Synergistic Effects of the Neuropeptide Galanin Analog 810-2 with the Antiseizure Medication Levetiracetam (Keppra ®) in Rodent Seizure Models

Abstract found on PubMed 

Objective: The use of many antiseizure medications (ASMs) is limited due to pharmacoresistance and dose-limiting side effects, suggesting an unmet need for novel therapeutic approaches. The neuropeptide galanin reduces seizures in several preclinical seizure and seizure models but its clinical utility is limited due to rapid metabolism and poor blood-brain barrier penetration. The lead galanin analog 810-2 is systemically bioavailable and reduces seizures when administered alone. Further development of this analog, with the potential for use as an add-on therapy in patients with epilepsy, requires a better understanding of the use of this analog in combination with approved ASMs. We sought to evaluate 810-2 in combination with commonly used ASMs in rodent models of seizures.

Methods: The mouse 6 Hz seizure assay was used to test efficacy of 810-2 in combination with either levetiracetam (LEV), valproic acid (VPA), or lacosamide (LCM) using 1:1 dose ratios in isobolographic studies. Further characterization was performed for the combination of 810-2 and LEV in the mouse corneal kindling and rat 6 Hz assays.

Results: While the combination of 810-2 with VPA and LCM yielded additive interactions, the combination of 810-2 with LEV demonstrated a synergistic interaction in the mouse 6 Hz assay. Supra-additive effects were also observed in the mouse corneal kindling and rat 6 Hz assays for this combination.

Significance: The combination of the neuropeptide galanin analog 810-2 with levetiracetam suggests the potential for this galanin analog to be further developed as an add-on therapy for patients with epilepsy, particularly when co-administered with levatiracetam.

Study to Use Tracking Technology to Predict Epileptic Seizure Patterns

Article published by Mid-Tech Innovation News

A new study will use long term seizure tracking technology to monitor and potentially predict patterns in epileptic seizures using continuous data collection of brain activity in people with drug-resistant epilepsy.

The Real World Testing and Cost-effectiveness Analysis of Subcutaneous EEG (REAL-ASE) trial, which is being led by the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London and funded by the NIHR, hopes to establish if the use of a small implant that records brain activity can improve outcomes for treatment and care.

While seizures can occur in predictable patterns, it is difficult to accurately track how often seizures occur as it relies on the person affected manually documenting their attacks in a diary. As seizures can have an amnesic effect, and can happen while a person is asleep, accurately recording these events is often not possible.

Subcutaneous implanted EEG is a new technology. Conventional EEG technology either requires the person to be admitted to hospital or be tested at home, using EEG electrodes glued to their scalp, which can be undertaken for only a few days. NHS waiting lists for these tests can vary from months to years. Subcutaneous implanted EEG, the technology being trialed in this study, enables researchers to continuously record EEG in an unobtrusive way, for up to 15 months, while the person lives their life completely normally.

The trial will recruit 33 people with drug resistant epilepsy and implant a miniaturised electroencephalogram (EEG) device just under their scalp during a minimally invasive, twenty-minute procedure that is performed under local anaesthetic. Researchers will then monitor each person’s brainwaves over six months. By tracking the brainwaves, researchers can count the person’s seizures, which enables them to provide reliable information to clinicians, as an alternative to seizure diaries.

Long Term Outcomes After New-Onset Refractory Status Epilepticus (NORSE): Treatment with Vagus Nerve Stimulation

Abstract found on Wiley Online Library

New-onset refractory status epilepticus (NORSE) is associated with high mortality, therapy resistant epilepsy (TRE) and poor cognitive and functional outcomes. Some patients develop multifocal TRE, for whom surgery with a curative intention, is not an option. In these patients, Vagus Nerve Stimulation (VNS) is performed as a palliative treatment. We report the long-term outcomes regarding seizure frequency, functional and cognitive outcome, and effectiveness of VNS in two patients with TRE as a consequence of NORSE. In the first patient with cryptogenic new-onset refractory status epilepticus, vagus nerve stimulation implantation occurred during the acute stage, probably contributing to the cessation of her status epilepticus. However, in the long-term follow-up, the patient persisted with daily multifocal seizures. In the second patient, VNS implantation was delayed to manage his epilepsy when the NORSE, ultimately due to autoimmune encephalitis, had resolved. During long-term follow-up, no reduction in seizure frequency was achieved. The current evidence supporting the use of vagus nerve stimulation in patients with therapy resistant epilepsy after new-onset refractory status epilepticus warrants further investigation.

