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 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.

Improving Compliance in Adults with Epilepsy on a Modified Atkins Diet: A Randomized Trial

PURPOSE: To determine whether use of a ketogenic formula during the first month of the modified Atkins diet (MAD) in adults with drug-resistant epilepsy (DRE) improves seizure reduction and compliance compared to MAD alone.

METHODS: Eighty adults (age ?18 years) with DRE and ?4 reliably quantifiable seizures/month were enrolled. All participants were trained to follow a 20?g/day net carbohydrate limit MAD. Patients were randomized to receive one 8-ounce (237?mL) tetrapak of KetoCal®, a 4:1 ketogenic ratio formula, daily in combination with MAD during the first month (treatment arm) or second month (control/cross-over arm). Patients recorded urine ketones, weight, and seizure frequency and followed up at 1 and 2 months.

RESULTS: By 1 month, 84% of patients achieved ketosis (median of 4-4.5 days). At 1 month, the treatment arm had a significantly higher ketogenic ratio and more patients with a ?1:1 ketogenic ratio compared to the control arm. There was no difference in median seizure frequency, proportion of responders (?50% seizure reduction), or median seizure reduction from baseline between groups. However, patients treated with KetoCal® during the first month were significantly more likely to continue MAD for 6 months or more.

CONCLUSION: Although supplementing MAD with a ketogenic formula in the first month did not increase the likelihood of reducing seizures compared to MAD alone, significantly more adults remained on MAD long-term with this approach. This suggests a potential strategy for encouraging compliance with MAD in adults with DRE.

Bloom Science Launches to Develop Neuroprotective Epilepsy Treatments in Orphan Indications with Exclusive Technology License from UCLA

Bloom Science announced that it has secured an exclusive technology license around preclinical research demonstrating that gut bacteria play a critical role in the anti-seizure effects of the ketogenic diet.

The research was published in the peer-reviewed journal Cell in an article titled “The gut microbiota mediates the anti-seizure effects of the ketogenic diet in mouse models of refractory epilepsy.” On behalf of the Regents of the University of California, the UCLA Technology Development Group has filed a patent on the technology that mimics the ketogenic diet to provide seizure protection and has exclusively licensed it to Bloom Science, which will explore potential clinical applications.

The ketogenic diet, developed in the 1920s to treat epilepsy, has been proven to manage seizures in rare types of epilepsy and in patients who don’t respond to other forms of treatment, but compliance with the low-carb/high-fat diet is extremely challenging. New technologies to interrogate the relationship between the gut microbiome and the brain now explain why it works.

Senior author of the Cell publication, Elaine Hsiao, PhD, Assistant Professor, Department of Integrative Biology and Physiology in the Life Sciences Division of the UCLA College, and the UCLA David Geffen School of Medicine, led the research that showed in two preclinical mouse models that the ketogenic diet increases the abundance of certain gut bacteria, and those specific strains of bacteria are both necessary and sufficient to confer seizure protection. The bacteria work together to regulate circulating metabolites that fuel neurotransmitters in the brain – specifically gamma-aminobutyric acid (GABA), a neurotransmitter that is responsible for counterbalancing the excitation of neurons by glutamate. Bloom Science is developing proprietary products from these microbes that aim to modulate GABA, thereby re-establishing the delicate balance of GABA and glutamate and delivering a neuroprotective effect for patients with epilepsy.

Study: Efficacy and Safety of Ketogenic Diet for Treatment of Pediatric Convulsive Refractory Status Epilepticus

CONCLUSIONS: This series suggests efficacy and safety of ketogenic diet (KD) for treatment of pediatric convulsive refractory status epilepticus (RSE).

PURPOSE: To describe the efficacy and safety of ketogenic diet for convulsive refractory status epilepticus.

METHODS: RSE patients treated with KD at the 6/11 participating institutions of the pediatric Status Epilepticus Research Group from January-2011 to December-2016 were included. Patients receiving KD prior to the index RSE episode were excluded. RSE was defined as failure of ?2 anti-seizure medications, including at least one non-benzodiazepine drug. Ketosis was defined as serum beta-hydroxybutyrate levels >20?mg/dl (1.9?mmol/l). Outcomes included proportion of patients with electrographic (EEG) seizure resolution within 7?days of starting KD, defined as absence of seizures and ?50% suppression below 10??V on longitudinal bipolar montage (suppression-burst ratio ?50%); time to start KD after onset of RSE; time to achieve ketosis after starting KD; and the proportion of patients weaned off continuous infusions 2 weeks after KD initiation. Treatment-emergent adverse effects (TEAEs) were also recorded.

RESULTS: Fourteen patients received KD for treatment of RSE (median age 4.7 years, interquartile range [IQR] 5.6). KD was started via enteral route in 11/14 (78.6%) patients. KD was initiated a median of 13?days (IQR 12.5) after the onset of RSE, at 4:1 ratio in 8/14 (57.1%) patients. Ketosis was achieved within a median of 2?days (IQR 2.0) after starting KD. EEG seizure resolution was achieved within 7?days of starting KD in 10/14 (71.4%) patients. Also, 11/14 (78.6%) patients were weaned off their continuous infusions within 2 weeks of starting KD. TEAEs, potentially attributable to KD, occurred in 3/14 (21.4%) patients, including gastro-intestinal paresis and hypertriglyceridemia. Three month outcomes were available for 12/14 (85.7%) patients, with 4 patients being seizure-free, and 3 others with decreased seizure frequency compared to pre-RSE baseline.

Updated Recommendations on the Optimal Clinical Management of Children Receiving Dietary Therapies for Epilepsy

Ketogenic dietary therapies (KDT) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDT were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre?KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow?up, side events, and KDT discontinuation. It has been helpful in outlining a state?of?the?art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research.

Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. Additionally, authors completed a survey of their institution’s practices, which was compared to responses from the original consensus survey, to show trends in management over the last ten years.