Fetal Exposure to Epilepsy Medications Does Not Affect Neurodevelopment in Children

Article published by News Medical Life Sciences

Most mothers who took prescription antiseizure medications during pregnancy can breathe a sigh of relief: A new study published today in Lancet Neurology found that young children who were exposed to commonly-prescribed medications in utero do not have worse neurodevelopmental outcomes than children of healthy women.

Commonly used antiseizure medications such as lamotrigine and levetiracetam are generally considered effective and safe, especially compared to many first-generation epilepsy treatments that carried profound risks to the unborn child. But while epilepsy may no longer be the reason that prevents someone from starting a family, there is still not enough information about how drugs taken by the mother affect maternal and child outcomes after delivery.

The new study provides reassurance to patients and offers guidance to neurologists who are faced with a challenge of maintaining fragile balance between prescribing drug dosages that suppress mother’s seizures but carry no increased risks of neurological complications for the baby.

“A blanket saying that all antiseizure medications are bad is overly simplistic and doesn’t make sense biologically. Being able to say that no, taking these medications will not put their future child at a greater risk of autism or learning disabilities, has a huge impact for women with epilepsy who are considering pregnancy,” said Page Pennell, M.D., senior author, professor and chair of neurology at the University of Pittsburgh

Epilepsy is a neurological disorder of abnormal electrical activity in the brain that affects over one million American women of childbearing age. With its sudden and debilitating seizures and limited number of medications, which caused significant risks to the developing fetus, the condition was considered incompatible with pregnancy for much of the 20th century, though that landscape is gradually changing.

The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study was launched two decades ago with the goal of delivering high-quality information about how antiseizure medications affect both the mother and the child. The prospective observational study recruited women who were treated for epilepsy at twenty medical centers across the United States and followed them and their babies over the course of pregnancy and several years postpartum.

Previous research that has come out from the study highlighted the need to carefully monitor and adjust the dosage of antiseizure medications to achieve adequate control of seizures without compromising the health of the fetus. The new study focused on determining whether exposure to these drugs causes long-term neurodevelopmental effects that negatively affect the child.

To assess the effects of fetal exposure to medications, children at the age of three years old were tested for their vocabulary and verbal comprehension skills as well as ability to describe simple pictures. Children of women with epilepsy were as good at verbally describing simple objects and pictures as children of women without epilepsy. Their ability to understand language was also comparable to children of the same age who were born to women without epilepsy, highlighting that both lamotrigine and levetiracetam pose low risks for negatively affecting cognitive outcomes.

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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A Novel Wearable Device for Automated Real-time Detection of Epileptic Seizures

Abstract found on PubMed

Background: Epilepsy is a neurological disorder that has a variety of origins. It is caused by hyperexcitability and an imbalance between excitation and inhibition, which results in seizures. The World Health Organization (WHO) and its partners have classified epilepsy as a major public health concern. Over 50 million individuals globally are affected by epilepsy which shows that the patient’s family, social, educational, and vocational activities are severely limited if seizures are not controlled. Patients who suffer from epileptic seizures have emotional, behavioral, and neurological issues. Alerting systems using a wearable sensor are commonly used to detect epileptic seizures. However, most of the devices have no multimodal systems that increase sensitivity and lower the false discovery rate for screening and intervention of epileptic seizures. Therefore, the objective of this project was, to design and develop an efficient, economical, and automatically detecting epileptic seizure device in real-time.

Methods: Our design incorporates different sensors to assess the patient’s condition such as an accelerometer, pulsoxymeter and vibration sensor which process body movement, heart rate variability, oxygen denaturation, and jerky movement respectively. The algorithm for real-time detection of epileptic seizures is based on the following: acceleration increases to a higher value of 23.4 m/s2 or decreases to a lower value of 10 m/s2 as energy is absorbed by the body, the heart rate increases by 10 bpm from the normal heart rate, oxygen denaturation is below 90% and vibration should be out of the range of 3 Hz -17 Hz. Then, a pulsoxymeter device was used as a gold standard to compare the heart rate variability and oxygen saturation sensor readings. The accuracy of the accelerometer and vibration sensor was also tested by a fast-moving and vibrating normal person’s hand.

Results: The prototype was built and subjected to different tests and iterations. The proposed device was tested for accuracy, cost-effectiveness and ease of use. An acceptable accuracy was achieved for the accelerometer, pulsoxymeter, and vibration sensor measurements, and the prototype was built only with a component cost of less than 40 USD excluding design, manufacturing, and other costs. The design is tested to see if it fits the design criteria; the results of the tests reveal that a large portion of the scientific procedures utilized in this study to identify epileptic seizures is effective.

