Single Target, Multiple Possibilities: MicroRNA Holds Promise for Epilepsy Treatment

Article published by News Medical Life Sciences

Featuring the work of former CURE Epilepsy grantee Dr. David Henshall

In a recent study published in the PNAS Journal, a group of researchers investigated the role of micro-ribonucleic acid (miRNA) miR-335-5p as a potential therapeutic target for epilepsy by regulating neuronal excitability through the modulation of voltage-gated sodium channels (VGSCs).

Epilepsy affects millions of individuals worldwide, and current antiseizure medications (ASMs) target VGSCs. However, some forms of epilepsy, like Dravet syndrome, are treatment-resistant due to loss of VGSC function. To develop better therapies, researchers are exploring miRNAs that regulate gene expression.

MiRNAs can control VGSC expression, making them attractive therapeutic targets. Triangulating miRNA datasets and studying miRNA alterations caused by effective ASMs could reveal potential therapeutic miRNAs for epilepsy.

Cannabidiol (CBD), approved for treatment-resistant epilepsy, is an example of an effective ASM with an unknown mechanism of action, arising the need for further investigation.

The study focused on investigating epilepsy using animal models. Animals were kept in controlled conditions with a 12-hour light-dark cycle, proper temperature, and humidity, with food and water freely available.

The researchers used two epilepsy models: the PPS model of temporal lobe epilepsy (TLE) in rats and the pentylenetetrazol (PTZ) model in mice. For the perforant path stimulation (PPS) model, electrodes were implanted, and seizures were induced using paired-pulse stimuli. For the PTZ model, mice received a convulsant dose of PTZ to trigger seizures.

Various treatments were administered to investigate their effects on epilepsy. They modulated miRNA through antisense oligonucleotide “antimir” injections and viral particles expressing specific miRNAs. Additionally, they administered CBD, a compound derived from cannabis, to study its potential effects on epilepsy.

The researchers analyzed miRNA and mRNA expression in the brain tissues of the animals. They also identified miRNA-target interactions and performed pathway enrichment analyses to understand the molecular mechanisms involved in epilepsy.

Natural Language Processing Identifies Patients Who May be Good Candidates for Epilepsy Surgery

Article published by AJMC

A review of 6 studies found natural language processing (NLP) showed moderate-to-high performance levels in identifying suitable candidates to undergo epilepsy surgery, an effective, but oftentimes underutilized treatment, in which approximately 50% to 60% of patients became seizure-free after surgery.

“This study has found that there is evidence, using multiple algorithms, that NLP may aid in the identification of candidates who may benefit from referral for epilepsy surgery evaluation,” wrote the researchers of the study. “It is noteworthy that these studies have shown that the NLP approaches may identify suitable candidates prior to the time that treating neurologists refer their patients.”

The systemic review is published in the Journal of Clinical Neuroscience.

Similar to machine learning, NLP uses computers to analyze or interact with human language and has various uses in health care, including information extraction, information retrieval, document categorization, and text summarization. Furthermore, NLP can aid in generating meaningful information, such as diagnosis or prognosis from electric health record data.

Previous research has suggested that NLP may be useful in identifying patients with drug-resistant focal epilepsy, who account for about 30% of individuals with epilepsy. In the current review, researchers aimed to examine previous studies using NLP to identify patients for epilepsy surgery.

A data search identified 1369 publication results from PubMed (n = 324), EMBASE (n = 94) and Cochrane library (n = 951), in which 58 full-text articles were identified for review.

After exclusion, 6 studies were selected for analysis. Most studies were conducted in a single study center, with 1 study utilizing data from 2 centers, and 1 study from 6 centers. Study characteristics included were the number of participants, age, gender, and NLP information, such as task assigned, ground truth (gold standard), and the type of NLP algorithms used.

Five of the 6 studies used support vector machines and 1 study used NLP strategies, such as random forest models and gradient boosted machines. Furthermore, all studies showed moderate-to-to-high levels of performance.

Some of the studies showed that NLP could identify patients 1 to 2 years prior to the treating clinicians initial referral. However, none of the studies identified evaluated the influence of implementing these algorithms on health care systems or patient outcomes.

“NLP is a promising technology for the identification of patients who may benefit from epilepsy surgery referral,” wrote the researchers.

