Epilepsy Research News: September 2020

In this month’s research news, we highlight studies suggesting that unprovoked seizure onset in US veteranspsychogenic nonepileptic seizure (PNES), and socioeconomic status can have severe impacts on people with epilepsy. We also feature a study that states antiepileptic drugs (AEDs) do not increase the risk of a fetus developing genetic mutations. Finally, we report on a non-invasive treatment for severe pediatric, treatment resistant seizures.

Summaries of these research studies are presented below.

Research Discoveries

  • Seizure Onset and Dementia: US military veterans over the age of 73 who developed unprovoked seizures of unknown cause were twice as likely to develop dementia compared to veterans without seizures. Veterans who developed these seizures were more likely to be younger, black, have lower income, and a higher prevalence of co-existing illnesses. Learn more
  • PNES Misdiagnoses and Death: Almost 25% of people who are admitted to a hospital for uncontrolled seizures actually do not have epilepsy. Instead, they have psychogenic nonepileptic seizures (PNES), which resemble epileptic seizures but have a psychological cause rather than a neurological one. Researchers found that patients with PNES are 2.5 times more likely to die compared to people of their same age, and this risk is even greater for people under 30 years of age. Learn more
  • SUDEP and Socioeconomic Status: Lower socioeconomic status is associated with higher rates of Sudden Unexpected Death in Epilepsy (SUDEP), according to a review of medical records from three geographically diverse areas in the US. People with epilepsy living in the poorest communities were found to be more than twice as likely to suffer from SUDEP than those living in more affluent areas. Learn more
  • Differing Interpretations of Genetic Data: Different genetic testing laboratories may show conflicting interpretations of genetic data. Because genomic testing has become routine in the diagnosis, management, and treatment of pediatric epilepsy, consistency in data interpretation is important. Learn more
  • Antiepileptic Drugs and Birth Defects: A small study found that antiepileptic drugs (AEDs) taken during pregnancy do not increase the risk of a fetus’ developing new genetic mutations, i.e., those that arise in the sperm, egg, or fertilized egg rather than being inherited from one or both of  parents. Learn more
  • Body Cooling and Refractory Seizures: A treatment that lowers the body’s temperature called “therapeutic hypothermia” can shorten long-lasting seizures and improve outcomes in children with severe and treatment-resistant forms of epilepsy. Learn more

Body Cooling May Shorten Refractory Seizures in Dravet and Other Epilepsies

Used in addition to standard treatments, therapeutic hypothermia — based on lowering the body’s temperature — can shorten the duration of long-lasting seizures in drug-resistant forms of epilepsy, including Dravet syndrome, a study finds.

The study, “Therapeutic hypothermia for pediatric refractory status epilepticus May Ameliorate post-status epilepticus epilepsy,” was published in the Biomedical Journal. Dravet syndrome is a severe type of epilepsy that usually manifests early on in life. It is characterized by convulsive seizures that typically fail to respond to treatment with anti-epileptic drugs (AEDs). Refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE) are two of the most severe types of drug-resistant convulsive seizures. RSE seizures are those lasting more than one hour despite treatment with first- and second-line AEDs, while SRSE seizures last or return over a period of more than 24 hours after the patient is placed under general anesthesia.

Both RSE and SRSE seizures are normally managed with anesthetic agents like propofol, midazolam, barbiturate, or ketamine. “Unfortunately, these medications only achieve [a therapeutic] effect in 64–78% of patients. Thus, alternative therapeutic approaches with better efficacies are needed for patients with RSE/SRSE,” the researchers wrote.

Therapeutic hypothermia (TH), a form of therapy used to prevent organ and neuronal damage, has previously been used as a complementary treatment for RSE seizures. However, studies assessing TH’s effectiveness in controlling seizures have had variable results, particularly those concerning children.

A team of researchers in Taiwan carried out a retrospective study to compare clinical outcomes between a group of children experiencing RSE/SRSE seizures and given TH therapy with a group who were not. They reviewed the medical records of 23 children with RSE/SRSE seizures who were admitted to the pediatric intensive care unit (PICU) of the Taoyuan Chang Gung Children’s hospital and Kaohsiung Chang Gung Memorial Hospital between January 2014 and December 2017. Of the 23 children included in the study, 11 received TH in combination with anticonvulsants to control seizures, and 12 received anticonvulsants only (control group). TH was applied using Medivance’s Artic Sun temperature management system with Artic Gel pads that were placed over the patients’ skin. Treatment was applied for 48 to 72 hours, until patients’ body temperature dropped to 34–35 C (93–95 F). Investigators assessed and compared the duration of RSE/SRSE seizures, the time patients remained in the pediatric intensive care unit, and scores of the Glasgow Outcome Scale (GOS; a measure of neurological impairment) in both patient groups.

