FDA Safety Warning on the Cardiac Effects of Lamotrigine: An Advisory From the Ad Hoc ILAE/AES Task Force

Summary, originally published in Epilepsia Open

The International League Against Epilepsy (ILAE) / American Epilepsy Society (AES) Task Force on the cardiac effects of lamotrigine was convened in response to a recent addition to the lamotrigine label by the US Food and Drug Administration (FDA). Lamotrigine is the nonproprietary name for a medicine that is sold under its generic name and several brand names including Lamictal™. The present advisory is based on an assessment of currently available evidence. It is not intended to replace regulatory requirements, nor is it intended to be an exhaustive review. The purpose of this advisory is to advise healthcare professionals worldwide on how to minimize cardiac safety risks associated with lamotrigine use.

The Psychiatric Effects of Ketogenic Diet Therapy on Adults With Chronic Epilepsy

Abstract, originally published in Epilepsy & Behavior

Objectives: Patients with epilepsy are known to exhibit high rates of comorbid psychiatric disorders such as depression, anxiety, and other mood disorders. Little is known about the psychiatric effects of a ketogenic diet therapy (KDT) on adults with epilepsy. The objective of this study was to better understand the relationship between KDT and psychological state based on depressive and anxiety symptoms in adults with chronic epilepsy.

Methods: Adults at the Johns Hopkins Adult Epilepsy Diet Center on a modified Atkins diet (MAD) for at least one month were surveyed retrospectively. Adults who were diet naïve were given a baseline survey and an additional survey after 3 months or more on MAD. Surveys included validated measures of depressive and anxiety symptoms as well as their severity. Participant demographics, seizure frequency, and use of concomitant antiseizure drugs (ASDs), chronic anxiolytics (excluding as-needed benzodiazepines for seizure rescue only), and/or antidepressant drugs were extracted from electronic medical records.

Results: One-hundred participants aged 19-75 enrolled in the study. Sixty participants filled out a single retrospective survey. Of 40 diet naïve participants who filled out a baseline prospective survey, 19 completed a follow-up survey while on MAD and 21 participants were lost to follow-up. Longer diet duration was significantly associated with fewer anxiety and depressive symptoms, based on psychiatric measure scores, in retrospective study participants. Lower seizure frequency was also significantly associated with less anxiety symptoms in the retrospective cohort. Prospective study participants did not experience significant change in anxiety or depressive symptoms on the diet. There was a significant correlation between higher ketone level and responder rate (?50% seizure reduction) in the prospective cohort, although no correlation between ketone level and change in psychiatric symptoms was seen.

Significance: Psychiatric comorbidity among patients with epilepsy is quite common and can be influenced by multiple factors such as seizure frequency, the use of various ASDs, social factors, and underlying etiology. Although ketogenic diet therapies have been in clinical use for one century, the psychiatric impacts have been insufficiently explored. This study provides preliminary evidence that ketogenic diet therapy may have a positive impact on psychological state independent of seizure reduction or ketone body production and may be influenced by longer duration of diet therapy. These results support further investigation into specific effects and potential therapeutic benefits on various psychiatric disorders.

Developmental Outcome After Corpus Callosotomy for Infants and Young Children with Drug-Resistant Epilepsy

Abstract, originally published in Epilepsy & Behavior

Aim: To examine the developmental and seizure outcomes after corpus callosotomy (CC) in early childhood.

Methods: We retrospectively identified 106 patients who underwent CC for drug-resistant epilepsy before the age of 6 years, at the Nagasaki Medical Center, between July 2002 and July 2016. Patients’ developmental outcomes were evaluated one year after CC using the Kinder Infant Development Scale.

Results: The mean preoperative developmental quotient (DQ) was 25.0 (standard deviation [SD], 20.8), and the mean difference between preoperative DQ and one-year postoperative DQ was -1.6 points (SD, 11.6). However, 42.5% of patients had a mean DQ increase of 6.5 points (SD, 6.4), one year after CC from that before surgery. Factors related to the improvement in postoperative DQ were ‘low preoperative DQ’, ‘developmental gain 1 month postoperatively’, and ‘postoperative seizure-free state’. Approximately 21.7% of patients were seizure-free 1 year after CC.

Interpretation: Performing corpus callosotomy, in infancy and early childhood for patients with drug-resistant epilepsy and severe developmental impairment, was associated with improved development in 42.5% of patients. Remission of seizures, even if only for a short period, contributed to developmental improvement. From a developmental perspective, corpus callosotomy for drug-resistant epilepsy in early childhood is an effective treatment.

