Efficacy of Dietary Therapies in Childhood Drug-Resistant Epilepsy

Although the ketogenic diet (KD) is the most effective dietary therapy for childhood drug-resistant epilepsy (DRE), the modified Atkins diet (MAD) and low-glycemic index therapy (LGIT) are also effective, better tolerated, and less restrictive, according to research presented at the 2019 American Academy of Neurology’s Annual Meeting, held May 4 to 10 in Philadelphia.

The presentation provided an overview of 9 studies analyzing dietary therapies for childhood DRE, including 6 randomized controlled trials, that took place at a tertiary care center in North India over the last 12 years. Approximately 1500 children received various dietary therapies from infancy to adolescence, and 595 were enrolled in 9 trials. Teleconsultation services were initiated to support the implementation of dietary therapies. Algorithms for the Dietary Therapy Evaluation of Compliance and Caregiver Satisfaction with Dietary Therapy questionnaire have been developed, and the role of a variety of biomarkers such as beta hydroxybutyrate, gut microbiota, glycated hemoglobin, and polyunsaturated fatty acids are being evaluated.

Can the Effects of the Ketogenic Diet Help Prevent Epilepsy After Traumatic Brain Injury?

Featuring the work of CURE Grantee Chris Dulla

Neuroscientists led by Chris Dulla at Tufts University School of Medicine prevented the development of epileptic activity in mice after traumatic brain injury by using a drug that mimics the metabolic effects of the ketogenic diet. An advance copy of the study is published today in JCI Insight.

The ketogenic diet was originally developed in the 1920s to treat drug-resistant epilepsy in children. By limiting carbohydrates in the diet, the body is forced to burn fat rather than glucose, the usual source of energy in the body. Although researchers do not know exactly how the therapeutic effects of the diet works, evidence to date suggests the change in metabolism is key.

“While we know the ketogenic diet can control seizures in people with epilepsy, we wanted to learn if it would be able to prevent the development of post-traumatic epilepsy,” says Jenny Koenig, an M.D. and Ph.D. student at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts who works in Dulla’s lab.

Post-traumatic epilepsy develops within three years of a traumatic brain injury (TBI) in about 1 out of 10 people. TBIs lead to the dysfunction of the brain’s inhibitory network, including the cells that normally quiet down brain activity. Without inhibition, brain activity increases, causing the behavioral and cognitive challenges seen after injury.

Along with increased activity comes an increased demand for energy production through a process called glycolysis, a system that provides energy to the brain by burning glucose, or sugar. Rather than focus directly on reducing neuronal activity, the research team inhibited glycolysis with a drug called 2-deoxyglucose (2-DG) to mimic the metabolic effects of the ketogenic diet.

By recording brain activity from cells in the injured area with a common electrophysiological technique called whole-cell recording, the researchers determined that excitatory cells were more active in injured tissue, compared to control brain tissue from mice.

How Often is Antiseizure Drug-Free Ketogenic Diet Therapy Achieved?

The ketogenic diet (KD) is often started not only for seizure reduction but also to potentially wean antiseizure drugs (ASDs) in children with epilepsy. Although there have been several publications regarding ASD reduction on the KD, it is unknown how often complete medication withdrawal occurs.

Researchers reviewed the charts of all children started on the KD at Johns Hopkins Hospital and Johns Hopkins All Children’s Hospital from 1/11 to 4/18. Children were defined as achieving drug-free diet (DFD) status if they started the KD on at least 1 ASD and achieved a period of time where they were on the KD alone.

Over the time period, 232 children were evaluated; drug-free diet status occurred in 43 (18.5%), of which 32 (13.8% of the full cohort) remained off antiseizure drugs for the remainder of their ketogenic diet treatment course. Eleven children restarted antiseizure drugs after a mean of 7 months. Children achieving drug-free diet therapy were more likely to be younger, have fewer antiseizure drugs at ketogenic diet onset, have Glut1 deficiency or epilepsy with myoclonic-atonic seizures, but were less likely to have Lennox-Gastaut syndrome or a gastrostomy tube.

Can Ketogenic Supplements Delay Seizures Due to Oxygen Toxicity?

Hyperbaric oxygen therapy is a treatment used in at least 14 different disorders. A significant risk of this treatment is oxygen toxicity which can lead to seizures. A recent clinical study explored the effects of ketogenic supplements on delaying oxygen-induced seizures in a preclinical study.