Of the 11 children who received TH in combination with anticonvulsants, seven had febrile infection-related epilepsy syndrome (FIRES), one had Dravet syndrome, and three a traumatic brain injury. More than half (58.13%) of the children in the control group had also been diagnosed with FIRES. Children given therapeutic hypothermia as an add-on therapy had shorter seizures compared to those who only received anticonvulsants (a median of 24 hours vs. 96 hours). Moreover, children in the TH group had higher GOS scores compared with those in the control group (a median of 4 vs. 3), indicative of milder neurological impairments and better long-term clinical outcomes. Later chronic refractory epilepsy was reported in less than half (45%) of the TH group children, whereas all in the control group developed this form of epilepsy after one year of follow-up. Duration of stay in a pediatric intensive care unit was similar in both groups.

The child with Dravet, an 8-year-old boy, developed “refractory SE [status epilepticus] due to an influenza infection,” with poor response to AEDs because of a persistent high fever. “We applied TH along with continuous midazolam infusions. … The patient recovered well after rewarming, without cognition or motor function deteriorations,” the researchers wrote.

“Collectively, our findings support that TH effectively shortens the seizure duration in pediatric patients with RSE/SRSE,” they concluded. Apart from electrolyte imbalances, which were manageable, therapeutic hypothermia was found to be “safe for use in pediatric patients with RSE/SRSE.” (Electrolytes are minerals in the blood and other body fluids, such as calcium, magnesium or phosphate, that carry an electric charge and are necessary for muscle function, blood acidity, and other key processes.)

“Our study provides evidence that shortened seizure durations in the acute symptomatic phase of SE can reduce the occurrence of post-status epilepticus epilepsy and improve patients’ long-term functional outcomes,” the researchers added.

Epilepsy Research News: August 2020

This month’s research news includes two new approaches for developing epilepsy treatments. One is a new antiseizure drug target and the other creates a completely novel type of antiseizure drug based on a vitamin.

Recent studies also broadened our understanding of developmental outcomes in people with epilepsy and possible causes of intellectual delays in some individuals. A research team demonstrated that there is no difference in the developmental or behavioral outcomes of children who have febrile seizures following vaccination compared to children who do not have these seizures. In addition, data from another study shows that two specific genetic mutations which cause the development of epilepsy, as well as intellectual disability affect the same brain protein in the same way.

In addition, research suggests that many people with epilepsy living in rural areas of China could become seizure-free with expanded access to routine neurosurgery. Finally, in the US the FDA has approved Epidiolex® (cannabidiol) oral solution for the treatment of seizures associated with tuberous sclerosis complex (TSC) in patients age 1 and older. Patients and their families can read the full FDA statement here.

Summaries of these research discoveries and news highlights are below.

Research Discoveries

  • Novel Target for Antiseizure Drugs: An international study, featuring the work of former CURE grantee Dr. David Henshall, discovered that a small set of molecules called microRNAs, which control gene activity in the brain, are elevated in epilepsy. The team created inhibitors of these microRNAs, and when three of these inhibitors were combined, they were found to stop seizures in laboratory tests. Learn more
  • Novel Antiseizure Drug: Researchers report that a novel vitamin K-based therapy has proved effective in reducing seizures in mouse models of medication-resistant seizures. Learn more
  • Vaccination and Seizures: A study demonstrated that there is no difference in developmental and behavioral outcomes for children who have febrile seizures after vaccination, children who have febrile seizures not associated with vaccination, and children who have never had a seizure. Learn more
  • Intellectual Disability and Epilepsy: Two mutations identified in people with developmental and epileptic brain disease can be traced back to the same brain protein known as TRPM3, which is responsible for sensing heat and pain. Researchers have determined how both mutations independently make the protein overly active and extremely sensitive to stimulation, taking the first step towards unraveling what causes the symptoms in patients with these mutations. Learn more
  • Neurosurgery in China: A study researching the causes and outcomes of epilepsy in people who live in rural China found that at least one million individuals could be candidates for a surgical procedure that may leave them seizure-free. Learn more
  • New Therapy for Tuberous Sclerosis Complex (TSC): The FDA recently approved Epidiolex® (cannabidiol) oral solution for the treatment of seizures associated with TSC in patients 1 year of age and older. Epidiolex had previously been approved for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. Learn more

Join leading epilepsy experts as they discuss the current research landscape during Unite to CURE EpilepsyThis live streamed evening showcasing tenacity, discovery, and hope will also feature inspirational stories from the CURE community and special performers, including Eric Church.

