Medicinal oil reduces debilitating epileptic seizures associated with Glut 1 deficiency, trial shows

Two years ago, the parents of Chloe Olivarez watched painfully as their daughter experienced epileptic seizures hundreds of times a day. The seizures, caused by a rare metabolic disease that depleted her brain of needed glucose, left Chloe nearly unresponsive, and slow to develop.

Within hours, treatment with an edible oil dramatically reduced the number of seizures for then-4-year-old Chloe, one of 14 participants in a small UT Southwestern Medical Center clinical trial.

“Immediately we noticed fewer seizures. From the Chloe we knew two years ago to today, this is a completely different child. She has done amazingly well,” said Brandi Olivarez, Chloe’s mother.

For Chloe and the other trial participants who suffer from the disease called Glut1 deficiency (G1D), seizure frequency declined significantly. Most showed a rapid increase in brain metabolism and improved neuropsychological performance, findings that suggested the oil derived from castor beans called triheptanoin, ameliorated the brain glucose-depletion associated with this genetic disorder, which is often undiagnosed.

“This study paves the way for a medical food designation for triheptanoin, thus significantly expanding therapeutic options for many patients,” said Dr. Juan Pascual, Associate Professor of Neurology and Neurotherapeutics, Physiology, and Pediatrics at UT Southwestern and lead author of a study on the findings, published in JAMA Neurology.

For the estimated 38,000 Americans suffering from this disease, the only proven treatment has been a high-fat ketogenic diet, which only works for about two-thirds of patients. In addition, this diet carries long-term risks, such as development of kidney stones and metabolic abnormalities.

Based on the results of this trial, triheptanoin appears to work as efficiently as the ketogenic diet; however, more research needs to be done before the oil is made available as a medical food therapy, researchers said.

“Triheptanoin byproducts produced in the liver and also in the brain refill brain chemicals that we found are preferentially diminished in the disorder, and this effect is precisely what defines a medical food rather than a drug,” said Dr. Pascual, who heads UT Southwestern’s Rare Brain Disorders Program, maintains an appointment in the Eugene McDermott Center for Human Growth and Development, and holds The Once Upon a Time Foundation Professorship in Pediatric Neurologic Diseases.

The oil, approved for use in research only, is an ingredient in some cosmetic products and is added to butter in some European countries. It is not commercially available in the U.S. for clinical use.

Triheptanoin’s success as an experimental treatment for other metabolic diseases, along with preclinical success in G1D mice, led Dr. Pascual and his trial collaborator, Dr. Charles Roe, Clinical Professor of Neurology and Neurotherapeutics, to first conceive the idea and then launch this trial for G1D patients. The 14 pediatric and adult patients in the study consumed varying amounts of the oil, based on their body weight, four times a day. Given the trial’s success, Dr. Pascual plans further research to refine the optimal dosage toward the goal of facilitating medical food designation of triheptanoin as a new G1D treatment.

While some trial participants reported mild stomach upset as a side effect, for Chloe the oil has been a miracle medicine without negative effects. Her parents, Brandi and Josh Olivarez of Waco, Texas, continue to be amazed by her progress.

“Before, she was having so many seizures a day that she couldn’t even talk. Now she sings all the time, she can eat whatever she wants, and her speech is greatly improved. She still has some learning delays, but has come a long way,” said Mrs. Olivarez.

Many Glut1 patients suffer from movement disorders that limit their physical capabilities, but that does not appear to be the case with Chloe. As for the seizures, she still has minor ones occasionally, but they are not debilitating.

“She is now able to run a solid mile without stopping. This would not have been possible without the oil,” Mrs. Olivarez said. “Before, she had almost no muscle tone, was lethargic and had a very wide gait due to trying to balance herself while walking, which was very tiring for her.”

To better understand this disease, UT Southwestern established a patient-completed registry to track G1D incidence and what treatments work or do not work for those registered.

Molecular imbalance linked to brain tumour seizures

Researchers in France may have discovered why some patients with a type of brain tumour have epileptic seizures.

“This small study is interesting and shows that glioma-linked epilepsy may be connected to certain channels found in the membranes of nerve cells” - Dr Robin Grant, Edinburgh Cancer Research UK Centre

Their study, published in Science Translational Medicine, suggests that seizures in patients with glioma may be linked to an imbalance of chloride – which is involved in nerve activity – in certain brain cells.

Whether a patient has seizures is linked to how aggressive their tumour is – with less aggressive cases being more prone to epilepsy as tumour cells slowly progress and alter brain tissue.

It is hoped that further research could explore treatments for glioma-linked epilepsy by controlling chloride levels in the brain.

Glioma develops from specialised brain cells known as ‘glial cells’ that usually help to keep brain nerve cells in place, providing support and protection to ensure correct brain function.

