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.

Vagus nerve stimulator placement, corpus callostomy, or ketogenic diet initiation could help children with pharmacoresistent epilepsy

According to a study, “Seizure control and quality of life in children with epilepsy after vagus nerve stimulator placement, corpus callostomy, or ketogenic diet initiation” [1]:

Vagus nerve stimulator placement, corpus callostomy, and ketogenic diet was successful in reducing both generalized and focal seizure types, [with] ketogenic diet showing a trend towards slightly better success.

Parents of 210 patients, who had 292 (VNS, n=150; CC, n=44; KD, n=98) treatment modalities, agreed to participate in a phone interview. 60% were male with ages ranging from 8 months to 20 years. Seizure control, cognitive and behavioral factors, quality of life and treatment satisfaction was rated via a 9-item telephone questionnaire.

Improvements observed in cognitive and behavioral domains, better seizure control and less falls positively affected quality of life. Parent overall satisfaction was greater than 75%, which far outweighed seizure reduction or behavioral improvements.

These findings support palliative management for those with pharmacoresistant epilepsy who are not candidates for surgical resection.

CURE Conversations: Timothy Simeone, PhD

Get to know our researchers! CURE Conversations features interviews with our scientists and discusses the focus of their work as well as recent breakthroughs in the field of epilepsy research. These investigators are the people behind the scenes who work diligently in the labs to unravel the mysteries of epilepsy, studying the science that will one day lead to cures for the epilepsies.

Can you share some details about what you do?
Our group investigates mechanisms of hyperexcitability and novel anti-seizure therapeutics. The epileptic brain is quite different from the non-epileptic brain in many ways, including its response to therapeutics. Therefore, we employ animal models that naturally develop epilepsy to tease out novel mechanisms that may have been missed with models that rely on wild-type brains. We utilize in vivo and in vitro electrophysiological and neurobiological techniques to examine multiple levels of activity—from whole brain to neuronal networks to single neurons to intracellular organelles (mitochondria) and signaling.

What motivated you to become interested in this area of research?
I find the brain absolutely fascinating. From single neurons to networks, it is beautiful and baffling. It seems deceptively simple on the surface, but unimaginably complex as you dive deeper. How does it work? What processes lead to dysfunction? There seem to be multiple paths that can lead to epilepsy and with each mechanistic discovery we learn something about the brain and potentially how to fix it. Fascinating and promising. I naturally gravitated towards studying epilepsy. On a more personal note, early in my graduate career it was made clear to me that many discoveries and therapeutics used for epilepsy were applicable in many other neurological disorders. I grew up with family members that are afflicted with neurological disorders of varying severity, and I knew I wanted to study something that could potentially help a wide array of people. If my team and collaborators are able to make a contribution—no matter how small—that furthers our understanding of epilepsy or translates into helping patients, we will deem our entire careers successful.

What is your current research focus?
We are currently attempting to elucidate the anti-seizure mechanism of the ketogenic diet. I was first introduced to the ketogenic diet as a post-doctoral fellow in the laboratory of Jong M. Rho, M.D. As everyone who has interacted with Dr. Rho would agree, his passion for the ketogenic diet (KD) is infectious. He instilled in me a belief that the KD holds the key to discovering novel molecular targets that will be useful in treating a significant portion of patients with refractory epilepsy. In the lab, we try to figure out what changes the KD induces in the brain of epileptic animals and then manipulate the identified targets with pharmacologic and genetic techniques to see whether seizures are changed and/or reduced.

Can you share some of the latest findings?
We have found that a molecular target useful in treating Type II Diabetes Mellitus may be responsible for much of the anti-seizure and neuroprotective effects of the KD. At the time of our initial discovery, we were completely ignorant of ongoing research indicating that this target may also have therapeutic use in other neurological disorders such as Alzheimer’s and Parkinson’s diseases. This raises the possibility that many neurological disorders may have commonalities that perhaps differ in regional expression and degrees of severity, resulting in the wide array of disorders and symptoms. Therefore, our findings from researching the KD may be applicable to other neurological disorders. We are currently preparing a manuscript detailing our findings thus far, which will hopefully be published by the time this interview is published.

What is the ultimate goal for the research and how will it impact patients with epilepsy?
Our ultimate goal is to identify viable targets that will aid in the development of new anti-seizure medication, specifically for refractory epilepsies. Ideally, these novel treatment(s) will treat the disease and not just the symptoms.

What accomplishment—personal or professional—are you most proud of?
My children are and continue to be my biggest accomplishment. They have taught me so much in such a short time. Not the least is giving me a better understanding and empathy for parents of children with epilepsy. Outwardly, I am not an emotional person, to which my wife will attest, but the stories that parents and patients share through the AES, CURE, and EFA mediums affect me deeply. The empathy my laboratory personnel (I have been lucky to find stellar technicians, students, and collaborators) and I feel for families dealing with epilepsy continues to align our investigational goals with the mission of CURE and drive our research forward.