FDA Approves Epidiolex® (cannabidiol) for Treatment of Another Severe Epilepsy Syndrome

FDA statement, originally published on FDA.gov

The FDA approved Epidiolex (cannabidiol) [CBD] oral solution for the treatment of seizures associated with tuberous sclerosis complex (TSC) in patients one year of age and older. Epidiolex was previously approved for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS). This is the only FDA-approved drug that contains a purified drug substance derived from cannabis. It is also the second FDA approval of a drug for the treatment of seizures associated with TSC.

CBD is a chemical component of the Cannabis sativa plant. However, CBD does not cause intoxication or euphoria (the “high”) that comes from tetrahydrocannabinol (THC). It is THC (and not CBD) that is the primary psychoactive component of cannabis.

“The FDA continues to believe the drug approval process represents the best way to make new medicines, including any drugs derived from cannabis, available to patients in need of appropriate medical therapy such as the treatment of seizures associated with these rare conditions. This paradigm ensures new therapies are safe, effective, and manufactured to a high quality that provides uniform and reliable dosing for patients,” said Douglas Throckmorton, M.D., deputy center director for regulatory programs in the FDA’s Center for Drug Evaluation and Research. “The agency is committed to supporting rigorous scientific research on the potential medical uses of cannabis-derived products and working with product developers who are interested in bringing patients safe and effective, high quality products.”

TSC is a rare genetic disease that causes non-cancerous (benign) tumors to grow in the brain and other parts of the body like the eyes, heart, kidneys, lungs, and skin. TSC usually affects the central nervous system and can result in a combination of symptoms including seizures, developmental delay, and behavioral problems, although the signs and symptoms of the condition, as well as the severity of symptoms, vary widely. TSC affects about 1 in 6,000 people.

Epidiolex’s effectiveness for the treatment of seizures associated with TSC was established in a randomized, double-blind, placebo-controlled trial where 148 patients out of a total of 224 in the study received Epidiolex. The study measured the change from baseline in seizure frequency. In the study, patients treated with Epidiolex had a significantly greater reduction in the frequency of seizures during the treatment period than patients who received placebo (inactive treatment). This effect was seen within eight weeks and remained consistent throughout the 16-week treatment period.

The most common side effects that occurred in Epidiolex-treated patients with TSC in the clinical trial were: diarrhea, elevated liver enzymes, decreased appetite, sleepiness, fever, and vomiting. Additional side effects for patients with LGS, DS, or TSC include: liver injury, decreased weight, anemia, and increased creatinine.

Epidiolex must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. As is true for all drugs that currently treat epilepsy, including Epidiolex, the most serious risks may include an increase in suicidal thoughts and behavior, or thoughts of self-harm. Patients, their caregivers, and their families should be advised to monitor for any unusual changes in mood or behavior, such as worsening depression, suicidal thoughts or behavior. Patients, caregivers, and families should report behaviors of concern immediately to healthcare providers. Epidiolex also caused liver injury in some patients. Most cases were generally mild, but a risk of rare, but more severe liver injury exists. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, and/or dark urine.

The FDA granted Priority Review designation for this application. The approval of Epidiolex was granted to Greenwich Biosciences Inc., of Carlsbad, California.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Do Interictal EEG Findings Reflect Cognitive Function in Juvenile Myoclonic Epilepsy?

Abstract, published in Epilepsy & Behavior

Purpose: This study investigated the relationship between frontal lobe cognitive function and frontal focal electroencephalography (EEG) findings in patients with juvenile myoclonic epilepsy (JME).

Methods: The study enrolled 60 patients diagnosed with JME and followed at the Epilepsy Outpatient Clinic of the University of Health Sciences, Bak?rkoy Psychiatric Hospital, and 30 healthy volunteers. Demographic and clinical features were recorded. Frontal lobe cognitive functions were tested in both groups. Video-EEG recordings of patients with JME were evaluated. The presence and duration of generalized discharges, the presence and lateralization of focal findings, and the presence of generalized discharges during hyperventilation and photic stimulation were recorded during EEG. Cognitive function test results were compared between the two groups, and the relationship between the EEG findings and cognitive function was investigated.