In the latest study, scientists from Sorbonne University studied brain tissue samples from 47 glioma patients and found that nerve tissue infiltrated by glioma cells behaves in similar ways to other forms of epilepsy.

Looking at the patient samples, the team found that a particular type of nerve cell – called a pyramidal cell – released excessive amounts of chloride from inside the cells when exposed to a molecule called GABA, which is also involved in transmitting nerve signals.

GABA was released by other neighbouring nerve cells called ‘interneurons’. And the researchers believe that the release of chloride through specialised molecular channels in the membrane of nerve cells, may be responsible for the seizures experienced in some glioma patients.

Dr Robin Grant, an expert in epilepsy and glioma from the Edinburgh Cancer Research UK Centre, who was not involved in the research, said that the channels may make good drug targets for further investigation, but a finer understanding of the involvement of other processes is still needed.

“This small study is interesting and shows that glioma-linked epilepsy, as with other types of epilepsy, may be connected to certain channels found in the membranes of nerve cells.

“More research will be needed to understand the finer details of this process in glioma and whether these channels, along with other similar channels found in nerve cells, could be good targets for drugs to help control the condition.”

GABA actions and ionic plasticity in epilepsy

Concepts of epilepsy, based on a simple change in neuronal excitation/inhibition balance, have subsided in face of recent insights into the large diversity and context-dependence of signaling mechanisms at the molecular, cellular and neuronal network level. GABAergic transmission exerts both seizure-suppressing and seizure-promoting actions. These two roles are prone to short-term and long-term alterations, evident both during epileptogenesis and during individual epileptiform events. The driving force of GABAergic currents is controlled by ion-regulatory molecules such as the neuronal K-Cl cotransporter KCC2 and cytosolic carbonic anhydrases. Accumulating evidence suggests that neuronal ion regulation is highly plastic, thereby contributing to the multiple roles ascribed to GABAergic signaling during epileptogenesis and epilepsy.

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Neural Transplant Reduces Absence Epilepsy Seizures in Mice

New research from North Carolina State University pinpoints the areas of the cerebral cortex that are affected in mice with absence epilepsy and shows that transplanting embryonic neural cells into these areas can alleviate symptoms of the disease by reducing seizure activity. The work may help identify the areas of the human brain affected in absence epilepsy and lead to new therapies for sufferers.

Absence epilepsy primarily affects children. These seizures differ from “clonic-tonic” seizures in that they don’t cause muscle spasms; rather, patients “zone out” or stare into space for a period of time, with no memory of the episode afterward. Around one-third of patients with absence epilepsy fail to respond to medication, demonstrating the complexity of the disease.

NC State neurobiology professor Troy Ghashghaei and colleagues looked at a genetic mouse model for absence epilepsy to determine what was happening in their brains during these seizures. They found that the seizures were accompanied by hyperactivity in the areas of the brain associated with vision and touch – areas referred to as primary visual and primary somatosensory cortices in the occipital and parietal lobes, respectively.

“There are neurons that excite brain activity, and neurons that inhibit activity,” Ghashghaei says. “The inhibitory neurons work by secreting an inhibitory neurotransmitter called gamma-aminobutyric acid, or GABA. The ‘GABAergic’ interneurons were recently shown by others to be defective in the mice with absence seizures, and we surmised that these malfunctioning neurons might be part of the problem, especially in the visual and somatosensory cortical areas.”

Ghashghaei’s team took embryonic neural stem cells from a part of the developing brain that generates GABAergic interneurons for the cerebral cortex. They harvested these cells from normal mouse embryos and transplanted them into the occipital cortex of the genetic mice with absence seizures. Absence seizure activity in treated animals decreased dramatically, and the mice gained more weight and survived longer than untreated mice.

“This is a profound and remarkably effective first result, and adds to the recent body of evidence that these transplantation treatments can work in mouse models of epilepsy. But we still don’t understand the mechanisms behind what the normal inhibitory cells are doing in areas of the visual cortex of absence epileptic mice,” Ghashghaei says. “We know that you can get positive results even when a small number of transplanted neurons actually integrate into the cortex of affected mice, which is very interesting.  But we don’t know how the transplanted cells are connecting with other cells in the cortex and how they alleviate the absence seizures in the mouse model we employed.

“Our next steps will be to explore these questions. In addition, we are very interested in methods being devised by multiple labs around the world to ‘reprogram’ cells from transplantation patients to generate normal GABAergic and other types of neurons. Once established, this would eliminate the need for embryonic stem cells for this type of treatment. The ultimate goal is to develop new therapies for humans suffering from various forms of epilepsies, especially those for whom drugs do not work.”

First Non-Study Site to Implant Device for Stopping Uncontrolled Seizures

NYU Langone Medical Center last month became the first hospital outside of a clinical trial site to implant a pacemaker-like device in the brain that may be a game-changer for patients with epilepsy.

