Better Seizure Control with Ketogenic Diet in Infants with Genetic Epilepsy

Infants and young children with epilepsy due to a confirmed genetic abnormality had a better response to treatment with ketogenic diet compared to patients with other types of epilepsy, according to a review of 10-year experience at Ann & Robert H. Lurie Children’s Hospital of Chicago. Results were published in Scientific Reports.

“Overall, we observed that ketogenic diet continues to be a safe, effective and well-tolerated treatment for patients under 3 years of age with drug-resistant epilepsy,” says study author John Millichap, MD, an epilepsy specialist at Lurie Children’s and Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “Based on our experience, clinicians could consider offering ketogenic diet earlier to infants diagnosed with genetic epilepsy, perhaps even before it becomes clear that the patient is not responding to anticonvulsant medication.”

Ketogenic diet is a high fat, low carbohydrate and protein restricted diet that is rigorously medically supervised. It is widely recognized as an effective treatment for epilepsy that does not respond to medications.

“The ketogenic diet helps control seizures by reducing fluctuations of blood sugar, which reduces hyper-excitability in the brain,” explains Dr. Millichap. “At Lurie Children’s we have used it since 1963.”

Microbiome Research in Epilepsy: Hope or Hype?

The human body, though a miraculous machine, is also a sort of mobile terrarium for other living things. In fact, 99% of the genes in your body aren’t yours – they belong to bacteria, viruses, fungi and other microorganisms. These microorganisms live almost everywhere—in the mouth, eyes, nasal passages, genitals and on the skin—but mostly, they’re in your gut.

The gut microbiome includes hundreds of species of bacteria, comprising 100 trillion cells—more than exist in a human body. Yet until very recently, the idea that these microorganisms could influence human health and behavior was soundly rejected.

Over the past decade, however, the gut biome has gained some respect. It’s now recognized as an important part of human health and function, with effects implicated in a variety of conditions, from the obvious (inflammatory bowel disease) to the not-so-obvious (Parkinson’s disease). Neurodevelopmental and mental disorders (such as autism and depression) have been studied most extensively. Neurological disorders, such as stroke and epilepsy, have remained scarcely examined, although interest has been growing.

The gut-brain axis

Given the blood-brain barrier, the idea that bacteria in the gut could influence the brain was even harder to swallow. But an increasing number of studies are finding intimate communication between the gut and brain, as well as complex interplay among the gut microbiome, the brain and the rest of the body.

Given their range of effects on the body and their constant interactions with the nervous system, gut microbiota are now thought to play a role in many neurological disorders. For example, giving antibiotics to mice prone to Alzheimer’s disease — in order to destroy most of the gut bacteria—reduced the number of clumped proteins in the brain that have been linked with dementia. A later study gave young mice antibiotics for only a week; as they grew, their brains showed less evidence of Alzheimer’s.

Do they play a role in epilepsy? Can gut microbiota affect seizure frequency? Can certain populations of bacteria predispose to seizures, and can we harness the power of the microbiome to stop seizures?

Visit the ILAE website to learn more.

CURE Discovery: A Potential Link Between Gut Bacteria and Epilepsy

Key Points

  • Dr. Tore Eid’s CURE-funded research aims to understand how gut bacteria can impact seizure development, inflammation, and neurodegeneration.
  • The team found increased levels of certain amino acids, potentially made by gut bacteria, in the epileptic brain regions of individuals with focal epilepsies.
  • Short-term treatment with these amino acids reduced spontaneous seizures in a rat model of epilepsy, while a long-term treatment worsened seizure frequency.
  • Dr. Eid’s studies have the potential to develop epilepsy treatments such as dietary interventions and other safe manipulations of gut bacteria.
Deep Dive

CURE grantee, Dr. Tore Eid, and his team at Yale University, are conducting exciting research to understand how gut bacteria can influence the development and manifestation of seizures. This impactful work, funded by the Heldman-Kirshner family grant in honor of Alex Heldman, could lead to simpler and safer treatments for epilepsy.

ffb08cad-f59b-4586-b913-140d701d2c1f.pngOver 500 different types of bacteria live in our gut alone.1 This dense collection of bacteria, called gut microbiota, helps us digest food, provides important nutrients, builds immunity, and protects us from harmful pathogens. Disruptions to the gut microbiota play a role in many diseases including irritable bowel disease, colitis, and diabetes. There is also evidence that gut microbiota problems are linked to anxiety, depression, and autism spectrum disorders.2 How and whether these bacteria influence epilepsy development and progression is not very well studied. There is some evidence that the ketogenic diet, which is effective in reducing seizure frequency in a number of different epilepsies, may work by modifying the gut microbiota.3

To better understand the role gut bacteria may play in epilepsy, Dr. Eid and his team analyzed brain fluid samples from people with focal epilepsy. They found that epileptic brain regions had increased levels of certain amino acids called branched chain amino acids, which can be made by gut bacteria. Levels of some of these branched amino acids increased in the brain three hours before a spontaneous seizure occurred, while levels of other branched amino acids increased an hour before. This may indicate that there is a “fine-tuning” of these amino acids happening within the body which potentially impacts seizure occurrence.

