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.

Epilepsy Research News: July 2020

This month’s epilepsy news includes a recent study that documents the potential risk of suicide in people with epilepsy who experience hallucinations and what treating physicians can do to intervene. Another important study for clinicians and families to be aware of suggests that there may be an increased risk of death among Alzheimer’s patients who take antiepileptic drugs (AEDs).

In FDA news, Fintepla® (fenfluramine) was approved for the treatment of seizures associated with Dravet syndrome in patients age 2 and older. While this is exciting news, we recommend that families considering this treatment option review the full FDA statement first.

Lastly, highlights from two interesting studies are presented. The first suggests an unexpected therapeutic effect of listening to Mozart’s piano compositions in people with epilepsy. The second details the development of a novel noninvasive method of mapping seizure foci in preparation for epilepsy surgery.

Summaries of these research discoveries and news highlights are below.

Research News

  • Hallucinations and Suicide Risk: Approximately 8% of people with epilepsy experience hallucinations unrelated to their seizures. This study showed that 65% of these individuals had a diagnosable mental illness and 53% had attempted suicide at least once. The data suggest that hallucinations are critical markers of suicide risk and emphasize the importance of clinicians routinely asking about hallucinations and assessing the mental state of their patients with epilepsy. Learn more
  • Alzheimer’s Disease and Antiepileptic Drugs: A Finnish study suggests that use of AEDs increases the rate of death among those who suffer from Alzheimer’s disease. According to this study, older AEDs increase the probability of death compared to more recently developed ones. Although researchers cautioned that the reasons for prescribing the AED could partly explain the data, they also stressed the need for close monitoring of adverse effects. Learn more
  • New Therapy for Dravet Syndrome Approved: The FDA recently approved Zogenix’s Fintepla® (fenfluramine) for the treatment of seizures associated with Dravet syndrome in patients older than 2 years of age. Individuals who are prescribed this drug do need to undergo cardiac monitoring, due to the risk of two specific cardiac concerns. Learn more
  • The Magic of Mozart: An intriguing yet preliminary study found that daily listening to one of Mozart’s piano sonatas reduced the frequency of seizures in people with epilepsy. Importantly, nothing else was changed, including the dosage of their AEDs. While these results are promising, the next step is to conduct larger studies with more patients over a longer period of time. Learn more
  • Epilepsy Surgery: A recently described approach to finding the area in the brain responsible for a person’s seizures does not require invasive brain surgery, but instead combines artificial intelligence and 76 scalp electrodes. This method has been shown to be just as effective at pinpointing the location and extent of the seizure source as implanted electrodes. Learn more

National funding for epilepsy research is in jeopardy. Scientists are facing extreme challenges due to COVID-19 and its impact on funding. Critically important research hangs in the balance. Donate today to support continued scientific progress aiming to create a world without epilepsy.

Sirolimus (Rapamune®) Improves Seizure Control in Pediatric Patients with Tuberous Sclerosis

Abstract, published in Seizure

Purpose: This study aimed to analyze the therapeutic effect of sirolimus on seizures in pediatric patients with tuberous sclerosis.

Methods: Researchers first compared the efficacy of controlling seizures in all patients after they had taken sirolimus for one year, and then we performed a subgroup analysis based on whether the administered antiepileptic drugs (AEDs) were changed to determine whether the efficacy was associated with changes of AEDs.

Results: A total of 91 eligible children were enrolled. The response rate was 78.0% (71/91), and 47.2% (43/91) of all patients were became seizure-free. The improvement in seizure control before and after treatment with sirolimus was significant. In the AEDs unaltered group, 34 were responders (34/45, 75.6%), of which 24 were seizure-free (24/34, 70.6%). In the AEDs-altered group, 37 were responders (37/46, 80.4%), of which 19 were seizure-free (19/37, 51.4%). There was no significant difference between the two groups for reductions in rate of seizure frequency. In the patients with refractory epilepsy, treatment with sirolimus was also effective. Further analysis showed that age was an important factor affecting outcome of epilepsy.

Conclusions: Sirolimus has a significant effect on seizures associated with tuberous sclerosis complex (TSC), with no or only moderate adverse events after long-term administration. Sirolimus could be used as the first-line medication for pediatric patients with TSC-associated epilepsy.

Treatment Comparison of Perampanel (Fycompa®) Versus Brivaracetam (Briviact®) as Add-On Therapy for Epilepsy

Abstract, published in Epilepsy Research

Purpose: To date, there has not been a single randomized controlled trial (RCT) conducted to directly compare the efficacy and safety of perampanel to brivaracetam in the add-on treatment of focal-onset seizures. Focal seizures are those that begin in a single area of the brain, which can then spread to the rest of the brain (secondarily generalization) and often be accompanied by violent convulsions (tonic-clonic).