A study published in Physiological Reports aimed to confirm the results of previous studies on ketogenic supplements for delaying seizures. Experiments were run on 18-month old rats. The age of the rats correlates to a middle-aged human model. Groups of nine or ten rats received either water, a 10g/kg dose of a ketogenic ester, 5g/kg dose of a ketogenic ester, 5g/kg dose of a ketogenic ester along with a medium-chain triglyceride, or a ketogenic salt. The multi-chain triglycerides were added to achieve a higher level of ketone bodies in the blood.

All rats were allowed to eat regular rat chow consisting of 75% carbohydrates. After the treatment was administered, the rats were placed in the hyperbaric chamber until a seizure would occur. The researchers from the University of South Florida hypothesized that the ketogenic supplements causing the highest elevation of ketone bodies would be the most effective at delaying seizures.

The time-to-seizure period was delayed in the three groups of rats receiving ketogenic supplements before entering the hyperbaric chamber. A significant difference was noted between the group of rats receiving the ketogenic supplements at 10g/kg and 5g/kg.

Implementation of Ketogenic Diet in Children with Drug-Resistant Epilepsy in a Medium Resources Setting: Egyptian Experience

BACKGROUND: Even with the extensive use of ketogenic dietary therapies (KD), there still exist many areas of the world that do not provide these treatments. Implementing the ketogenic diet in different countries forms a real challenge in order to match the cultural and economic differences.

AIM: To assess the feasibility of implementing a ketogenic diet plan in a limited resource setting with identification of the compliance, tolerability and side effects in the target population and to assess the efficacy of the ketogenic diet in children with intractable epilepsy.

METHOD OF THE STUDY: The medical records of 28 patients with intractable epilepsy, treated at The Children’s Hospital – Cairo University from December 2012 to March 2014 with ketogenic dietary therapy were reviewed. The non-fasting protocol was followed without hospital admission. All children were started on a standardized classic ketogenic diet with a ratio ranging from 2.5-4:1 (grams of fat to combined carbohydrate and protein). Patients were followed at 1, 3 and 6 months after diet initiation.

RESULTS: The median age was 60 months (range, 30-110). After 1 month from diet initiation, 16 patients (57%) remained on the diet. One of them (6.3%) had more than 90% reduction in seizure frequency, an additional 6 patients (37.5%) had a 50-90% reduction in seizure frequency. In total, seven out of the 16 patients continuing the diet for 1 month (43.8%) had more than 50% improvement in seizure control from the base line. Despite having 50-90% seizure control, three children discontinued the diet after one month. Three months after diet initiation, 6 patients (22%) remained on diet, 4 of them (66.7%) had more than 50% reduction in seizure frequency. At 6 months, only 3 patients remained on diet, 2 of them (66.6%) had 50-90% reduction in seizure frequency, while one patient (33.3%) showed better than 90% decrease in seizure.

CONCLUSION: The current study shows that the ketogenic diet could be implemented in medium resources countries and should be included in the management of children with intractable epilepsy.

Ketogenic Supplements Delay Seizures Without Imposing Dietary Restrictions

The ketogenic diet has proven successful in helping people lose weight and improve their overall health, including those with epilepsy. The low-carb diet transitions the body from burning sugar to burning fat and ketones for energy. New research suggests that increasing blood ketones by using ketogenic supplementation can reduce seizures without dietary restriction.

A new study published in Physiological Reports finds supplementing a normal, carbohydrate-rich diet with specific ketogenic agents may significantly delay tonic-clonic seizures caused by exposure to high levels of oxygen.

Oxygen toxicity is a complication that can arise following hyperbaric oxygen therapy, an FDA approved treatment used to manage various medical conditions, such as carbon monoxide poisoning, air/gas embolism and diabetic wounds. It involves inhaling pure oxygen in a pressurized or hyperbaric chamber.

Ketogenic Diet Prevents Relapse in Infantile Spasms with Structural and Genetic Etiology

In the United States, adrenocorticotropic hormone (ACTH) and vigabatrin are first-line therapies for patients with infantile spasms (IS). However, IS and other seizure types are often refractory to pharmacological and surgical treatments in patients with IS of focal-structural and genetic etiologies. Thus, research has focused on the important task of identifying alternative safe and effective therapeutic options for this population.