Next, the team fed these branched chain amino acids to a rat model of epilepsy they developed. A short-term treatment decreased spontaneous seizures while a long-term treatment worsened seizure frequency and caused neuronal loss in an area of the brain called the hippocampus.4 These results provide evidence that molecules derived from gut bacteria can impact brain chemistry and seizure development.

The team is also interested in understanding how bacteria living in the gut can influence epilepsy development and progression in the brain, focusing on a large nerve called the vagus nerve. This nerve allows the brain and the gut to directly communicate with each other. Dr. Eid’s team has developed techniques to selectively stimulate or suppress signaling only through the afferent vagus nerve, which transmits messages from the gut to the brain, without affecting the efferent nerve, which transmits messages from the brain to the gut and other organs.

In future studies, Dr. Eid and his team will perform careful manipulations of gut bacteria in a rat model of epilepsy by feeding the animals specific types of bacteria. The types of bacteria the team plans to use make molecules which can influence brain chemistry and thus potentially affect seizures. The team will study the effect of this treatment along with afferent vagal nerve stimulation/suppression on seizure development, brain inflammation, and neuronal loss in the rats.

These studies have the potential to impact epilepsy treatment through safe manipulations of gut bacteria through, for example, dietary interventions, probiotics, or antibiotics.

1 Eckburg PB et.al. Diversity of the human intestinal microbial flora, Science. 2005 Jun 10;308(5728):1635-8
2 E.Y. Hsiao et.al Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders, Cell. 155 (2013) 1451-1463
3 Olson CA, Vuong HE et. al. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet, Cell. 2018 Jun 14;173(7):1728-1741.e13. doi: 10.1016/j.cell.2018.04.027
4 Gruenbaum SE, Dhaher R et. al., Effects of Branched-Chain Amino Acid Supplementation on Spontaneous Seizures and Neuronal Viability in a Model of Mesial Temporal Lobe Epilepsy, J Neurosurg Anesthesiol. 2019 Apr;31(2):247-256

Epilepsy Research Findings: May 2019

In this month’s research news, treatments, genetic analysis, and preclinical work offer hope to those impacted by hard-to-treat or difficult-to-diagnose forms of epilepsy.

Exciting treatment developments include a positive Phase 3 clinical trial outcomefor the cannabidiol-based drug EPIDIOLEX® for the treatment of seizures associated with tuberous sclerosis complex. In addition, an improved treatment regimen targeting the severe, prolonged seizures that make up status epilepticus has been created.

In promising genetics news, a report from CURE’s own Epilepsy Genetics Initiativeunderscores the value of continued reanalysis of genetic information from people with epilepsy to increase their chances of obtaining a genetic diagnosis for their epilepsy.

Additionally, important preclinical work led by CURE Grantees Dr. Chris Dulla and Dr. Janice Naegele uncovers a potential drug to treat post-traumatic epilepsy and a way to restore the balance of brain activity and reduce seizures in temporal lobe epilepsy, respectively.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

Treatment Advances

GW Pharmaceuticals Reports Reduction in Seizure Frequency for EPIDIOLEX® (cannabidiol) Oral Solution in Patients with Seizures Associated With Tuberous Sclerosis Complex
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GW Pharmaceuticals and Greenwich Biosciences announced positive top-line results of a Phase 3 clinical trial of EPIDIOLEX® (cannabidiol or CBD) in the treatment of seizures associated with Tuberous Sclerosis Complex (TSC). TSC is a rare and severe form of childhood-onset epilepsy. In this trial, EPIDIOLEX met its primary endpoint, which was a reduction in seizure frequency in the group given EPIDIOLEX compared to the placebo group.

Breakthrough for Children with Serious Epileptic Seizures
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A new treatment regimen of administering levetiracetam and phenytoin one after the other has given emergency medicine doctors a better way to treat severe, prolonged epileptic seizures in children. These treatment modifications will lower the chances of intubation and intensive care, as well as increase the chances of children recovering more quickly.