Epilepsy Research News: July 2023

This issue of Epilepsy Research News includes summaries of articles on:

Beating Seizures by Jamming the Cellular Circuitry

Researchers have shown for the first time how the commonly prescribed antiseizure and pain medication gabapentin (Neurontin®) acts to affect cell function, potentially opening the door to new, more effective treatments for diseases like epilepsy. This research shows how gabapentin interacts with proteins called voltage-gated calcium channels, which are critical to the function of the brain. Voltage-gated calcium channels control the flow of calcium in and out of the cell and regulate brain excitation. By utilizing a technique called cryo-electron microscopy, the researchers confirmed the site where gabapentin binds to the channel to affect its function. The researchers also discovered that gabapentin interferes with the actions of a protein known as EMC. This interference could inhibit the actions of the ion channel, possibly decreasing the amount of calcium that gets into brain cells, in turn reducing brain activity and seizures. The study authors noted that by showing how gabapentin binds to calcium channels, there may be the opportunity to design a new generation of therapies.

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Identifying Seizures that Occur While Driving, Before Epilepsy Diagnosis

Five percent of people with focal epilepsy had a seizure while driving prior to being diagnosed with epilepsy, according to a new study. Researchers looked at clinical descriptions from study participants’ seizure diaries and medical records to classify types of seizures, seizure occurrence, and information about seizures while driving. They found 23 out of 447 participants, or 5% of participants, experienced one or more seizures while driving, for a total of 32 seizures while driving prior to diagnosis. Of these 23 people, seven people, or 30%, had more than one seizure while driving prior to diagnosis. The consequences of these seizures while driving included 19 motor vehicle accidents and 11 hospitalizations for injuries ranging from a tongue bite and a dislocated thumb to a near drowning. “From our study, we estimate nearly 6,500 people per year may experience pre-diagnosis seizures while driving in the United States alone, leading to nearly 4,000 possible motor vehicle accidents and over 2,200 hospitalizations,” stated the study authors. “Much of this may be preventable by earlier diagnosis.”

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Understanding Autism and Epilepsy

A study has increased our understanding and identified a possible treatment target for people with autism and epilepsy due to a lack of the ANK2 gene. This study showed that mice lacking the ANK2 gene in certain brain cells that contribute to brain excitation have autism spectrum disorder-like behaviors and juvenile seizure-related death. The researchers identified increased excitability of cortical neurons in these ANK2-deficient mice. These changes were accompanied by decreases in the function of a particular type of potassium channel in the brain. When the researchers used retigabine, an antiseizure medication, to enhance potassium channel function in the mice, they were able to restore neuronal excitability to normal levels and reduce seizure-induced deaths, suggesting that activation of potassium channels may be effective in treating epilepsy caused by ANK2 defects.

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Brain Inflammation and Drug-Resistant Epilepsy

New research investigated how inflammation contributes to the development of drug-resistant epilepsy. To study this, researchers examined brain tissue obtained during resective epileptic brain surgery. The researchers used a genetic sequencing technique called cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), which gathers information on RNA and surface proteins in single cells. They uncovered a proinflammatory microenvironment in drug-resistant epilepsy lesions that resembles brain autoimmune diseases, such as multiple sclerosis. They found that the drug-resistant epilepsy microenvironment includes activated microglia and other proinflammatory immune cells, and they captured cellular interactions with additional molecular analyses. The researchers noted that these results provide insight into the immune microenvironment in epileptic tissue, which may aid the development of new therapeutics.

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Reducing Seizures After Brain Tumor Treatment

According to a recent study, inhibiting a mutated gene can reduce seizure activity in adult-type diffuse gliomas, which are the most common type of malignant tumors arising in the central nervous system and which commonly cause seizures that are difficult to control with medication. Previous research has shown that gliomas with mutations in the IDH (IDHMut) gene are more likely to cause seizures because the mutated gene produces D-2-hydroxyglutarate (D2HG), a chemical which excites neurons and leads to an increase in seizure activity. In the recent study, scientists found that AG881, a newly discovered small molecule inhibitor that can cross the blood-brain barrier, can reduce seizure activity in mice with IDHmut gliomas by more than 50 percent. IDHmut inhibition also inhibited the production of D2HG by IDHmut glioma cells. The researchers stated that these findings provide a potential basis for treating seizures in human glioma patients.

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Patterns of Psychotropic Drug Use in Veterans with Epilepsy: Do Drug Interactions Matter?

Abstract found on PubMed

Rationale: Patients with epilepsy are likely to suffer from psychiatric comorbidities, including depression and anxiety. They often require treatment with multiple psychotropic drugs (PDs). While it is clear that CYP enzyme-inducing ASMs (EIASMs) can increase the oral clearance of multiple medications (thus lowering systemic exposure), it is less clear that all PK interactions are clinically meaningful (e.g. lower efficacy). As a first step in addressing this issue, this study sought to quantify the potential impact of ASM choice, whether EIASM or non-inducer (NIASM), on surrogate markers of suggestive of clinical use, including resultant antidepressant (AD) or antipsychotic (AP) dose, frequency of combination use of AD & AP, and number of multiple drug switches of PDs. Our hypothesis is that because of PK interactions, EIAED treatment would be associated with higher psychotropic drug doses, more frequent Rx adjustments and poly psychotropic comedication, all in order to optimize therapeutic response.