Everolimus in Adult Tuberous Sclerosis Complex Patients With Epilepsy: Too Late for Success? A Retrospective Study

Abstract, originally published in Epilepsia

Objective: There is evidence that everolimus (EVE) significantly reduces seizure frequency in epilepsy patients with tuberous sclerosis complex (TSC). Given that TSC-related proliferative processes are more dynamic during brain development, seizure outcomes of patients treated with EVE may be age-related and may be less convincing in adult patients. The aim of this study was to assess the effectiveness and the safety profile of EVE in adults in clinical practice.

Methods: We performed a multicenter retrospective chart review of TSC subjects with active epilepsy who started EVE in adulthood (?18 years of age) at seven German epilepsy centers. The primary endpoint was the retention rate after 6 months.

Results: A total of 45 subjects with a mean age of 31.6 ± 11.1 years at EVE start fulfilled the inclusion criteria. Retention rate after 6 months was 98% (43/44 evaluable subjects). Response rate (seizure reduction – 50%) was 33% (14/43 evaluable subjects; four completely seizure-free). We did not find a significant relationship between epilepsy outcome parameters and patient age at EVE start. Adverse events were reported in 19 subjects and were judged to be serious in six patients. Three patients died during the observation period.

Significance: Evidence suggests that EVE is an effective add-on treatment for epilepsy in adult TSC patients, surprisingly without any age limit to individual benefit. A strong age-dependent effect within the period of adulthood seems unlikely. Even if there was no proof of a causal relationship between deaths and EVE intake, patients with EVE should be carefully monitored, especially for infections and stomatitis.

Montelukast: The New Therapeutic Option for the Treatment of Epilepsy

Abstract, originally published in DovePress

Currently, there is no definitive cure for epilepsy. The available medications relieve symptoms and reduce seizure attacks. The major challenge with the available antiepileptic medication is safety and affordability.

The repurposing of montelukast for epilepsy can be an alternative medication with a better safety profile. Montelukast is a leukotriene receptor antagonist that binds to the cysteinyl leukotrienes (CysLT) receptors used in the treatment of bronchial asthma and seasonal allergies. Emerging evidence suggests that montelukast’s anti-inflammatory effect can help to maintain BBB integrity. The drug has also neuroprotective and anti-oxidative activities to reduce seizure incidence and epilepsy. The present review summarizes the neuropharmacological actions of montelukast in epilepsy with an emphasis on the recent findings associated with CysLT and cell-specific effects.

Metabolic Bone Disease in Patients with Epilepsy and the Use of Antiepileptic Drugs

Summary, originally published in Seizure – European Journal of Epilepsy

The epilepsy patient population is identified to be at an increased risk of fractures, even after accounting for seizure-related fractures. In a large unselected population of Danish patients with epilepsy, researchers here examined if this is attributable to adverse effects of antiepileptic drugs (AEDs) by assessing the association between the use of AEDs and decreased BMD.

This cross-sectional study was performed including data retrieved from 835 patients visiting an outpatient Epilepsy Clinic in Glostrup, Denmark. An increased risk of osteoporosis was observed for patients with epilepsy who use enzyme-inducing AEDs, were on polytherapy with AEDs and had increased duration of epilepsy, even after accounting for many risk factors.

Astrocytes Might Be a Potential New Target to Better Treat Epilepsy

Summary, originally published in News Medical

A significant number of epilepsy patients does not respond to currently available drugs. A collaboration between researchers in Japan and at the Heinrich Heine University Düsseldorf (HHU) now addressed a cell type in the brain that has so far not received much attention in epilepsy therapy. In the current edition of the Journal of Neuroscience, they describe that astrocytes might be a potential new target to better treat this disease.

Together with colleagues in Japan, Prof. Dr. Christine Rose and her doctoral student Jan Meyer from the Institute of Neurobiology at HHU have performed a study to address the cellular mechanisms that promote the development of epilepsy. While up to now, most studies and anti-epileptic drugs targeted nerve cells (neurons), this research team focused on a class of glial cells known as astrocytes.

In their recent paper, the researchers show that epileptic discharges lead to a rise in the pH of astrocytes, that is in their intracellular ‘alkalization’. The change in pH disrupts the communication within the intercellular astrocyte networks. This reduced communication between astrocytes appears to exacerbate epileptic activity of neurons.

This finding points towards a potential new target for suppressing epileptogenesis at a very early stage, namely by using drugs to suppress changes in astrocytic pH accompanying neuronal activity.