Conclusion: This project is objectively targeted to design a medical device with multimodal systems that enable us to accurately detect epileptic seizures by detecting symptoms commonly associated with an episode of epileptic seizure and notifying a caregiver for immediate assistance. The proposed device has a great impact on reducing epileptic seizer mortality, especially in low-resource settings where both expertise and treatment are scarce.

CURE Epilepsy Public Service Announcement (PSA) Shares Community Voice on ESPN

CHICAGO, IL (July 2023) – CURE Epilepsy celebrates 25th anniversary as the leading nonprofit dedicated to finding a cure for epilepsy through research with a public service announcement (PSA) set to air on ESPN this summer.

The PSA features photos and video footage of fifteen people living with epilepsy or who have tragically lost their lives to the disorder. Epilepsy affects 3.4 million Americans – more people than multiple sclerosis, cerebral palsy, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS) combined – yet receives fewer federal dollars per patient than each of these. The intent of the thirty-second spot is to highlight the heterogeneity of epilepsy, inspire urgency to advance science, and raise awareness of CURE Epilepsy by showing real people impacted by this common neurological disorder.

One of the people featured in the PSA, thirteen-year-old Ella, was diagnosed with epileptic spasms just days after her first birthday. Ella is a happy and sweet girl who, despite all her seizures, medications, and hospital visits, lives in the moment and always has a smile on her face. After her diagnosis, Ella’s family created Ella’s Race to CURE Epilepsy to raise money in support of finding a cure for other kids like her. As of 2023, the race has raised almost $500,000 for epilepsy research. “One of the biggest obstacles in fundraising for epilepsy research is the lack of awareness of epilepsy itself. I am thrilled to be part of this PSA that helps to address this root cause,” said Ella’s mom, Shalee Cunneen.

Another featured CURE Epilepsy community member, Michael, is a baker whose epilepsy inspired his journey into starting his own business and food justice advocacy work. After receiving his epilepsy diagnosis, Michael was instructed to limit his physical activity. Michael adapted to his circumstances, going from gymnastics and swimming, to baking and advocating. He is working to make the world better one dessert at a time by passing out his cupcakes at homeless shelters and domestic abuse shelters, and he partners with other nonprofits focused on addressing food inequity.

CURE Epilepsy hopes that by sharing personal stories of epilepsy with a broad TV audience, it can raise the profile of this devastating and often misunderstood disorder, increasing federal research dollars and inspiring more individual contributions towards medical research.

CURE Epilepsy invites you to visit our website and get to know more about the research we help fund to create a world without seizures. CURE Epilepsy is laser-focused on finding a cure for epilepsy by promoting and funding patient-focused research. We offer educational programs such as our Seizing Life podcast, CURE Epilepsy CARES (Conversations Around Research in Epilepsy & Seizures), and webinars where people in the epilepsy community can access information to help them advocate for themselves and improve their outcomes.

As we celebrate our 25th year, we look forward to the cutting-edge advancements to come in the next 25. To learn more, please visit us at CUREepilepsy.org or contact us at info@CUREepilepsy.org. You can also follow us on Facebook at @CUREforEpilepsy, and Instagram, Twitter, and LinkedIn at @CUREepilepsy.

About CURE Epilepsy: CURE Epilepsy’s mission is to find a cure for epilepsy by promoting and funding patient-focused research. Since its inception 25 years ago, CURE Epilepsy has raised over $90 million to advance its goal of no seizures and no side effects. To date, CURE Epilepsy has funded more than 285 cutting-edge research projects in 18 countries around the world. As the nonprofit leader in epilepsy research, CURE Epilepsy is unwavering in its commitment to fund scientific study and accelerate research to achieve our vision – a world without epilepsy.

Increasing Challenges to Trial Recruitment and Conduct Over Time

Abstract found on PubMed

Objective: To evaluate how the challenges in the recruitment and retention of participants in clinical trials for focal-onset epilepsy have changed over time.

Methods: In this systematic analysis of randomized clinical trials of adjunct antiseizure medications for medication-resistant focal-onset epilepsy, we evaluated how the number of participants, sites, and countries has changed since the first such trial in 1990. We also evaluated the proportion of participants who completed each trial phase and their reasons for early trial exit. We analyzed these trends using mixed effects generalized linear models accounting for the influence of the number of trial sites and trial-specific variability.

Results: The number of participants per site has steadily decreased over decades with recent trials recruiting fewer than 5 participants per site (reduction by 0.16 participants/site/year, p<0.0001). Fewer participants also progressed from recruitment to randomization over time (Odds Ratio 0.94/year, p=0.014). Concurrently, there has been an increase in the placebo response over time (increase in median percent reduction of 0.4%/year, p=0.02; odds ratio of increase in 50% responder rate of 1.03/year, p=0.02), which was not directly associated with the number of sites per trial (p>0.20).

Discussion: This historical analysis highlights the increasing challenges with participant recruitment and retention, as well as increasing placebo response. It serves as a call to action to change clinical trial design to address these challenges.