Methods: Using VA pharmacy and national encounter databases, veterans with epilepsy were identified based on having a seizure diagnosis and being prescribed concomitantly an ASM and a psychotropic drug for at least 365 days between 10/1/2010 and 9/30/2014. Patients for whom psychotropic drugs were prescribed any time between beginning and end prescriptions dates of ASMs were considered. Among those, patients receiving both an EIASM + NEIASM concomitantly were categorized with the EIASM group. Patients were evaluated for AD only, AP only and both (AD & AP). To compute average drug doses per day, averages for each patient were computed and averaged again. Multiple drug switches were defined to be for patients who had been prescribed more than three psychotropic drugs during the observation period. Pearson’s Chi-Square test was used to compare relative proportions of AD, AP and AD + AP in both groups.

Results: In all, 16,188 patients were identified (57.0% on EIASM, 43.0% on NIASM) with a mean age of 58.7 years (91.2% male). A larger proportion of patients on EIASM received mono treatment with any psychotropic drug, as compared to NIASM (42.0% vs 36.1%). Among all, 59.6% received AD only, 6.5% received AP only, and 33.8% received both concurrently. Of EIASM, 62.5% were on AD, 5.9% on AP, and 31.7% on both AP & AD. For NIASM, 55.9% received AD, 7.4% AP, and 36.7% on AD & AP.Chi-square showed that the distribution of PD was statistically different between EIASM and NIASM groups. Z tests showed that each difference (AD, AP and both) in proportions was statistically significant (p values (4 tests, one Chi-square, 3 Z tests <0.001) between EIASM vs NIASM. Interestingly, mean doses of AD or AP did not appear to differ between ASM groups.

Conclusions: Concurrent psychotropic drug use is quite common in the VA population with epilepsy, and a large number of patients still receive enzyme-inducing ASMs that may complicate other medical therapies. Interestingly, in seeming contradiction to our hypothesis, mean daily doses of either AD or AP did not appear to differ between inducers vs non-inducers. Similarly, use of polytherapy, and/or multiple trials of various psychotropic drugs did not appear increased in the CYP-induced group. In fact, combination therapy of AD + AP was higher in NIASM than EIASM. These data suggest that perhaps these types of PK interactions may not in fact result in meaningful clinical differences. Since the present analyses did not include clinical psychiatric measures, future analyses examining direct clinical outcomes are clearly warranted.

Medicated Oral Film for Epilepsy, Green Concrete Among Ideas Supported by NUS Innovation Programme

Article published by The Straits Times

Local start-up PharLyfe+ has developed medicated oral films which can be easily administered to treat epilepsy.

The film, made of edible polymers, is stuck inside the patient’s cheek and medicine on the film is released directly into the bloodstream.

PharLyfe+ was one of the 14 start-ups featured at the National University of Singapore’s (NUS) Graduate Research Innovation Programme (Grip) Lift-Off Day on Wednesday.

Grip, now in its ninth run, is a three-month structured programme that guides participants to become deep-tech entrepreneurs, translating their research into start-ups.

At the end of the programme, teams present their start-ups to venture capitalists, incubators and industry players to secure funding and support.

Dr Tan Poh Leng, 37, co-founder of PharLyfe+, said: “As mothers, we have seen how difficult it is to get children to take injections. Some children also have difficulty swallowing tablets, especially big ones. So we feel that our films would address these problems as they are easy to take. It can be used for the elderly as well.”

People with epilepsy have seizures. The most common form of medication to stop the seizure is an injection to the arm or a medicine inserted to the rectum, which may be distressing for the patient and difficult to administer.

PharLyfe+’s innovation makes administering medicine to epileptics easier.

The buccal films are also being specialised for end-of-life care with a different combination of medicines and polymers.

PharLyfe+ is seeking regulatory approval for the films and is conducting human trials.