Successful Treatment of Adult Dravet Syndrome Patients with Cenobamate (XCOPRI ®)

Abstract found on Wiley Online Library

Dravet syndrome (DS) is a rare drug resistant severe developmental and epileptic encephalopathy caused by pathogenic variants in the ? subunit of the voltage-gated sodium channel gene SCN1A. Hyperexcitability in DS results from loss of function in inhibitory interneurons. Thus, sodium channel blockers are usually contraindicated in DS patients as they may lead to disease aggravation. Cenobamate (CNB) is a novel anti-seizure-medication (ASM) with promising rates of seizure freedom in patients with focal-onset drug resistant epilepsy. CNB blocks persistent sodium currents by promoting the inactive states of sodium channels. In a multi-center study, we analyzed retrospectively the effect of an add-on therapy of CNB in adult patients with DS. We report four adult patients with DS in whom the use of CNB resulted in a significant seizure reduction of more than 80%, with a follow-up of up to 542?days. CNB was the first drug in these patients that resulted in a long-lasting and significant seizure reduction. No severe adverse events occurred. We highlight cenobamate as an antiseizure medication that may lead to a clinically meaningful reduction of seizure frequency in adult patients with Dravet syndrome. It is, however, unclear if all patients with DS benefit, requiring further investigation and functional experiments.

Bone Development in Offspring of Pregnant Rats Treated with Carbamazepine: (Tegretol ®) Evaluation by Three Different Methods

Abstract found on Wiley Online Library

Objective: This study was carried out to determine the effect of intrauterine carbamazepine (Tegretol ®) exposure on fetal bone development during pregnancy.

Methods: In the study, 24 female pregnancy rats were used: Wistar. Rats were 20?weeks old. They have an average body weight of 150-200 grams. Pregnancy rats were randomly selected and divided (n=6) into control group, low dose CBZ (10 mg/kg/day) group, medium dose CBZ (25 mg/kg/day) group and high dose CBZ (50 mg/kg/day) group. The ossification length (mm) and ossification area (mm2) of the long bones of the fetuses in the experimental and control groups were calculated. The densities of alkaline phosphatase (AP) and tartrate resistant acid phosphatase (TRAP) were analyzed. The ossification regions of the femurs of the fetuses were examined under a light microscope. Microstructural images of the femurs were evaluated with scanning electron microscope photographs. The densities of minerals involved in the ossification process were analyzed.

Results: According to the results of the study, all three doses of CBZ caused loss of ossification areas and it was observed that this bone loss also increased statistically significantly depending on the dose increase (p<0.05). Calcium concentration decreased in the CBZ groups. When the electron microscope images were examined, it was determined that the cartilage matrix of the CBZ groups was thinned. In the histological evaluation of the groups, narrowing of the primary bone collar and smaller bone spicules in the ossification region compared to the control group were noted due to the increase in dose in the CBZ groups. In immunohistochemical staining; ?t was observed that the TRAP and AP expression values ??of the femurs were the lowest in the CBZ groups. These decreases were also statistically significant when compared with the control group.

Significance: As a result, it was revealed with both microscopic and macroscopic findings that exposure to intrauterine CBZ negatively affected ossification and bone growth.

CBD Epidiolex Fails to Improve Life Quality in Dravet Children in Study

Article published by Dravet Syndrom News

Management of Functional Seizures and Functi Six months of treatment with the oral cannabidiol (CBD) solution Epidiolex among children and adolescents with Dravet syndrome or Lennox-Gastaut syndrome (LGS) was not associated with improvements in caregiver-reported quality of life or adaptive behaviors.

