India Institute of Medical Sciences in New Delhi. “Our study found that this combination may reduce the chance of seizures by more than half.”

The modified Atkins diet is a combination of the Atkins diet and a ketogenic diet that includes food items such as soy products, heavy cream, butter and oils, leafy green vegetables, and animal protein including eggs, chicken, fish, and bacon. While the ketogenic diet has been shown to be effective in reducing seizures, its stringent requirements and restrictions can make it difficult to follow.

The study involved 160 adults and adolescents who had epilepsy for more than 10 years on average and had at least 27 seizures per month despite trying an average of four antiseizure medications at the maximum tolerated dose. They were randomly assigned to receive either standard drug therapy alone or drugs plus the modified Atkins diet over six months.

The study also looked at quality of life, behavior and side effects at six months. The group that had drug therapy and followed the modified Atkins diet showed an improvement in all areas compared to the group that had drug therapy alone.

Tripathi noted that 33% of the participants did not complete the study due to poor tolerance of the diet, lack of benefit or the inability to follow-up in part due to COVID-19. However, Tripathi said tolerance of the modified Atkins diet was better than what is seen with the ketogenic diet.

Core Outcome Set Development for Childhood Epilepsy Treated with Ketogenic Diet Therapy: Results of a Scoping Review and Parent Interviews

Abstract found on Seizure Journal

Purpose: Clinical trials on childhood epilepsy treated with ketogenic diet (KD) use a wide range of outcomes, however, patients and decision-makers often do not perceive the outcomes used as the most important. We sought parental opinion on outcomes of importance and compared these to outcomes reported in published research.

Methods: Ethical approval (London-Surrey-REC19/LO/1680). A scoping review identified outcomes reported in previous studies of childhood epilepsy and KD. Parents were recruited from nine KD centres (UK), charities and social media (international), then interviewed (Jan-April 2020) to explore priority outcomes. Content analysis identified all outcomes in transcripts. Parent identified outcomes were compared with those in the scoping review. Outcomes were collated and grouped into domains according to the COMET Taxonomy.

Results: Of 2663 articles;147 met inclusion criteria. 921 verbatim outcomes were sorted into 90 discrete outcomes, reduced to 70 in consultation with the study advisory group, then classified into 21 domains. Parents (n = 21) identified 39 outcomes as important from the scoping review and seven new outcomes. They prioritised both physiological and functional outcomes in contrast to past studies, which prioritised physiological outcomes.

Conclusion: Little consistency exists in the outcomes used in childhood epilepsy and KD research. Those traditionally used do not adequately reflect parents’ important outcomes for their child. Clinical trials should consider the broader priorities of parents when choosing outcomes, in particular, functional outcomes. Identified outcomes will inform an international two-round Delphi-study with parent, professional and researcher participants to develop a core outcome set for this clinical area (COMET registration #1116).

Limiting Energy In Neurons Exacerbates Epilepsy

Article published in Science Blog

Epilepsy, one of the most common neurological disorders, is characterized by the spontaneous repetition of seizures caused by the hyperactivity of a group of neurons in the brain. Could we therefore reduce neuronal hyperactivity, and treat epilepsy, by reducing the amount of energy supplied to neurons and necessary for their proper functioning? This was tested by a team led by scientists from the University of Geneva (UNIGE) and the EPFL. The researchers discovered that, in mice, the seizures were actually exacerbated. They observed that a reduction in the amount of energy led to an increase in the level of calcium in neurons, making them hyperexcitable. These dysfunctions could be corrected when mice were fed a ketogenic diet, which is rich in lipids and has been used since antiquity. This work is published in the journal eLife.

Our brain, which represents only 2% of our body weight, consumes more than 20% of the sugar we ingest. This considerable need for sugar provides the energy necessary for the function of the billions of neurons responsible for the emission and propagation of nervous messages, via electrical signals. This conversion of sugar, and more precisely of glucose, into energy is carried out by the mitochondria, small intracellular organelles considered as the “energy factories” of the cell.

The laboratory of Jean-Claude Martinou, professor in the Department of Molecular and Cellular Biology at the Faculty of Science, is interested in how mitochondria work. His group had already discovered the universal carrier that allows pyruvate, a product of glucose catabolism, to enter into mitochondria. He is now investigating the role of the mitochondrial pyruvate carrier (MPC) in neuronal activity and whether a defect in the transport of pyruvate in mitochondria could be linked to certain neurological diseases, notably epilepsy.