Epilepsy Research News: June 2023

This issue of Epilepsy Research News includes summaries of articles on:

CURE Epilepsy’s Team Science Post-Traumatic Epilepsy (PTE) Initiative: Approach and Advances

CURE Epilepsy’s PTE Initiative united six preclinical and clinical research teams to form a consortium focused on improving ways to study PTE in a laboratory setting, understanding changes in the brain that occur after a traumatic brain injury (TBI) that lead to PTE, and uncovering risk factors associated with the development of PTE. PTE is a debilitating type of epilepsy that can develop in the months or even years following a TBI. Currently, there is no way to predict who will develop PTE or any way to prevent it. A recently published paper from the PTE Initiative describes scientific advances from CURE Epilepsy’s PTE Initiative, as well as its methods, implementation, and emphasis on team science and collaboration. Work on the PTE Initiative is ongoing, with the ultimate goal of understanding who is at risk for PTE, and laying the groundwork for the development of ways to prevent it from occurring. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Psychological Health and Traumatic Brain Injury Research Program under Award No. W81XWH-15-2-0069.

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Genetic Mutations Contributing to Adult Epilepsy

A recent study sheds new light on the role of changes in DNA known as somatic mutations in patients who develop mesial temporal lobe epilepsy (MTLE). Unlike inherited DNA mutations, which are passed down from a person’s parents, somatic mutations occur after a person is conceived. To examine the role of somatic mutations, researchers analyzed DNA from brain tissue samples collected from 105 patients with drug-resistant MTLE as well as 30 people who did not have epilepsy. The team pinpointed 11 somatic mutations that were enriched in the hippocampus (the region of the brain where seizures typically originate in MTLE) of 11 patients with drug-resistant MTLE. All but one of the 11 mutations were connected to a specific genetic pathway known as the RAS/MAPK pathway. The researchers noted that certain anti-cancer drugs target this pathway, opening a new avenue of therapeutic possibilities for MTLE patients that are resistant to antiseizure medications. In addition to suggesting a potential path to treatment, the findings could also be used to help inform treatment decisions for patients who harbor these somatic mutations.

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Improving Seizure Freedom After Epilepsy Surgery

A network of connections in the brain could be the key to improving frontal lobe epilepsy surgery, according to new research. This research suggests that disconnecting certain pathways in the frontal lobe could lead to longer-lasting seizure freedom after brain surgery. These pathways link the frontal lobe to brain structures deep in the brain, including areas called the thalamus and striatum. The researchers analyzed the cases of 47 people who underwent surgery for drug-resistant frontal lobe epilepsy and found that disconnection of these pathways was associated with seizure freedom after three and five years. The research found that this surgery also did not have negative effects on language or executive functions like planning, self-control, and focus. However, other functions, such as mood and emotions, still need to be studied. These findings provide hope that disconnection could lead to improved outcomes and long-term seizure freedom in people with frontal lobe epilepsy.

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Predictors of Epilepsy in Children with Complex Febrile Seizures

Four predictors of future epilepsy in children with complex febrile seizures (CFS) have been identified in a recently published study. These include experiencing more than three febrile seizures in 24 hours, a certain type of brain activity seen on a post-CFS electroencephalogram (EEG), a family history of seizures not associated with fever, and CFS onset at age three or later. The researchers retrospectively examined 621 children and found that having all four risk factors raised the risk of developing epilepsy to over 75%. The researchers noted that early identification of children who will develop epilepsy after a CFS is essential to future management and counseling for parents and caregivers.

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Diacomit Safe and Effective as Add-On Therapy in Dravet Infants

Article published by Dravet Syndrome News

Diacomit (stiripentol) was safe and clinically effective at reducing seizures when given to infants with Dravet syndrome, ages 2 or younger, according to a 30-year real world study. It also reduced emergency hospitalizations due to long-lasting seizures.

“This 30-year, real-world experience shows that initiating stiripentol before the age of 2 years is highly beneficial for patients with Dravet syndrome,” researchers wrote in “Initiating stiripentol before 2 years of age in patients with Dravet syndrome is safe and beneficial against status epilepticus,” which was published in Developmental Medicine & Child Neurology.

Long-lasting seizures and status epilepticus are hallmark symptoms of Dravet syndrome’s onset and usually begin in the first year of life. They remain at high risk of occurrence during infancy and middle childhood. The seizures are life-threatening and interfere with development, affecting “quality of life, medical needs,” and families’ economic well-being.

Treatments focus on reducing seizures frequency and duration, and helping prevent and manage status epilepticus. For infants younger than 2, therapies remain limited, however, mainly due to the low frequency of seizures and their severity.

Diacomit, an antiseizure medication marketed by Biocodex, is administered as an add-on therapy to children with Dravet, including infants. Data on its effectiveness in infants younger than 2 is scarce, however, and individual efficacy or safety data are “often incomplete or pooled with those from older children,” the researchers wrote.

