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.

Altered Cytokine Levels in Cerebrospinal Fluid Following Ketogenic Diet of Children with Refractory Epilepsy

Abstract, originally published in Epilepsy Research

Ketogenic diet is an effective treatment which has the potential to achieve a significant seizure reduction in drug-resistant epilepsy. The mechanism behind this effect is unclear, but one hypothesis is that the mechanism is anti-inflammatory. In this prospective study on pediatric patients we compared levels of cytokines and chemokines in the cerebrospinal fluid before and after three months on treatment to evaluate a possible anti-inflammatory effect.

We analyzed 34 cytokines and chemokines in the cerebrospinal fluid of pediatric patients (n = 21) with refractory epilepsy by a multiplex assay. Beta-hydroxybutyric acid was measured in blood and cerebrospinal fluid. Seizure frequency in relation to diet treatment was assessed. For 9 different cytokines (CCL 7, CCL 21, CCL 22, CCL 25, CCL 27, IL-2, IL-10, CX3CL1 and MIF), a significant decrease ranging from 7 to 27% was seen after three months as compared to levels before the diet. In contrast, no cytokine displayed a significant increase during diet. A seizure reduction ? 50 % was seen in 15/21 patients (71 %) but no significant differences in cytokine decreases were found between responders and non-responders during treatment. A non-significant trend towards higher initial pre-treatment levels of cytokines was seen in responders, which were reduced following treatment. The levels of betahydroxybutyric acid were not related to seizure response.

We conclude that while it is not possible to state a primary anti-inflammatory effect by dietary treatment from these data, an unequivocal immunological effect is seen and may be a part of the mechanism of ketogenic dietary treatment.

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.