Seizure Detection Devices: Exploring Caregivers’ Needs and Wishes

Abstract, originally published in Epilepsy & Behavior

Introduction: User preferences for seizure detection devices (SDDs) have been previously assessed using surveys and interviews, but these have not addressed the latent needs and wishes. Context mapping is an approach in which designers explore users’ dreams and fears to anticipate potential future experiences and optimize the product design.

Methods: A generative group session was held using the context mapping approach. Two types of nocturnal SDD users were included: three professional caregivers at a residential care facility and two informal caregivers of children with refractory epilepsy and learning disabilities. Participants were invited to share their personal SDD experiences and briefed to make their needs and wishes explicit. The audiotaped session was transcribed and analyzed together with the collected material using inductive content analysis. The qualitative data was classified by coding the content, grouping codes into categories and themes, and combining those into general statements (abstraction).

Results: “Trust” emerged as the most important theme, entangling various emotional and practical factors that influence caregiver’s trust in a device. Caregivers expressed several factors that could help to gain their trust in an SDD, including integration of different modalities, insight on all parameters overnight, personal adjustment of the algorithm, recommendation by a neurologist, and a set-up period. Needs regarding alerting seemed to differ between the two types of caregivers in our study: professional caregivers preferred to be alerted only for potentially dangerous seizures, whereas informal caregivers emphasized the urge to be alerted for every event, thus indicating the need for personal adjustment of SDD settings.

Conclusion: In this explorative study, we identified several key elements for nocturnal seizure detection devices implementation including the importance of gaining trust and the possibility to adjust seizure detection devices settings for different types of caregivers.

Epilepsy Research News: January 2021

This month’s research news includes announcements about CURE Epilepsy’s Frontiers in Research seminar series, and an announcement from the CDC about an incidence and etiology funding opportunity.

We also share that the NINDS Clinical Trials Methodology Course is accepting applications, and that the deadline to apply to the National Science Foundation Enabling Discovery Through Genomics (EDGE) Program is March 16.

These news items are summarized below.

Research Highlights

CURE Epilepsy’s Frontiers in Research Seminar Series has gone virtual!

As part of our on-going commitment to supporting the research community through these difficult times, we are conducting our research seminar series virtually with the topics below. Mark your calendars!

The virtual Frontiers in Research Seminar Series is sponsored by the Nussenbaum-Vogelstein Family.

Learn more

CDC Epilepsy Incidence and Etiology Funding Opportunity Announcement
Projects are intended to inform incidence and social determinants of epilepsy including risk factors and protective factors that affect epilepsy incidence. Information about epilepsy incidence will provide invaluable information to help better guide interventions or services for preventing epilepsy, treating and rehabilitating people with epilepsy, and minimizing their health disparities and adverse outcomes.

Click here for details. Search opportunity number by RFA-DP-21-004 and SIP 21-007.

Learn More

NINDS Clinical Trials Methodology Course-Application Deadline February 28
The NINDS Clinical Trials Methodology Course (CTMC) is accepting applications for the 2021 cohort. The overarching goal of the CTMC is to help investigators develop scientifically rigorous, yet practical clinical trial protocols. The focus is on investigators who have not previously designed their own prospective, interventional clinical trials.

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National Science Foundation Enabling Discovery Through Genomics (EDGE) Program-Application Deadline March 16
The goal of the EDGE program is to provide support for genomic research and associated theory, approaches, tools, and infrastructure development to address the mechanistic basis of complex traits in diverse organisms within the context (environmental, developmental, social, and/or genomic) in which they function.

Learn More

First-Ever Attempt to Treat Naturally Occurring Epilepsy in an Animal Using Transplanted Cells

Abstract, originally published by University of California San Francisco

A cellular therapy for epilepsy developed at UC San Francisco has been employed for the first time in a sea lion with intractable seizures caused by ingesting toxins from algal blooms. The procedure is the first-ever attempt to treat naturally occurring epilepsy in any animal using transplanted cells.

Since 2009, the lab of former CURE Epilepsy Grantee Dr. Scott Baraban has been developing a way to replace these damaged interneurons by transplanting embryonic MGE (medial ganglionic eminence) progenitor cells into the hippocampus. As discovered two decades ago by Baraban’s UCSF colleagues Arturo Álvarez-Buylla, PhD, and John Rubenstein, PhD, MGE cells normally migrate into hippocampus during brain development and integrate themselves into the local circuitry as inhibitory neurons.

Baraban’s group has shown that it’s possible to transplant embryonic MGE cells into the brains of adult rodents with temporal lobe epilepsy, where they quickly spread through the hippocampus and repair its damaged circuitry. The procedure reliably reduces seizures in these animals by 90 percent, along with other side effects of epilepsy, such as anxiety and memory problems.