News Topics: Treatments

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.

Purified CBD Reduces Seizures in Rare Form of Childhood Epilepsy by Almost 50%, Study Finds

Highly purified cannabidiol (CBD) at a dose of 10mg/kg/day can reduce convulsive seizures in children with Dravet syndrome by almost 50%, a study published in Neurology has found.

Dravet syndrome is a rare, severe form of childhood epilepsy and current medicines are unable to provide complete seizure control.

The study investigated 199 patients with Dravet syndrome who were already taking a median of three anti-epileptic drugs. The patients, who had a mean age of 9 years, were randomized to receive either highly purified CBD at 20mg/kg/day (CBD20), highly purified CBD at 10mg/kg/day (CBD10) or placebo.

The researchers then examined the change in convulsive seizure frequency over a 14-week treatment period by comparing it to the 4 weeks before treatment.

They found that in the group taking CBD20, the number of convulsive seizures was reduced by 46%, while in the CBD10 group the number of seizures was reduced by 49%. In the placebo group, the number of seizures reduced by 27%.

“It’s exciting to be able to offer another alternative for children with this debilitating form of epilepsy, and their families,” said study author Ian Miller, a neurologist at Nicklaus Children’s Hospital in Florida.

“The children in this study had already tried an average of four epilepsy drugs with no success, and [when the study was conducted] were taking an average of three additional drugs, so to have this measure of success with cannabidiol is a major victory.”

Alternative Treatment for Epileptic Seizures in Children Identified

A new study published in The Lancet, involving researchers from the University of Liverpool and Alder Hey Children’s Hospital Trust, has identified a ‘user friendly’ treatment for the most common life-threatening neurological emergency in children.

Convulsive status epilepticus (CSE) is the situation when a tonic-clonic seizure doesn’t stop either on its own or with anticonvulsants. It is the most common life-threatening neurological emergency in children.

Currently, CSE is treated using an algorithm which incorporates 10 min intervals between treatments. Second-line treatment is given when CSE persists either after two doses of the first-line treatment, which is an anticonvulsant called a benzodiazepine, or the child’s personalized emergency (rescue) treatment.

The anticonvulsant medication phenytoin has been used as the usual second-line treatment of CSE for several decades and is known to have rare but potentially dangerous side effects. However, some evidence suggests that another medication, levetiracetam could be an effective and safer alternative. To ascertain which treatment was safest and most effective the EcLiPSE Team, made up of doctors from Alder Hey and Bristol Children’s Hospitals together with research teams from the Universities of Liverpool and the West of England, conducted a trial to compare the efficacy and safety of both drugs for second-line management of CSE.

“Our results suggest that levetiracetam could be considered as an alternative treatment to phenytoin for second-line management of pediatric CSE. Possible benefits of levetiracetam over phenytoin include its ease of preparation and administration, minimal interaction with antiepilepsy and other drugs, and easy conversion to oral maintenance therapy. Further randomised clinical trial and meta-analysis data could help to confirm our results and might lead to levetiracetam being the preferred second-line anticonvulsant in children with benzodiazepine-resistant convulsive status epilepticus.

Lower Hospitalization Rates In Epilepsy Patients Treated With Adjunctive FYCOMPA® (perampanel) CIII

Eisai Inc. presented the latest clinical results on FYCOMPA® (perampanel) CIII, at the 2019 American Academy of Neurology Annual Meeting in Philadelphia, including analyses highlighting the health and economic benefits of FYCOMPA. Twenty-one scientific abstracts were presented by both Eisai and independent investigators, underscoring a collective commitment to advancing research in epilepsy care across the age spectrum.

“At Eisai, we are working to develop solutions, including medications and technology, with the ultimate goal of helping epilepsy patients achieve seizure freedom,” said Lynn Kramer, MD, Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai Inc. “The FYCOMPA data we’ve presented at AAN provides insights that we hope will help improve patient care and shows Eisai’s commitment to continuing research that supports the epilepsy community in this mission.”

Key findings show that:

* Patients treated with perampanel had a significantly greater reduction in all-cause hospitalizations compared to those treated with lacosamide, (25.3% vs 30.3%; p=0.0010; respectively). A similar result was seen for epilepsy-related hospitalizations (a reduction of 19.6% vs. 22.6%; p=0.0376, perampanel and lacosamide, respectively).