Ketogenic diet therapies are evidence based treatments proven to reduce seizures in children and adults with intractable epilepsy, often started alongside other pharmacological treatments for seizures. At our center, all patients with IS are treated according to a standardized clinical pathway with ACTH, vigabatrin, or a combination of both medications followed by the option of the classic ketogenic diet (KD). This study was completed to examine the efficacy of the classic KD in preventing IS relapse and seizure occurrence in patients with IS.

The classic KD is a safe and effective therapy to prevent IS relapse in patients with focal-structural and genetic etiologies. However, the classic KD does not significantly prevent the occurrence of other seizure types in patients with IS with focal-structural and genetic etiology. Thus, although the classic KD may prevent IS relapse, these patients will need to be monitored for other seizure types. The classic KD had no significant impact on preventing relapse or seizure occurrence in patients with IS of unknown etiology. However this population is less likely to have IS relapse or seizure occurrence overall.

Improving the Control of Epilepsy by Combining a Diet and a Drug

It has long been recognized that some epilepsy patients, particularly children, can benefit from a high fat, low carbohydrate ‘ketogenic’ diet, where the activity of the diet was thought to be through the production of chemicals called ‘ketones’.

However, recent work led by Professor Robin Williams, from Royal Holloway’s Centre for Biomedical Sciences, suggest that it is fatty acids provided in the diet that block seizures, by inhibiting specific receptors in the brain.

In a collaboration with Professor Matthew Walker at the Institute of Neurology, University College London, and Dr Philip Chen also from Royal Holloway’s Centre for Biomedical Sciences, the team suggested that the diet could be combined with the drug Perampanel which is used to help reduce epileptic seizures by acting on the same receptors.

Some Cognitive Benefit To The Ketogenic Diet In Patients With Epilepsy: A Systematic Overview.

Abstract

The ketogenic diet (KD) has been found to be effective in reducing seizures in patients with treatment-refractory epilepsy. Less attention has been paid to additional cognitive benefits of KD. The aim of the present paper was to provide a comprehensive overview of the studies reporting effects on cognition after KD treatment in adults and children with epilepsy. To address this aim, the clinical literature on cognitive effects of KD in patients with epilepsy was reviewed using a systematic approach. We conclude that using subjective assessments of the patient’s experience, cognitive improvements are frequently reported during KD treatment in the domains of alertness, attention, and global cognition. Studies that used objective neuropsychological tests confirmed benefits on alertness but found no improvement in global cognition. There are indications that these improvements are caused by both seizure reduction and direct effects of KD on cognition. The improvements appear to be unrelated to medication reduction, age when KD is started, type of KD, and sleep improvement. The findings in the present overview contribute to a better understanding of the beneficial effects of KD in patients with epilepsy.

Prospective Study of the Efficacy of a Ketogenic Diet in 20 Patients with Dravet Syndrome

PURPOSE: We evaluated the efficacy and tolerability of the ketogenic diet (KD) on generalized convulsions and status epilepticus (SE) in patients with Dravet syndrome (DS).

METHODS: Patients with DS having ?2 generalized convulsions/month despite drug treatment were included in this study and placed on a KD for 6 months. From 3 months before (baseline) to 6 months after KD initiation, caregivers recorded patients’ seizure activity, antiepileptic drug use, and adverse events. The KD efficacy was determined by examining the frequency and duration of seizures at 3 and 6 months vs. baseline. Responders were defined as individuals whose generalized convulsions decreased in frequency by ?50% vs. baseline. Seizures lasting ?5?min and SE were specifically evaluated. Patients’ cognition was also assessed at 3 and 6 months via questionnaire.

RESULTS: Twenty patients continued the KD for at least 3 months. Of the 17 responders identified at month 3, seizures decreased by 50-89% and 90-99% in nine and two patients, respectively; six patients were seizure free. The KD was ineffective in three patients, who discontinued the diet. By month 6, seizures decreased by 50-89% and 90-99% in six and one patient(s), respectively; 10 patients were seizure free. The frequency of other seizure types also improved. During all 6 months, neither generalized convulsions lasting ?5?min nor SE was detected in the 17 responders. The KD also improved patients’ cognition.

CONCLUSION: The ketogenic diet is a good treatment option for medically intractable epilepsy.

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