Results: The study included 35 (58.3%) female and 25 (41.6%) male patients and 17 (56.7%) female and 13 (43.3%) male healthy controls. The mean ages of the group with JME and controls were 28.3 ± 8.6 (16-50) and 31.3 ± 7.9 (17-45) years, respectively. Patients with JME performed more poorly on the frontal lobe cognitive tests than controls (p < 0.05). Patients whose generalized discharges were longer than 1 s performed more poorly on tests evaluating attention and made more perseverative errors (p < 0.05). There was no significant correlation between the presence of focal EEG findings and the scores on frontal lobe cognitive functions tests in the group with JME (p > 0.05).

Conclusion: Frontal lobe cognitive functions are affected in patients with juvenile myoclonic epilepsy. The cognitive effects were more pronounced in patients with prolonged generalized discharges on EEG.

FDA Approves New Therapy for Dravet Syndrome

FDA Press Release

On June 25, 2020, the U.S. Food and Drug Administration approved Fintepla® (fenfluramine) for the treatment of seizures associated with Dravet syndrome in patients age 2 and older.

“Dravet syndrome is a debilitating disease that takes a tremendous toll on both patients and their families,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Fintepla offers an additional effective treatment option for the treatment of seizures associated with Dravet syndrome. The FDA will continue to work with companies on drug development for Dravet syndrome and other types of epilepsy.”

The effectiveness of Fintepla for the treatment of seizures associated with Dravet syndrome was demonstrated in two clinical studies in 202 subjects between ages 2 and 18. The studies measured the change from baseline in the frequency of convulsive seizures. In both studies, subjects treated with Fintepla had significantly greater reductions in the frequency of convulsive seizures during the trials than subjects who received placebo (inactive treatment). These reductions were seen within 3-4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.

Fintepla labeling includes a boxed warning stating the drug is associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH). Because of these risks, patients must have cardiac monitoring using echocardiograms performed before treatment, every six months during treatment, and once three to six months after treatment is discontinued. If the echocardiogram shows signs of VHD, PAH, or other cardiac abnormalities, health care professionals must consider the benefits and risks of continuing treatment with Fintepla for the patient.

Because of the risks of VHD and PAH, Fintepla is available only through a restricted drug distribution program, under a risk evaluation and mitigation strategy (REMS). The Fintepla REMS requires health care professionals who prescribe Fintepla and pharmacies that dispense Fintepla to be specially certified in the Fintepla REMS and that patients be enrolled in the REMS. As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive Fintepla.

The most common adverse reactions in clinical studies were decreased appetite; drowsiness, sedation and lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue or lack of energy; ataxia (lack of coordination), balance disorder, gait disturbance (trouble with walking); increased blood pressure; drooling, salivary hypersecretion (saliva overproduction); pyrexia (fever); upper respiratory tract infection; vomiting; decreased weight; risk of falls; and status epilepticus.

The FDA granted this application Priority Review. Fintepla received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Fintepla to Zogenix, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Body Cooling May Shorten Refractory Seizures in Dravet and Other Epilepsies

Summary

A study published in the Biomedical Journal shows that therapeutic hypothermia — based on lowering the body’s temperature — can shorten the duration of long-lasting seizures in drug-resistant forms of epilepsy, including Dravet syndrome.

Refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE) are two of the most severe types of drug-resistant convulsive seizures. RSE seizures are those lasting more than one hour despite treatment with first- and second-line AEDs, while SRSE seizures last or return over a period of more than 24 hours after the patient is placed under general anesthesia. Both RSE and SRSE seizures are normally managed with anesthetic agents like propofol, midazolam, barbiturate, or ketamine, but these medications achieve a therapeutic effect in only 64–78% of patients. Thus, alternative therapeutic approaches with better efficacies are needed for patients with RSE/SRSE,” the researchers wrote.

Therapeutic hypothermia (TH), a form of therapy used to prevent organ and neuronal damage, has previously been used as a complementary treatment for RSE seizures.

However, studies assessing TH’s effectiveness in controlling seizures have had variable results, particularly those concerning children. Thus, a team of researchers in Taiwan carried out a retrospective study to compare clinical outcomes between a group of children experiencing RSE/SRSE seizures and given TH therapy with a group who were not.