* The risk of all-cause inpatient hospitalizations decreased in Medicaid patients with epilepsy who were treated with perampanel for one year (38% pre-perampanel vs 30% post-perampanel; risk ratio of 0.79 [0.69-0.90]). A similar result was seen for epilepsy-related hospitalizations (32% pre-perampanel vs 25% post-perampanel; risk ratio of 0.78 [0.67-0.91]).

* In patients with uncontrolled epilepsy, treatment with a long half-life AED was associated with a significantly lower risk of hospitalization than those treated with a short half-life AED (in both unadjusted [0.81, 95% CI: 0.73, 0.89; p<0.001] and adjusted relative risk of hospitalization [0.84, 95% CI: 0.76, 0.93; p=0.0007]).

Rates of Adherence to Antiepileptic Drug Monotherapy for Focal Seizure

Patients receiving eslicarbazepine acetate (ESL) monotherapy may have similar-to-higher rates of adherence compared with patients receiving generic carbamazepine (CBZ) and oxcarbazepine (OXC), according to research presented at the 2019 American Academy of Neurology’s Annual Meeting, held May 4-10, in Philadelphia.

This retrospective cohort study examined rates of adherence to antiepileptic drug (AED) monotherapy treatment for patients with focal seizures by comparing ESL with generic CBZ and OXC. Investigators analyzed patient-level administrative claims data from the Quintiles IMS PharMetrics Database. These drugs have varied side effect profiles, and prior research has suggested that the differences in adverse effects across AEDs are likely associated with treatment adherence differences. Prior research suggests nonadherence to AEDs is associated with adverse outcomes.

Breakthrough for Children with Serious Epileptic Seizures

Emergency medicine doctors now have a better way to treat severe epileptic seizures in children, thanks to a New Zealand-Australian study.

Prolonged epileptic seizures are the most common neurological emergency in children seen by hospitals. The seizures are potentially fatal: up to five percent of affected children die, and a third suffer long-term complications from brain damage. Crucially, the longer the seizure, the greater the chance of long-term complications.

The study – which will change management of this condition internationally – was published in the prestigious medical journal The Lancet. It was led by Professor Stuart Dalziel from the Faculty of Medical and Health Sciences at the University of Auckland and Starship Children’s Hospital, and the senior author was Professor Franz Babl at Melbourne’s Murdoch Children’s Research Institute.

Diazepam Nasal Spray Safe to Treat Frequent Breakthrough Seizures in Epilepsy

Diazepam nasal spray is safe and well tolerated in patients with epilepsy who experience frequent breakthrough or acute repetitive seizures, according to research presented at the 2019 American Academy of Neurology Annual Meeting, held May 4-10, 2019, in Philadelphia, Pennsylvania.

In this interim analysis, investigators assessed the long-term safety of diazepam after repeat doses administered to patients with epilepsy who experienced frequent breakthrough seizures or acute repetitive seizures over 12 months. Doses (5 mg, 10 mg, 15 mg, or 20 mg) were based on age and body weight and were modified as needed; participants documented time and duration of seizures in patient diaries, along with any outcome events.

The safety population included 109 patients who received at least 1 dose of diazepam. A total of 1585 seizure episodes were treated with diazepam over the study period. In 1457 (92%) episodes, a single dose of diazepam was adequate to stop the seizure.

Study Reveals How Glial Cells May Play Key Epilepsy Role

A study provides potential new targets for treating epilepsy and novel fundamental insights into the relationship between neurons and their glial “helper” cells. In eLife, scientists at MIT’s Picower Institute for Learning and Memory report 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.

About 60 million people worldwide have epilepsy, a neurological condition characterized by seizures resulting from excessive neural activity. The “zydeco” model flies in the study experience seizures in a similar fashion. Since discovering zydeco, the lab of MIT neurobiologist Troy Littleton, Menicon Professor in Neuroscience, has been investigating why the flies’ zydeco mutation makes it a powerful model of epilepsy.

