Polytherapy, Improved Medication Adherence Reduce Risk for SUDEP in Swedish Cohort

Article, originally posted on Healio

Polytherapy, especially the use of three or more antiepileptic drugs, correlated with a substantially decreased risk for sudden unexpected death in epilepsy, according to findings from a nationwide case-control study conducted in Sweden.

The findings, which were published in Neurology, also demonstrated a link between statin use and a decreased risk for sudden unexpected death in epilepsy.

“There is an urgent need to reduce the risk of sudden unexpected death in epilepsy (SUDEP),” the researchers wrote. “Risk factors related to drug treatment may represent opportunities for prevention.”

Olafur Sveinsson MD, PhD, of the departments of neurology and clinical neuroscience at the Karolinska Institute in Sweden, and colleagues performed the population-based, case-control study to determine the relationship between AEDs, selective serotonin reuptake inhibitors (SSRIs) and “other potentially relevant drugs” and SUDEP risk.

“These results provide support for the importance of medication adherence and intensified AED treatment for patients with poorly controlled GTCS in the efforts to reduce SUDEP risks and suggest that comedication with statins may reduce risks,” Sveinsson and colleagues wrote.

Risk-Benefit Assessment of Treatment of Epileptic Women of Childbearing Age With Valproic Acid

Abstract, originally published in Seizure

Aim: Valproic acid (VPA) is a widely used anti-epileptic drug (AED) of demonstrated efficacy. However, its teratogenic effects have resulted in many regulatory agencies recommending that it should not be administered to women of childbearing age unless they are taking contraceptives. The aim of this study was to determine the willingness of candidate patients to change their treatment and to monitor the evolution of their attitude.

Methods: We identified patients aged between 15 and 45 years old who had been diagnosed with epilepsy and were being treated with VPA. A shared decision-making visit was arranged, during which variables related to their epilepsy were recorded. The patients were informed about the teratogenic effects of VPA and the risks/benefits of a change in treatment. The patient, or legal guardian, then freely chose the course of treatment that they wished to follow. On a follow-up visit, six months later, seizure control and tolerance to the chosen treatment were recorded. The variables related to each patient’s willingness to their change treatment were analysed.

Results: A total of 60 patients, with a median age of 32.7 years, were included in the study. Of these, 25 (41.7%) suffered some form of intellectual disability. Only one (1.7%) had poor seizure control. After the initial visit, 41 patients (68%) opted to continue with the VPA treatment, six opted to stop receiving VPA, and 13 decided to switch to another AED. The median age of the patients who opted to change treatment was significantly lower than that of those who opted to continue with the VPA treatment (29.1 vs. 34.4, p = 0.024). The absence of intellectual disability (p = 0.047) and a length of treatment of less than five years (0.016) were both significantly associated with the decision to change treatment. Of the 19 patients who changed treatment, nine (47%) returned to the initial treatment with VPA.

Conclusions: Despite being informed of the teratogenic risk associated with VPA, a significant number of patients and legal guardians opted to continue with this treatment; the reasons given for this were the low possibility of pregnancy and the risk of breakthrough seizures. In almost half the cases studied, the pharmacological alternatives to VPA were poorly tolerated and did not provide a good level of seizure control.

Controlling Seizure Effects Using a New Potassium Channel Activator

Article, originally posted on News-Medical.net

A group from The Mount Sinai Hospital / Mount Sinai School of Medicine have identified and characterized a novel potassium-channel activator, GiGA1, capable of selectively opening a subset of potassium channels to produce an antiseizure effect in animal models.

This study presents an integrated approach to GIRK1-specific activators, employing both computational modeling and subsequent biochemical and physiological studies. The resultant seizure mitigation produced in an acute epilepsy mouse model demonstrates a potential role for this compound in the treatment of brain disorders.

Silencing ‘Poison Exon’ Eliminates Deadly Seizures in Mice

Article, published on SpectrumNews.com (featuring the work of former CURE Grantee, Dr. Lori Isom)

A new treatment curbs deadly seizures in a mouse model of Dravet syndrome, a severe form of epilepsy, according to a new study. A clinical trial is evaluating the drug’s safety in children with the syndrome.

The new drug, which consists of short pieces of RNA called ‘antisense’ molecules, counteracts the effects of SCN1A mutations. The molecules boost the expression of the intact copy of SCN1A, allowing cells to produce normal levels of the sodium channel the gene encodes. They do so by silencing a ‘poison exon’ in SCN1A, a sequence of DNA that ordinarily limits the gene’s expression.