Children given therapeutic hypothermia as an add-on therapy had shorter seizures compared to those who only received anticonvulsants (an average of 24 hours vs. 96 hours). Moreover, children in the TH group had milder neurological impairments compared with those in the control group, indicative of better long-term clinical outcomes. Later chronic refractory epilepsy was reported in less than half (45%) of the TH group children, whereas all in the control group developed this form of epilepsy after one year of follow-up. Duration of stay in a pediatric intensive care unit was similar in both groups.

According to the researchers, therapeutic hypothermia was found to be “safe for use in pediatric patients with RSE/SRSE.” This study shows that “shortened seizure durations in the acute symptomatic phase of SE can reduce the occurrence of post-status epilepticus epilepsy and improve patients’ long-term functional outcomes.”

Importance of Prompt Diagnosis in Pediatric Epilepsy Outcomes

Abstract

Purpose: Recognition of childhood epilepsy has improved worldwide, and children with epilepsy require immediate healthcare evaluation and monitoring. The interval between the onset of the first seizures and pediatric neurology assessment may influence the epilepsy outcome at follow-up assessments. This study aimed to assess the quality of medical care for children with first seizure onset and determine the impact of pediatric neurology clinic waiting times on epilepsy outcomes.

Methods: This was a retrospective cohort study based on chart reviews and included patients who underwent their first seizure evaluation at the Royal University Hospital in Saskatoon, Canada between January 1, 2012 and December 31, 2015. Waiting time (the time interval between seizure onset and the first clinical assessment) and baseline factors were examined in relation to epilepsy outcome on follow-up.

Results: Of a total 1157 patients evaluated for epilepsy for the period 2012-2015, 197 patients (~17%) had unprovoked seizures and were eligible for this study. The average age of the patients at seizure onset was 5.6 years, with average waiting and follow-up times of 4.33 months and 20.9 months, respectively. Shorter waiting times in the clinic led to a more favorable seizure outcome. Of the 197 assessed at the last seizure assessment, 132 (67%) patients had a favorable epilepsy outcome with no seizures at follow-up appointments and 65 (33%) showed an unfavorable epilepsy outcome with persistent seizures at follow-up appointments.

Conclusion: Early assessment of first seizure onset is crucial for the management of children with epilepsy. Waiting time and other factors may influence epilepsy outcome and thus represent opportunities to improve standard medical care.

Doctor sits with little boy in the hospital bed, showing him information on a tablet.

Importance of Prompt Diagnosis in Pediatric Epilepsy Outcomes

Abstract, published in Seizure

Purpose: Recognition of childhood epilepsy has improved worldwide. Children with epilepsy require immediate healthcare evaluation and monitoring. The interval between the onset of the first seizures and pediatric neurology assessment may influence the epilepsy outcome at follow-up assessments. This study aimed to assess the quality of medical care for children with first seizure onset and determine the impact of pediatric neurology clinic waiting times on epilepsy outcomes.

Results: Of a total 1157 patients evaluated for epilepsy for the period 2012-2015, 197 patients had unprovoked seizures and were eligible for this study. The average age of the patients at seizure onset was 5.6 years, the average waiting time was 4.33 months, and the average follow-up time was 20.9 months. Shorter waiting times in the clinic led to a more favorable seizure outcome. Of the 197 assessed at the last seizure assessment, 132 (67 %) patients had a favorable epilepsy outcome with no seizures at follow-up appointments and 65 (33 %) showed an unfavorable epilepsy outcome with persistent seizures at follow-up appointments.

Conclusion: Early assessment of first seizure onset is crucial for the management of children with epilepsy. Waiting time and other factors may influence epilepsy outcome and represent opportunities to improve standard medical care.

Autism and Seizures May Share Roots in Development

Early behavioral signs predict seizures in autistic children, according to a new study.

Previous work has shown that 5 to 46 percent of people with autism experience seizures. And autistic adults with epilepsy have, on average, less cognitive ability and weaker daily living skills than their autistic peers who do not have seizures.

The new study shows that people with autism who begin having seizures during childhood show small but significant behavioral differences before they ever experience a seizure, compared with those who do not develop epilepsy. They score lower than their peers on measures of quality of life and adaptive behaviors, which include communication, daily living skills, socialization and motor skills. They score higher on a measure of hyperactivity.

The results suggest that seizures and certain behavioral issues in autism could have common origins, says co-lead investigator Jamie Capal, associate professor of pediatrics and neurology at the University of North Carolina at Chapel Hill.

“I think it really does show us that in individuals with autism who eventually have epilepsy, there is some shared mechanism early on that we just haven’t been able to identify,” Capal says.