Results: Eight RCTs (four comparing perampanel to placebo and four comparing brivaracetam to placebo) were included. For patients taking concomitant levetiracetam (Keppra®), which is chemically similar to brivaracetam, perampanel showed a significantly better responder rate compared to brivaracetam. For patients who had previously, or never, taken levetiracetam, there was no difference in the responder rate. In the overall population, both perampanel and brivaracetam were more effective than placebo in terms of responder rate, seizure freedom, and secondarily generalized tonic-clonic seizure responder rate; however, for these outcomes, no evidence of a difference between perampanel and brivaracetam was found. Patients taking brivaracetam showed significantly less dizziness compared to patients taking perampanel. No differences for any other safety outcome were found.

Conclusions: Perampanel and brivaracetam are effective for the add-on treatment of focal-onset seizures and display similar adverse event profiles. Perampanel demonstrated an improved focal-onset seizure responder rate compared to brivaracetam in patients taking concomitant levetiracetam. This may be due to the similarity in the mechanism of action between brivaracetam and levetiracetam.

Actual Experience with Direct Brain-Responsive Neurostimulation for Focal Onset Seizures

Abstract, published in Epilepsia

Objective: The RNS System® is a direct brain-responsive neurostimulation system that is approved by the US FDA for adults with drug-resistant seizures that begin in one area of the brain, based on safety and effectiveness data from controlled clinical trials. The purpose of this study was to retrospectively evaluate the real-world safety and effectiveness of the RNS System.

Results: One hundred fifty patients met the criteria for analysis. The average reduction in seizures was 67% at 1 year, 75% at 2 years, 82% at 3 years or more, and 74% at last follow-up (average = 2.3 years). Thirty-five percent of patients had a ?90% seizure frequency reduction, and 18% of patients reported being clinically seizure-free at last follow-up. Seizure frequency reductions were similar regardless of patient age, age at epilepsy onset, duration of epilepsy, location of seizure onset, magnetic resonance imaging findings, prior intracranial monitoring, prior epilepsy surgery, or prior vagus nerve stimulation treatment. The infection rate per procedure was 2.9%; five of the six patients had an implant site infection, and one had a bone infection. Lead revisions were required in 2.7%, and 2.0% of patients had a subdural hemorrhage (a collection of blood outside the brain), none of which had long-lasting neurological consequences.

Significance: In this real-world experience, safety was similar and clinical seizure outcomes exceeded those of the prospective clinical trials, corroborating effectiveness of this therapy and suggesting that clinical experience has informed more effective programming of the RNS device.

Misdiagnosis of Lamotrigine (Lamictal®) Toxicity as Transient Ischemic Attack or Stroke

Abstract, published in Epilepsy & Behavior

Purpose: Lamotrigine (LTG) is one of the most used antiseizure medications (ASMs). Titration is indicated for incomplete seizure control, but toxicity with dizziness, impaired coordination, and double vision may ensue. Lamotrigine concentration would be the optimal diagnostic test. However, patients often receive a stroke evaluation when seen in the emergency department (ED), leading to unnecessary cost and delayed management. We investigated the frequency of stroke evaluation for symptoms associated with LTG toxicity and attempted to identify factors leading to this expensive evaluation.

Results: Thirteen patients with LTG toxicity had 16 negative stroke evaluations in the emergency room. Their average age was 62 years (range: 43-79) as compared with 47 years for all patients treated with LTG. The average daily LTG dose was 621 mg (range: 300-900 mg). A LTG serum concentration was requested on the day of evaluation in 7 instances, though the result was never available until at least the next day. In 4 instances, the LTG level was drawn 1-3 days after the patient had been seen. Five of the patients in this group were among 71 patients with clinical LTG toxicity and LTG concentration >20.

Conclusions: Emergency departments will frequently call a stroke alert for patients taking LTG and having symptoms consistent with LTG toxicity, particularly in seniors at greater risk of stroke. This adds not only expense but also radiation and contrast exposure from computed tomography (CT) studies. We recommend that a rapid LTG assay be made available and always ordered in patients receiving LTG, avoiding the considerable expense of an unnecessary stroke evaluation.

Dosing Recommendations for Delayed or Missed Doses of Valproic Acid (Depakote®) in Patients with Epilepsy

Abstract, published in Epilepsy & Behavior

Objective: Delayed or missed doses are unavoidable in the pharmacotherapy of epilepsy and significantly compromise the efficacy of antiepileptic drug treatment. An inappropriate remedial regimen can cause seizure relapse or serious adverse events. This study investigated the effect of delayed or missed doses on the metabolism of valproic acid (VPA) in patients with epilepsy and established remedial dosing recommendations for nonadherent patients.

Methods:. The following four remedial strategies were investigated for each delayed dose: A) A partial dose or a regular dose is taken immediately; a regular dose is taken at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed dose and a partial dose are taken; the next scheduled time is skipped, and the regular regimen is resumed. D) Double doses are taken when missed one dose or two doses, and the regular regimen at the subsequent scheduled time is resumed.

Results: The recommended remedial dose was related to the delay duration and daily dose. Remedial dosing strategies A and B were almost equivalent, whereas strategy C was recommended when the delayed dose was close to the next scheduled dose. strategy D was only suggested for delayed two doses.