Heading into the study, the team led by postdoc Shirley Weiss knew that the zydeco mutation was specifically expressed by cortex glial cells and that the protein it makes helps to pump calcium ions out of the cells. But that didn’t explain much about why a glial cell’s difficulty maintaining a natural ebb and flow of calcium ions would lead adjacent neurons to become too active under seizure-inducing stresses such as fever-grade temperatures or the fly being jostled around.

The activity of neurons rises and falls based on the flow of ions – for a neuron to “fire,” for instance, it takes in sodium ions, and then to calm back down it releases potassium ions. But the ability of neurons to do that depends on there being a conducive balance of ions outside the cell. For instance, too much potassium outside makes it harder to get rid of potassium and calm down.

The need for an ion balance – and the way it is upset by the zydeco mutation – turned out to be the key to the new study. In a four-year series of experiments, Weiss, Littleton and their co-authors found that excess calcium in cortex glia cells causes them to hyper-activate a molecular pathway that leads them to withdraw many of the potassium channels that they typically deploy to remove potassium from around neurons. With too much potassium left around, neurons can’t calm down when they are excited, and seizures ensue.

“No one has really shown how calcium signaling in glia could directly communicate with this more classical role of glial cells in potassium buffering,” Littleton said. “So this is a really important discovery linking an observation that’s been found in glia for a long time – these calcium oscillations that no one really understood – to a real biological function in glial cells where it’s contributing to their ability to regulate ionic balance around neurons.”

Paving the Way for Innovative Treatment of Epilepsy

A drug commonly used to treat multiple sclerosis may, after necessary modifications, one day be used to treat patients with epilepsy, researchers in Prof. Inna Slutsky’s lab at the Sackler Faculty of Medicine and Sagol School of Neuroscience at Tel Aviv University have discovered.

This is good news for patients with Dravet syndrome, one of the most dangerous forms of childhood epilepsy, for which there is currently no effective treatment.

According to a new study published on April 29 in Neuron, Tel Aviv University researchers uncovered a piece of a puzzle that has eluded scientists for 100 years of studying homeostasis: What is the mechanism that maintains activity set points in neural circuits?

While it is well-understood that the brain functions in a narrow range of activity between status epilepticus and coma, how neural circuits maintain stable activity in a constantly changing environment has remained unknown.

“The concept of homeostasis has a long history in physiology, starting from the work of Claude Bernard in the middle of 19th century on the stability of the milieu interior. In the middle of 20th century, James Hardy proposed a model in which homeostatic mechanisms maintain physiological variables with an acceptable range around a ‘set point’ value. However, the research of neuronal homeostasis began only 25 years ago, and we still don’t understand how it works,” explains Prof. Slutsky. “What we have found is a homeostatic mechanism that acts as a sort of a thermostat of the neural circuits, which ensures the return to a set point after each event that increases or decreases brain activity.

“Our findings may serve as a basis for the development of drugs for a range of neurological and neurodegenerative diseases such as Alzheimer’s and Parkinson’s, which, like epilepsy, are characterized by instability of brain activity.”

Study Shows Vagus Nerve Stimulation Has a Beneficial Effect on Symptoms of Depression in Patients with Difficult-To-Treat Epilepsy

PURPOSE: Vagus nerve stimulation (VNS) is well established in the treatment of epilepsy and disorders of depression. The prevalence of depression is high in patients with epilepsy, but still it remains unclear how patients with a comorbidity of epilepsy and symptoms of depression respond to VNS.

METHODS: Researchers investigated 59 patients with different subtypes of disorders of depression as a comorbidity of epilepsy, who underwent VNS-surgery. Before and one year after VNS surgery, the severity of symptoms of depression was evaluated by a psychiatrist using Montgomery-Åsberg Depression Rating Scale (MADRS) and Beck-Depressions-Inventory (BDI). Response towards epilepsy was measured by a seizure reduction of at least 50%.

RESULTS: Symptoms of depression ameliorated in response to VNS in the overall of all patients MADRS 29 to 18 (p < 0,001) and BDI 24 to 14 (p < 0,001) and all subtypes of disorders of depression. Seizure reduction of at least 50% was achieved in two out of three of all patients two years after VNS.

CONCLUSION: This study was able to show the beneficial effect of vagus nerve stimulation in the treatment of patients with pharmacoresistant epilepsy and a comorbidity of symptoms of depression.