The device, called the RNS System, was implanted April 17, 2014 in a patient with seizures that previously could not be controlled with medication, or intractable epilepsy, by Werner Doyle, MD, an associate professor in the Department of Neurosurgery at NYU Langone. The patient has recovered completely from the surgery.

The first-of-its-kind device is similar to an implantable cardioverter-defibrillator (ICD), which delivers electrical pulses to the heart to prompt it to beat a normal rhythm and provides a new alternative treatment to vagus nerve stimulation and surgical removal of the focus site – parts in the brain where the seizures originate — for people with intractable epilepsy.

Prior to last month’s surgery, the only implants of the seizure-reducing medical device took place at U.S. medical centers that had previously researched the device’s effectiveness and safety, making NYU Langone the first non-study hospital in the U.S. and New York metropolitan area to offer the RNS System to patients.

"Medically intractable epilepsy is often a debilitating disorder that puts sufferers at risk from sudden loss of consciousness and uncontrolled movements. It stigmatizes patients and restricts their independence," said Dr. Doyle. "Epilepsy surgery is an important therapeutic option for patients, which can significantly or completely control their seizures and return their lives to normal. The RNS device improves our ability to control seizures with surgery and now offers patients who may not have been surgical candidates in the past a surgical option."

According to the Centers for Disease Control and Prevention, about 2.3 million Americans suffer from epilepsy, with about one in 26 people expected to be diagnosed in their lifetimes. Approximately one-third of patients do not respond to medications and face major challenges with daily living. Uncontrolled seizures may interfere with normal activities such as working, going to school and driving. Patients also face increased risk for anxiety, depression, injury, brain damage, and in rare cases, death.

The RNS System, manufactured by NeuroPace Inc. of Mountain View, Calif., is a responsive stimulation device that’s implanted in the skull along with brain electrodes to detect abnormal electrical activity in the brain associated with seizures. After two or more weeks of recording the activity, doctors program the device to specifically respond to these abnormal signals by delivering imperceptible electrical pulses to the brain that normalize the activity. The device essentially “reboots” the portion of the brain where the seizure is originating, thereby effectively interrupting the abnormal electrical activity before it spreads or causes its unwanted effects.

The RNS System received pre-market approval from the Food and Drug Administration in November 2013 to treat patients’ seizures that have not been controlled by two or more antiepileptic medications.

In clinical trials performed at medical centers across the U.S., including at Saint Barnabas Medical Center in New Jersey by Dr. Doyle and Orrin Devinsky, MD, director of the Comprehensive Epilepsy Center at NYU Langone, 55 percent of patients experienced a 50 percent or greater reduction in seizures two years post implantation.

"The RNS System represents one of the most important and innovative therapies to treat people with epilepsy," says Dr. Devinsky. "This new surgical therapy uses information to target and shut down points in the brain where seizures start without removing tissue, providing a novel option for patients with uncontrolled seizures."

For more information:

Neurology, Morrell et al, 2011.

Epilepsia, Heck et al, 2014.

NeuroPace

Widely Used Drug No More Effective Than FDA Approved Medication in Treating Epileptic Seizures in Children

A National Institutes of Health-sponsored study published in the Journal of the American Medical Association (JAMA) showed that lorazepam - a widely used but not yet Food and Drug Administration (FDA) approved drug for children - is no more effective than an approved benzodiazepine, diazepam, for treating pediatric status epilepticus.

Status epilepticus is a state in which the brain is in a persistent state of seizure. By the age of 15, 4 to 8 percent of children experience a seizure episode, which can be life threatening if they aren’t stopped immediately. Status epilepticus is a continuous, unremitting seizure lasting longer than five minutes or recurrent seizures without regaining consciousness between seizures for more than five minutes.

Before this current study, published April 23, there was no evidence indicating which of the two treatments might prove more effective. Although it is not yet approved by the FDA, James M. Chamberlain, MD, Division Chief of Emergency Medicine at Children’s National Health System, the study’s principal investigator, estimates that lorazepam is used as first-line therapy in most emergency departments.

“The study results provide reassurance to emergency medicine personnel who must act within minutes,” said Chamberlain. The study was conducted at 11 hospitals in the United States using the infrastructure of the Pediatric Emergency Care Applied Research Network (PECARN), under a contract from the National Institutes of Health’s (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Both lorazepam and diazepam are used to treat status epilepticus. Diazepam, also known as Valium, is the only one of the two drugs to have been approved by the FDA for use in adults and children.

Lorazepam, marketed under the trade name Ativan, has been approved by the FDA only for use in adults. Once the FDA has approved a drug for use in adults, physicians may then prescribe it for other uses and in pediatric patients if, in their best judgment, they believe their patients will benefit.