In model mice of Dravet syndrome, the drug significantly decreased the frequency of SUDEP, the new work found, lowering their likelihood of having a fatal seizure during the first 90 days of life from 77 to 3 percent.

Sex Differences in the Epilepsies and Associated Co-Existing Illnesses: Implications for Use and Development of Drug Therapies

Abstract, published in Pharmacological Reviews

The epilepsies are common neurologic disorders characterized by spontaneous recurrent seizures. Boys, girls, men, and women of all ages are affected by epilepsy and, in many cases, by associated co-existing illnesses as well. The primary courses of treatment are pharmacological, dietary, and/or surgical, depending on several factors, including the areas of the brain affected and the severity of the epilepsy. There is a growing appreciation that sex differences in underlying brain function and in the neurobiology of epilepsy are important factors that should be accounted for in the design and development of new therapies. In this review, we discuss the current knowledge on sex differences in epilepsy and associated co-existing disorders, with emphasis on those aspects most informative for the development of new drug treatments. Particular focus is placed on sex differences in the prevalence and presentation of various focal and generalized epilepsies; psychiatric, cognitive, and physiologic co-existing disorders; sex differences in brain development; the neural actions of sex and stress hormones and their metabolites; cellular mechanisms; and catamenial epilepsy in women, a type of epilepsy in which seizures increase during certain phases of the menstrual cycle. Further attention placed on potential sex differences in epilepsies, co-existing disorders, and drug effects will enhance therapeutic options and efficacy for all patients with epilepsy.

SIGNIFICANCE STATEMENT: Epilepsy is a common neurological disorder that often presents together with various co-existing disorders. The features of epilepsy and seizure activity as well as concurrent afflictions can vary between men and women. In this review, we discuss sex differences in types of epilepsies, associated co-existing disorders, pathophysiological mechanisms, and antiepileptic drug efficacy in both clinical patient populations and preclinical animal models.

Texas A&M Neuroscientists Discover New Therapy for Refractory Epilepsy

Summary, published by Texas A&M

Scientists around the world have been on an active pursuit to better understand refractory epilepsy and identify a better way to block the frequent seizures with targeted therapies. Research from  Samba Reddy, professor of neuroscience and experimental therapeutics at the Texas A&M University College of Medicine, offers a practical approach to a better treatment.

Epilepsy is a chronic neurological disorder characterized by unpredictable seizures that affects more than 65 million people in the world. Seizures can usually be controlled with antiepileptic medications, but as many as two out of five patients with epilepsy have seizures that are refractory. This occurs when seizures are frequent enough that it interferes with a person’s life, and cannot be controlled with current medications.

Reddy has been working for more than two decades to find solutions to this and other challenges in the epilepsy field. His lab has been conducting investigations on the molecular mechanisms of seizures and translating the concepts into innovative therapies for curing epilepsy.

His recent work, co-authored by his graduate student Shu-Hui Chuang, was published in the Journal of Pharmacology and Experimental Therapeutics. They used an arithmetic technique called isobolographic analysis to select the best combination regimen of two drugs in order to achieve the highest efficacy, and found that the positive interaction between two neurosteroids (brexanolone and ganaxolone) and two antiepileptic medications (tiagabine and midazolam) is so significant that it could help treat refractory epilepsy.

“Our study suggests the viability of launching neurosteroid combination therapy for epilepsy,” Reddy said. “A prospective clinical trial is needed to demonstrate overall clinical impact of this therapy, especially in adults and children with drug resistant epilepsy, but these findings for the first time provide a strong rationale for clinical use of neurosteroid plus tiagabine or neurosteroid plus midazolam for refractory seizures and other hyperexcitability conditions.”

Reddy hopes his findings will lead to a treatment of refractory seizures, and, in the long run, he hopes to find a cure for epilepsy.

“Epilepsy is one of the most complex brain disorders,” Reddy said. “There is some stigma associated with epilepsy. Imagine a patient having a seizure at a party, school or store. It’s a very difficult situation for them, and there is some part of discrimination that happens inherently. Most of what I am interested in is helping patients feel better.”

Reddy’s research has also laid the groundwork for neurosteroids — powerful anticonvulsants — in brain disorders. The first neurosteroid (brexanolone) was approved by the Food and Drug Administration for clinical use in post-partum depression. Another neurosteroid, called ganaxolone, is in Phase 3 clinical trials for treating seizure disorder.

The U.S. CounterACT Program, Office of the Director, National Institutes of Health and the National Institute of Neurologic Disorders and Stroke have supported this research.

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.

Dr. Sherine Chan check on the zebrafish in her lab.

