What’s the Right Amount of ‘Zapping’ in Epilepsy Laser Surgery?

In the largest study of its kind to date, researchers across 11 centers analyzed data on a relatively new minimally invasive alternative surgery for epilepsy, and discovered changes that could make the procedure more effective in both laser ablation and standard surgery.

“The field hasn’t had a unified approach to laser ablation surgery for epilepsy,” says corresponding author, neurosurgeon Chengyuan Wu, MD, Associate Professor in the Department of Neurological Surgery at Jefferson (Philadelphia University + Thomas Jefferson University) and the Vickie & Jack Farber Institute for Neuroscience – Jefferson Health. “With this study, we were able to answer the question: ‘How much ablation is enough, how much is too much, and exactly where should we be targeting?'”

The researchers, including co-first authors from the University of Miami, Jackson Memorial Hospital and Vanderbilt University analyzed the charts and images of 234 patients who underwent laser ablation therapy for epilepsy in 11 centers across the United States. During the procedure, a small laser catheter is placed under MRI-guidance in the part of the brain felt to be responsible for the patient’s epilepsy. Surgeons then deliver precise pulses of laser ablation to that particular region until the tissue is eliminated, in order to prevent further seizure. “The procedure has effects similar to open-brain surgery, which removes part of the brain,” says Dr. Wu. “But there’s significantly less trauma to the surrounding brain tissue with this approach.”

Review: New Anti-Seizure Medication for Elderly Patients with Epilepsy

Introduction: Epilepsy treatment in older people requires specific consideration owing to more physical co-morbidities, the risk of drug-to-drug interactions through polypharmacy, and differences in pharmacodynamics and pharmacokinetics. There are many ‘newer’ antiepileptic drugs (AEDs) widely used for various seizure types and seizure disorders. However, there is limited specific evidence for the efficacy, safety, and tolerability of these treatments in the elderly population.

Areas covered: This review summarizes the current and most robust evidence available for the use of the newer AEDs belonging to generation two and three in elderly people with epilepsy. The article provides practical evidenced based clinical information to help prescribers choose the most appropriate AED from the drugs discussed.

Expert opinion: Diagnosing new onset epilepsy in the elderly population requires specialist assessment. Treatment plans need to be tailored to accommodate an individual’s co-morbidities, concurrent medications, and general health status. To date, few clinical investigations consider the elderly population specifically despite the increased risk factors. There is a need for large quality trial data to assess the impact of the newest AEDs on seizure control and quality of life in this population with complex needs.

UCB announces NAYZILAM® (midazolam) nasal spray now approved by FDA to treat intermittent, stereotypic episodes of frequent seizure activity in people living with epilepsy

UCB announces NAYZILAM® (midazolam) nasal spray now approved by FDA to treat intermittent, stereotypic episodes of frequent seizure activity in people living with epilepsy in the US.

  • NAYZILAM® (midazolam) nasal spray CIV is a nasally administered benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 12 years of age and older.
  • NAYZILAM allows for administration by a non-healthcare professional in patients actively seizing when and where a seizure cluster occurs.
  • Approval of NAYZILAM adds to UCB’s already existing anti-epilepsy drug portfolio, reinforcing the company’s position as a global leader in epilepsy.

UCB announced the FDA has approved a New Drug Application for the company’s newest anti-epileptic drug (AED) NAYZILAM® (midazolam) nasal spray CIV, a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of  frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 12 years of age and older. NAYZILAM now provides patients and caregivers with the first and only FDA-approved nasal option for treating seizure clusters.

It is estimated that more than 150,000 people in the US with uncontrolled epilepsy also experience seizure clusters.1 Rescue treatment of seizure clusters is critical because when left untreated, seizure clusters can increase the risk of physical injury, neurological damage, prolonged seizures, and status epilepticus.2 Despite the impact of seizure clusters, many diagnosed patients may go untreated because currently available treatment options are not preferred.3, 4, 5, 6 

NAYZILAM is a short-term treatment for seizure clusters in patients with epilepsy. The nasal spray is designed as a single-use treatment that can be carried with a patient. NAYZILAM allows for administration by a non-healthcare professional in patients actively seizing when and where a seizure cluster occurs. NAYZILAM can provide value to patients who are experiencing these disruptive seizures.