Epilepsy Surgery in Early Infancy: A Retrospective, Multicenter Study

Abstract found on PubMed

Although epilepsy surgery is the only curative therapeutic approach for lesional drug-resistant epilepsy (DRE), there is reluctance to operate on infants due to a fear of complications. A recent meta-analysis showed that epilepsy surgery in the first six months of life can achieve seizure control in about two-thirds of children. However, robust data on surgical complications and postoperative cognitive development are lacking. We performed a retrospective multicenter study of infants who underwent epilepsy surgery in the first six months of life. 15 infants underwent epilepsy surgery at a median age of 134 days (IQR: 58) at four centers. The most common cause was malformation of cortical development, and 13 patients underwent a hemispherotomy. Two-thirds required intraoperative red-blood-transfusions. Severe intraoperative complications occurred in two patients including death in one infant due to cardiovascular insufficiency. At a median follow-up of 1.5 years (IQR: 1.8), 57% of patients were seizure-free. Three patients where reoperated at a later age, resulting in 79% seizure-freedom. Anti-seizure medication could be reduced in two-thirds, and all patients improved in their development. Our findings suggest that early epilepsy surgery can result in good seizure control and developmental improvement. However, given the perioperative risks, it should be performed only in specialized centers.

Optimizing Electrode Configurations for Wearable EEG Seizure Detection Using Machine Learning

Abstract found on PubMed

Epilepsy, a prevalent neurological disorder, profoundly affects patients’ quality of life due to the unpredictable nature of seizures. However, optimizing electrode configurations for such systems, which is crucial for balancing accuracy and practicality, remains to be explored. This study addresses this gap by developing a systematic approach to optimize electrode configurations for a seizure detection machine-learning algorithm.

Our approach was applied to an extensive database of prolonged annotated EEG recordings from 158 epilepsy patients. Multiple electrode configurations ranging from one to eighteen were assessed to determine the optimal number of electrodes.

Results indicated that the performance was initially maintained as the number of electrodes decreased, but a drop in performance was found to have occurred at around eight electrodes. Subsequently, a comprehensive analysis of all eight-electrode configurations was conducted using a computationally intensive workflow to identify the optimal configurations.

This approach can inform the mechanical design process of an EEG system that balances seizure detection accuracy with the ease of use and portability. Additionally, this framework holds potential for optimizing hardware in other machine learning applications. The study presents a significant step towards the development of an efficient wearable EEG system for seizure detection.

External Validation of the AntiEpileptic Drug Monitoring in PREgnancy (EMPiRE) Model for Predicting Seizures in Pregnant Women with Epilepsy

Abstract found on PubMed

Background: The AntiEpileptic Drug Monitoring in PREgnancy (EMPiRE) model is the only available tool for predicting seizures in pregnant women with epilepsy (WWE) using anti-seizure medications (ASMs); however, its predictive performance requires validation. This study aimed to evaluate the predictive ability of this model in pregnant Chinese WWE and its potential usefulness in clinical practice.

Methods: Data of the EMPiRE model were derived from the EMPiRE study, a prospective multicenter cohort study that recruited women on ASM monotherapy (lamotrigine, carbamazepine, phenytoin or levetiracetam) or polytherapy (lamotrigine with either carbamazepine, phenytoin or levetiracetam). Based on the applicable population of the EMPiRE model, we evaluated 280 patients registered in the Wenzhou Epilepsy Follow-up Registry Database from January 1, 2010, to December 31, 2020. A total of 158 eligible patients were included in the validation cohort. We collected data on the baseline characteristics of patients, eight predictors of the EMPiRE model and outcome events. The outcome was the occurrence of tonic-clonic or non-tonic-clonic seizures at any time in pregnancy up to 6 weeks postpartum. We used the equation of the EMPiRE model to obtain the predicted probabilities of seizures. The predictive ability of the EMPiRE model was quantified by the C-statistic (scale 0-1, values > 0.5 show discrimination), GiViTI calibration test and decision curve analysis (DCA).

Results: Of 158 eligible patients, 96 patients (60.8%, 96/158) experienced one or more seizures at any time between pregnancy and 6 weeks postpartum. The EMPiRE model showed good discrimination with a C-statistic of 0.76 (95% confidence interval [CI] 0.70-0.84). The GiViTI calibration belt showed that the predicted probabilities, which ranged from 16 to 96% (95% CI), were lower than the actual probabilities. DCA indicated that the highest net proportional benefit was obtained for predicted probability thresholds of 15-18% and 54-96%.

Conclusions: The EMPiRE model could discriminate well between WWE with and without seizures during pregnancy and 6 weeks postpartum, but the risk of seizures may be underestimated. The limitations of the model for specific medication regimens may limit its real-world application. If the model is further improved, it will be incredibly valuable.

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.