New vitamin K-based Drug Shows Promise Against Medication-Resistant Epilepsy

In the cover article of the June 11 issue of the Journal of Medicinal Chemistry, a team of researchers at the Medical University of South Carolina, led by Sherine Chan, Ph.D., and James Chou, Ph.D., reports that a new vitamin K-based drug has proved effective in mouse models of medication-resistant seizures.

Chan and Chou, both associate professors in the Department of Drug Discovery and Biomedical Sciences in MUSC’s College of Pharmacy, are two of the co-founders of Neuroene Therapeutics, a startup company with the mission of developing therapies for medication-resistant conditions, such as epilepsy, caused by mitochondrial dysfunction.

Of the 3.4 million patients with epilepsy in the U.S., about one-third live with medication-resistant epilepsy, meaning that their seizures cannot be controlled. Uncontrolled seizures can occur suddenly, without warning, putting patients at higher risk for injury and reducing quality of life. These patients are in urgent need of new treatment options.

The compound developed by Chan and Chou, a modified form of naturally occurring vitamin K, completely eliminated seizure activity in the mouse models.

“The cool thing about our drug is that it is orally bioavailable, has excellent brain penetration, is rapidly distributed in the central nervous system and is well-tolerated in mice and rats,” said Chan.

“It’s so exciting because it’s a new class of anti-seizure drug compound, and it’s literally vitamins,” said Chou. “It is structurally unique and unlike a lot of compounds out there.”

The successful vitamin K analog was developed along with 22 other compounds, all of which were modifications of the naturally occurring vitamin K molecule. All candidates were tested for their effectiveness in controlling seizures in different epilepsy types in mice. The authors believe it is the unique structure they have designed for this particular molecule that makes it effective in controlling medication-resistant, or refractory, seizures.

Epilepsy can be caused by mitochondrial dysfunction in brain cells that affects their ability to produce energy. Chan and Chou have a long history of working on conditions caused by mitochondrial dysfunction, and,  since starting at MUSC in 2009, they have been working together to develop treatments for mitochondrial dysfunction.

“Mitochondria produce most of the energy for the cell,” explained Chan. “When mitochondria are damaged, cells have a tough time producing sufficient energy. Brain cells require a significant amount of energy, and so mitochondrial dysfunction affects their function. This dysfunction is an underlying cause of many neurological diseases, including epilepsy, Parkinson’s disease and rare mitochondrial disorders.”

Treatment with the compound increased the brain cells’ ability to produce energy, the study showed. The researchers believe this could be the key to figuring out the mechanism by which the vitamin K analog actually works to control seizures.

The study tested the drug in mouse brain cells, followed by a widely used zebrafish seizure model and finally multiple mouse seizure models representing different types of epilepsy. After obtaining promising results in brain cells and zebrafish, the team was thrilled to see that they could  eliminate seizure activity in all mice tested, said Chou.

Few treatment options are currently available for those with medication-resistant epilepsy, according to Chan. “Treatments include going on a ketogenic diet, implanting a responsive neurostimulation device in the brain, vagus nerve stimulation (through an implant in the brain) and epilepsy surgery,” she added. Apart from being invasive, these treatments are not 100% effective. They are also usually coupled with other broad-spectrum anti-seizure medications. The use of implants in the brain also comes with the risk of infection and surgical complications.

The 25 or so anti-seizure drugs currently on the market are used for a variety of seizure types. Many of these drugs are used in combination, and many can have toxic side effects, said Chan, particularly for patients with mitochondrial dysfunction. In contrast, the new vitamin K analog remains non-toxic up to a dose of 800 mg/kg and protects mitochondrial health.

Chou emphasized that there is still a long way to go before patients can benefit from this new compound in the clinic. The next step for Neuroene is to secure federal funding and/or private investment to take the compound through the Investigational New Drug Application with the Food and Drug Administration. This is a crucial preclinical step in determining the safety and effectiveness of the compound before it is tested in human clinical trials. If funding is available, Chou predicts that the compound could be in clinical trial within two years.

Chan and Chou are optimistic that this new class of drugs will be an important new treatment option, not only for epilepsy but also for other mitochondrial dysfunction disorders such as Parkinson’s disease.

“We are targeting a new mechanism of action, which is not being targeted by any of the drugs currently out in the market. We are targeting mitochondrial dysfunction; that’s a big underlying cause for neurological disease,” said Chan. “If you are able to protect your mitochondria and help them function well and make enough energy, then you will help your brain cells to stay alive and do their job. That’s how we believe this compound is helping with neurological diseases.”

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.