1 Chen B, Choi H, Hirsch L, Katz A, Legge L, Wong R, Jiang A, Kato K, Buchsbaum R, Detyniecki K. Prevalence and risk factors of seizure clusters in adult patients with epilepsy. Epilepsy Research. 2017;133: 98-102.
2 Penovich PE, Buelow J, Steinberg K, Sirven J, Wheless J. Burden of seizure clusters on patients with epilepsy and caregivers: survey of patient, caregiver, and clinician perspectives. Neurologist. 2017;22(6):207-214.
3 Nunley S, Glynn P, Rust S, Vidaurre J, Albert DVF, Patel AD. A hospital-based study on caregiver preferences on acute seizure rescue medications in pediatric patients with epilepsy: intranasal midazolam versus rectal diazepam. Epilepsy Behav. 2019;92:53-56.
4 Holsti M, Dudley N, Schunk J, et al. Intranasal midazolam vs rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy. Arch Pediatr Adolesc Med. 2010;164(8):747-753.
5 de Haan GJ, van der Geest P, Doelman G, Bertram E, Edelbroek P. A comparison of midazolam nasal spray and diazepam rectal solution for the residential treatment of seizure exacerbations. Epilepsia. 2010;51(3):478-482
6 Bhattacharyya M, Kalra V, Gulati S. Intranasal midazolam vs rectal diazepam in acute childhood seizures. Pediatr Neurol. 2006;34(5):355-359.

New Drug Could Help Treat Neonatal Seizures

A new drug that inhibits neonatal seizures in rodent models could open up new avenues for the treatment of epilepsy in human newborns. Researchers have identified that gluconate—a small organic compound found in fruit and honey—acts as an anticonvulsant, inhibiting seizures by targeting the activity of channels that control the flow of chloride ions in and out of neonatal neurons. A paper describing the research, from an international team of scientists led by Penn State researchers, appears May 15, 2019 in the journal Molecular Brain.

“Neonates are the most vulnerable population to seizures but there is still no effective medication for the treatment of neonatal epilepsy,” said Gong Chen, professor of biology and the Verne M. Willaman Chair in Life Sciences at Penn State and the leader of the research team. “The incidence of epilepsy is highest in the first year of life, with two to four infant babies suffering from neonatal epilepsy for every 1,000 live births in the United States. Unfortunately, so far there is no effective drug available that is specifically developed for neonatal epilepsy patients.”

Brain Network Activity Can Improve in Epilepsy Patients After Surgery

Successful epilepsy surgery can improve brain connectivity similar to patterns seen in people without epilepsy, according to a new study published in the journal Neurosurgery.

The Vanderbilt University Medical Center (VUMC) study of 15 people with temporal lobe epilepsy is the first to show improvements in brain networks after surgery compared to a group of healthy subjects.

Brain networks involved in the study are important for keeping the brain awake and alert, according to senior author Dario Englot, MD, PhD, surgical director of VUMC’s Epilepsy Program.

“It’s important to realize that, over time, seizures lead to brain network problems which may be related to cognitive deficits seen in patients with epilepsy,” said Englot. “Our new results show some brain network activity can improve with surgery if you stop the seizures.”

Widespread Off-Label Use of Epilepsy Medications Could Put Some Patients at Risk

The off-label pervasive use of a type of anticonvulsant originally marketed to treat epilepsy – called gabapentinoids – could place some patients at risk, according to a new study led by a team at the McGill University Health Centre (MUHC) and published on May 10th in the Journal of Hospital Medicine. These findings could have important clinical implications, as gabapentinoids, initially intended to treat epilepsy, are now commonly prescribed as a pain killer to the general population, including to elderly patients with multiple conditions. The study found that one in eight adults admitted to a hospital in Quebec had been prescribed the drug as part of their usual home medications.

“In certain cases, some patients may derive benefit from the off-label use of gabapentinoids, but the public also needs to know about their possible harms. This class of medications is becoming increasingly common, despite very little evidence that it helps with pain, and despite evidence that the medications increase the risk of falls, fractures and memory impairment,” says senior author Dr. Emily G. McDonald, a physician in General Internal Medicine at the MUHC and an assistant professor of Medicine at McGill University, as well as a scientist at the Research Institute of the McGill University Health Centre (RI-MUHC).

Brivaracetam Not Associated with an Increase in Anger Levels in People with Focal or Generalized: A Prospective Open-Labelled Controlled Study

PURPOSE: The rate of brivaracetam-related behavioral adverse events is a current focus of discussion. This study aims to assess the effect of brivaracetam on anger levels in patients with epilepsy, adjusted by mood symptoms, history of psychiatric disorders, and seizure response.

METHOD: Prospective analysis of 37 patients assessed for anger levels (STAXI-2), depression-anxiety (HADS) and quality of life (QOLIE-10) before adjunctive brivaracetam treatment and reassessed 3-6 months later. A control group following the same protocol of assessment was used for 1:1 comparison. A high percentage of mood stabilizers were included in this control group.

RESULTS: Brivaracetam was indicated for patients including focal onset (79%) and generalized epilepsy (21%). Nearly 60% of responders and no psychiatric adverse events were found. This was similar to controls. The overall results revealed that brivaracetam was associated with better in anger levels, mood scores and quality of life at baseline. Prior use of levetiracetam or the presence of a psychiatric background did not influence the results. However, improvements in anger levels were seen in the brivaracetam responders.

CONCLUSION: This study shows that brivaracetam is not associated with an increased level of anger in patients with either focal or generalized epilepsy in the absence of psychiatric comorbidity. However, an improvement in anger levels is possibly influenced by a good seizure response.

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.