Diagnostic Advances

The Epilepsy Genetics Initiative: Systematic Reanalysis of Diagnostic Exomes Increases Yield
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Featuring CURE’s Epilepsy Genetics Initiative

Results from CURE’s Epilepsy Genetics Initiative (EGI) show that when the genetic information of a person with epilepsy is systematically reanalyzed, there is an increase in the return of a genetic diagnosis. Eight new diagnoses were made as a result of updated annotations or the discovery of novel epilepsy genes after the initial diagnostic analysis was performed. One novel epilepsy gene was discovered through dual interrogation of research and clinically generated whole-exome sequencing. According to this recently-published report, EGI’s contributions to gene discovery underscore the importance of data sharing and the value of collaborative enterprises.

Research Discoveries

Using a Drug that Mimics the Ketogenic Diet to Help Prevent Epilepsy after Traumatic Brain Injury
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Featuring the work of CURE Grantee Dr. Chris Dulla

Neuroscientists led by CURE Grantee Dr. 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.

Neural Stem Cell Transplantation May Reduce Abnormal Increases in New Cells in the Brains of Mice with Temporal Lobe Epilepsy
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Featuring the work of CURE Grantee Dr. Janice Naegele

According to a new, CURE-funded study featuring the work of grantee Dr. Janice Naegele, the transplantation of inhibitory cells into the brains of mice with temporal lobe epilepsy may reduce the abnormal growth of new neurons in an area of the brain called the hippocampus. This in turn could reduce brain hyperexcitability that leads to seizures.

Stimulating the Epileptic Brain Breaks Up Neural Networks to Prevent Seizures
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Responsive neurostimulation treats epilepsy by detecting seizures and intervening with a jolt of electric current. Over time, most patients find their seizures become fewer and further between. New evidence suggests responsive neurostimulation can remodel the brain to be less susceptible to seizures.

Scientists Discover Trigger Region for Absence Epileptic Seizures
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Scientists have discovered a neurological origin for absence seizures – a type of seizure characterized by very short periods of lost consciousness in which people appear to stare blankly at nothing. Using a mouse model of childhood epilepsy, a group of scientists has shown that absence epilepsy can be triggered by impaired communication between two brain regions: the cortex and the striatum.

Autism-Related Memory and Seizures Improved through Gene Repair in Adults
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Scientists have shown that correcting the protein deficiency caused by a genetic form of autism spectrum disorder in adult mice can improve behavioral and electrophysiological measures of both memory and seizure. The evidence suggests this is true even when the treatment is carried out well past what has traditionally been thought of as the critical window of early brain development.

Drug Used to Treat Multiple Sclerosis May Be Beneficial for Individuals with Epilepsy 
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A drug commonly used to treat multiple sclerosis may, after necessary modifications, one day be used to treat patients with epilepsy, according to research from the laboratory of Dr. Inna Slutsky.

Study Reveals How Glial Cells May Play Key Epilepsy Role
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A study provides potential new targets for treating epilepsy and novel fundamental insights into the relationship between neurons and their glial “helper” cells. This study reports finding a key sequence of molecular events in which the genetic mutation in a fruit fly model of epilepsy leaves neurons vulnerable to becoming hyper-activated by stress, leading to seizures.

Ketogenic Diet May Reduce Sudden Unexpected Deaths in Epilepsy, Mouse Study Suggests
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Sudden unexpected death in epilepsy (SUDEP) occurs more frequently during the early evening and is significantly prevented by prolonged use of the ketogenic diet, research in a mouse model of Dravet syndrome suggests. The reasons why this happens are unclear and should be examined in more depth by future studies, but these findings may be useful to understand why most SUDEP episodes happen at night and how certain diets can benefit people with epilepsy, especially those with Dravet syndrome, researchers say.

Attention, Behavioral Problems Common in New, Recent-Onset Juvenile Myoclonic Epilepsy
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Children with new recent-onset juvenile myoclonic epilepsy are more likely to have difficulty with executive, attention, and verbal faculties than their healthy peers and are also more likely to use a greater number of academic services, researchers found.

Also Notable

Zogenix Receives Refusal to File Letter from FDA for FINTEPLA® New Drug Application
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Zogenix announced that it received a Refusal to File letter from the FDA regarding its New Drug Application (NDA) for FINTEPLA® for the treatment of seizures associated with Dravet syndrome. Upon its preliminary review, the FDA determined that the NDA was not sufficiently complete to permit a substantive review.

Ketogenic

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.