In this study, French researchers retrospectively analyzed real-world data of Dravet patients who began Diacomit before they were 2 and were followed for 30 years (1991-2021). Data from 131 patients (59 women, 72 men) collected over four patient databases in France were analyzed.

Pharmacological Aspects of Antiseizure Medications: From Basic Mechanisms to Clinical Considerations of Drug Interactions and Use of Therapeutic Drug Monitoring

Abstract published by PubMed

Antiseizure medications (ASMs) are the cornerstone of treatment for patients with epilepsy. Several new ASMs have recently been introduced to the market, making it possible to better tailor the treatment of epilepsy, as well as other indications (psychiatry and pain disorders). For this group of drugs there are numerous pharmacological challenges, and updated knowledge on their pharmacodynamic and pharmacokinetic properties is, therefore, crucial for an optimal treatment outcome. This review focuses on educational approaches to the following learning outcomes as described by the International League Against Epilepsy (ILAE): To demonstrate knowledge of pharmacokinetics and pharmacodynamics, drug interactions with ASMs and with concomitant medications, and appropriate monitoring of ASM serum levels (therapeutic drug monitoring, TDM). Basic principles in pharmacology, pharmacokinetic variability, and clinically relevant approaches to manage drug interactions are discussed. Furthermore, recent improvements in analytical technology and sampling are described. Future directions point to the combined implementation of TDM with genetic panels for proper diagnosis, pharmacogenetic tests where relevant, and the use of biochemical markers that will all contribute to personalized treatment. These approaches are clinically relevant for an optimal treatment outcome with ASMs in various patient groups.

1 in 4 Patients with Epilepsy May Stop Epidiolex Due to Side Effects

Article published by Dravet Syndrome News

Up to 1 in 4 people with hard-to-treat epilepsy, including those with Dravet syndrome, were found to stop taking Epidiolex (cannabidiol) shortly after starting treatment, primarily due to side effects or a lack of efficacy, according to a real-world study.

“Epidiolex is generally well-tolerated and the majority continued long-term treatment,” researchers wrote, but noted that the data suggest that most patients who discontinued the therapy did so “within the first several months of treatment.”

“Further studies designed to evaluate early identification and potential mitigation of adverse [side] effects … are warranted,” the team wrote, adding that more research is needed to confirm these findings.

The study, “Real-world, long-term evaluation of the tolerability and therapy retention of Epidiolex (cannabidiol) in patients with refractory epilepsy,” was published in the journal Epilepsy & Behavior.

In people with epilepsy, problems in the functioning of the brain cause bursts of uncontrolled electrical activity called seizures. These events can lead to a wide range of mild to severe symptoms that in Dravet patients may present as developmental and cognitive delays, movement problems, and difficulties speaking and sleeping.

Previous trial data suggested Epidiolex can cause several potential therapy-limiting adverse effects or side effects, such as diarrhea, liver enzyme increases (a sign of liver damage), decreased appetite, somnolence or sleepiness, and sleep problems. The results also indicated that treatment interactions with certain medications may be therapy-limiting for some patients.

Now, a team of researchers at the University of Wisconsin-Madison, in the U.S., evaluated the long-term effectiveness of Epidiolex. The focus was on a combination of efficacy and tolerability in people with refractory epilepsy in a real-world setting.

The study included 108 patients seen at the researchers’ center and who took Epidiolex for at least two weeks between December 2018 and December 2020.

Soft Robot Brain Implant Designed to Treat Epilepsy

Article published by Informa

A new small-scale, soft robotic implant has been designed to help treat epilepsy.

The flexible robot is inserted into a patient’s skull and sits between the skull and the surface of the brain.

Created by a team from Switzerland’s Ecole Polytechnique Fédérale de Lausanne (EPFL), the robot is a tiny, foldable electrode array that can be unfurled once inserted through a hole in a patient’s skull, applying consistent pressure to certain parts of the brain.

This electrode array stimulates and monitors electrical activity in the brain for patients who suffer from neurological conditions such as epilepsy.

“Minimally invasive neurotechnologies are essential approaches to offer efficient, patient-tailored therapies,” says Stéphanie Lacour, EPFL’s neurotechnology expert. “We needed to design a miniaturized electrode array capable of folding, passing through a small hole in the skull and then deploying in a flat surface resting over the cortex. We then combined concepts from soft bioelectronics and soft robotics.”

The first prototype consists of an electrode array that fits through a hole 0.7 inches in diameter but can expand to cover a surface of the brain double the size.

According to the team, the robot’s folding and expanding capabilities are achieved by the device being turned inside out and then extended once deployed in the brain using a pressurized liquid, a method known as eversion.