“Sometimes physicians are forced to rely on their best judgment alone,” said George Giacoia, MD, of the NICHD’s Obstetric and Pediatric Pharmacology and Therapeutics Branch. “However, it’s always better to make treatment decisions on the evidence that comes only from conducting large comparison studies. We now know that lorezapam offers no advantage over diazepam in treating pediatric seizure disorder, and that diazepam is more suited to use by emergency teams.”

In 2007, the National Institutes of Health’s Pediatric Seizure study sought to determine which of two drugs—diazepam or lorazepam—was more effective in treating the life-threatening condition, status epilepticus. This condition can occur without warning. For reasons not fully understood, a child may be gripped by continuous seizures, which, if not stopped within minutes, may lead to brain damage or even death.

Because of the random nature of seizures and their significantly life altering affects, lorezapam is commonly prescribed to treat status epilepticus in children, even though it hasn’t been specifically approved for that use. The results of the Pediatric Seizure study do not support the use of lorezapam instead of diazepam for treating status epilepticus, Dr. Chamberlain said.  Also, because lorezapam needs to be refrigerated and diazepam does not, diazepam is more suited for use by ambulance crews.

A few previous studies indicated that lorazepam might be more effective at ending a seizure and might be less likely than diazepam to depress breathing—a side effect of benzodiazapines, the category of medications that includes both drugs.

In their study, Chamberlain and colleague wrote, “There is no conclusive evidence to support lorazepam as a superior treatment and there is little consensus as to which is the preferred agent.”

The current study was the largest, most comprehensive comparison study of the two treatments for pediatric seizure disorder. Dr. Chamberlain and his colleagues enrolled 310 children at the 11 institutions, between 2008 and 2012. The researchers found that both medications successfully halted seizures in 70 percent of cases, and each had rates of severe respiratory depression of less than 20 percent.

It’s important that “we get the most important scientific information about such medications so there are government approvals for pediatric use,” Chamberlain said. “Pediatric patients are not just small adults.”

(Image: Alamy)

Researchers reveal new cause of epilepsy

A team of researchers from Sanford-Burnham and SUNY Downstate Medical Center has found that deficiencies in hyaluronan, also known as hyaluronic acid or HA, can lead to spontaneous epileptic seizures. HA is a polysaccharide molecule widely distributed throughout connective, epithelial, and neural tissues, including the brain’s extracellular space (ECS). Their findings, published on April 30 in The Journal of Neuroscience, equip scientists with key information that may lead to new therapeutic approaches to epilepsy.

The multicenter study used mice to provide the first evidence of a physiological role for HA in the maintenance of brain ECS volume. It also suggests a potential role in human epilepsy for HA and genes that are involved in hyaluraonan synthesis and degradation.

While epilepsy is one of the most common neurological disorders—affecting approximately 1 percent of the population worldwide—it is one of the least understood. It is characterized by recurrent spontaneous seizures caused by the abnormal firing of neurons. Although epilepsy treatment is available and effective for about 70 percent of cases, a substantial number of patients could benefit from a new therapeutic approach.

“Hyaluronan is widely known as a key structural component of cartilage and important for maintaining healthy cartilage. Curiously, it has been recognized that the adult brain also contains a lot of hyaluronan, but little is known about what hyaluronan does in the brain,” said Yu Yamaguchi, M.D., Ph.D., professor in our Human Genetics Program.

“This is the first study that demonstrates the important role of this unique molecule for normal functioning of the brain, and that its deficiency may be a cause of epileptic disorders. A better understanding of how hyaluronan regulates brain function could lead to new treatment approaches for epilepsy,” Yamaguchi added.

The extracellular matrix of the brain has a unique molecular composition. Earlier studies focused on the role of matrix molecules in cell adhesion and axon pathfinding during neural development. In recent years, increasing attention has been focused on the roles of these molecules in the regulation of physiological functions in the adult brain.

In this study, the investigators examined the role of HA using mutant mice deficient in each of the three hyaluronan synthase genes (Has1, Has2, Has3).

“We showed that Has-mutant mice develop spontaneous epileptic seizures, indicating that HA is functionally involved in the regulation of neuronal excitability. Our study revealed that deficiency of HA results in a reduction in the volume of the brain’s ECS, leading to spontaneous epileptiform activity in hippocampal CA1 pyramidal neurons,” said Sabina Hrabetova, M.D., Ph.D., associate professor in the Department of Cell Biology at SUNY.

“We believe that this study not only addresses one of the longstanding questions concerning the in-vivo role of matrix molecules in the brain, but also has broad appeal to epilepsy research in general,” said Katherine Perkins, Ph.D., associate professor in the Department of Physiology and Pharmacology at SUNY.

“More specifically, it should stimulate researchers in the epilepsy field because our study reveals a novel, non-synaptic mechanism of epileptogenesis. The fact that our research can lead to new anti-epileptic therapies based on the preservation of hyaluronan adds further significance for the broader biomedical community and the public,” the authors added.