The biologists administered a pro-epileptic drug, capable of inducing epileptic seizures, to normal mice and to mice whose cortical neurons lacked the MPC. In normal mice, injection of a low dose of the drug did not induce seizures. On the other hand, and contrary to the initial hypothesis, in mice lacking the MPC, very severe, even fatal, seizures occurred as soon as low doses of the pro-epileptic drug were administered.

Keto Diet Resolves Non-Convulsive Seizures in 2 Girls With New Variant

Article appeared in Angelman Syndrome News

A ketogenic diet safely and rapidly controlled treatment-resistant prolonged non-convulsive seizure activity in two girls with Angelman syndrome caused by a new mutation in the UBE3A gene, a study shows.

These therapeutic benefits were observed before the detection of ketone bodies, the fat-derived molecules produced by the liver to serve as an energy source when glucose or sugar — the body’s go-to energy source — is not readily available.

These cases highlight the ketogenic diet as an effective approach to manage prolonged non-convulsive seizures related to Angelman and suggest that carbohydrate restriction may, by itself, have an effect on these seizures.

The study, “Novel UBE3A pathogenic variant in a large Georgian family produces non-convulsive status epilepticus responsive to ketogenic diet,” was published in the journal Seizure.

Ketogenic Diets Likely to Reduce Damage From Traumatic Brain Injury – Study

Article appeared in The Jerusalem Post

Consuming a ketogenic diet may reduce the effects of brain damage in people who have sustained Traumatic Brain Injuries (TBI), a new study by researchers at Tel Aviv University has shown.

A ketogenic diet is one where the majority of calories consumed come from foods high in protein and fat. The diet includes very few carbohydrates, which would typically be broken down into glucose and used as the brain’s main source of energy.

The peer-reviewed study led by Professor Chaim (Chagi) Pick and PhD student Meirav Har-Even Kerzher from the Sackler Faculty of Medicine at TAU was conducted using mice. Those fed a ketogenic diet showed improvements in spatial and visual memory, lower levels of brain inflammation and neuronal death, and reduced rates of cellular aging compared to mice fed a standard diet.

The exact mechanism by which the ketogenic diet works on the brain has yet to be identified, though some studies have suggested that it has an antioxidant and metabolic effect on cell mitochondria as well as reducing the production of free radicals and increasing Adenosine triphosphate (ATP), a compound that provides energy to cells.

Professor Pick explained the promise that these results may hold for future research, “The findings were unequivocal and showed that the ketogenic diet improves spatial memory and visual memory, lowers indices of inflammation in the brain and in addition, also slows the rate of cellular aging. These results may open the door to further research that will inspire hope for those suffering from traumatic brain injuries and their family members.”

Evaluation of the Effects of Ketogenic Diet Therapy on Sleep Quality in Children with Drug-Resistant Epilepsy and Their Mothers

Abstract, originally published in Epilepsy & Behavior

Background: Sleep disorders are common in drug-resistant children with epilepsy and their mothers. Ketogenic diet therapy (KDT) may have positive effects on sleep quality. The aim of this study was to evaluate the sleep quality of children with epilepsy and their mothers after starting KDT.

Methods: Using a prospective cross-sectional model, pre- and post-KDT questionnaires were given to the study subjects. A children’s sleep habits questionnaire was administered to children with epilepsy, and the Pittsburgh sleep questionnaire was administered to their mothers. Sociodemographic and some clinical categorical variables of the patient group were evaluated using descriptive statistics. Evaluation of the data was conducted using the Wilcoxon and paired t-tests as parametric and non-parametric tests.

Results: Of 24 patients scheduled to begin KDT between January 2019 and January 2020, 14 were included in the study. Regarding sleep quality, improvement was reported in 7 (50%) of 14 patients, deterioration in 5 (35.7%) patients, and no change was seen in 2 (14.3%) patients. Sleep quality was reported to improve in all working mothers. Seven (50%) patients reported no seizures and 6 (42.9%) patients reported more than 50% seizure reduction. Although there were improvements in sleep scores in both groups, these improvements were not statistically significant. A significant decrease in sleep anxiety was reported in children after the third month of the KDT (p = 0.09).

Conclusions: The results of this study determined that three months of ketogenic diet therapy offered significant improvement on the sleep anxiety of children with epilepsy. It was thought that paying attention to patient selection may lead to better sleep quality by increasing compliance to ketogenic diet therapy. However, a larger scale study and longer term follow-up should be done.