That’s according to a small Korean study — though researchers noted that the ability to identify such improvements may have been hampered by the clinical severity of the included patients. These children had treatment-resistant seizures, significant developmental delays, and intellectual disability.

“The relationship between CBD and [quality of life] needs to be investigated in larger patient populations,” the researchers wrote.

“CBD has been found to be an efficacious antiseizure drug for patients with Lennox-Gastaut syndrome and Dravet syndrome, but it did not improve [quality of life] in pediatric patients with treatment-resistant epilepsy in our study,” the team wrote.

The study, “Effects of Cannabidiol on Adaptive behavior and Quality of Life in Pediatric Patients With Treatment-Resistant Epilepsy,” was published in the Journal of Clinical Neurology.

Cannabidiol, also called CBD, is the major non-psychoactive component of the cannabis plant, and has received considerable recent attention for its therapeutic properties.

Expert Consensus Opinions Published in Neurology and Therapy Discuss Adjustment of Anti-Seizure Medication Dosing for Optimal Care

Published by SK Life Science

Featuring the work of CURE Epilepsy grantee Dr. Pavel Klein

Consensus opinions report that lowering the doses of certain anti-seizure medications (ASMs) when beginning treatment with XCOPRI® (cenobamate tablets) CV may help manage possible side effects. SK Life Science, Inc. announced the publication in the journal Neurology and Therapy.

“When a new medication is added to a patient’s antiseizure medication (ASM) regimen, it is important to consider the overall drug load that may increase the possibility for adverse reactions,” said Pavel Klein, M.D., epileptologist and neurologist, Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD. “To help manage those potential adverse events, when adding the new medication, you may consider reducing the dose of existing ASMs” 

Why Does Fasting Reduce Seizures?

Article found on MedicalXpress

Calorie restriction has long been associated with reduced seizures in epilepsy. New research from Boston Children’s Hospital helps explain how fasting affects neurons in the brain and could lead the way to new approaches that would avoid the need for fasting or restrictive diets. The findings were published August 30 in the journal Cell Reports.

“This study is the first step in understanding how dietary therapies for epilepsy work,” says first author Christopher J. Yuskaitis, MD, Ph.D., a neurologist with the Epilepsy Center and Epilepsy Genetics Program at Boston Children’s Hospital. “The mechanisms have until now been completely unknown.”


DEPDC5, mTOR, and fasting

To connect the dots between diet and seizures, the researchers began with existing knowledge. They knew that the well-known mTOR cellular pathway is involved in many neurological disorders and had shown previously that over-activation of this pathway in neurons increases susceptibility to seizures. Studies by others had shown that mTORC activity is inhibited by acute fasting, though these studies didn’t look at the brain.

In the new study, they showed in a mouse seizure model that mTOR signaling was reduced in the brain after fasting. Additional studies of cultured rat neurons in a dish suggest that this fasting effect is primarily driven by the lack of three amino acids (leucine, arginine, and glutamine).

Going further, the team demonstrated that the presence of these nutrients is sensed by the DEPDC5 protein. When they knocked out DEPDC5 in the brain, mTOR activity was not reduced and fasting no longer protected the mice against seizures.

Irritability and Its Relationship with Psychosocial Symptoms and Quality of Life in Adolescents with Epilepsy Receiving Levetiracetam Therapy: A Case-Control Study

Abstract found on PubMed 

Background: Levetiracetam, a widely used anticonvulsant drug in children and adolescents, has been associated with irritability, psychosocial symptoms, and low quality of life, which are also influenced by other epilepsy variables.

Purpose: The objective of this study was to investigate the level of treatment-related irritability in adolescents receiving levetiracetam, and to evaluate the relationship between irritability levels and psychosocial symptoms, and quality of life.

Methods: A cross-sectional, case-control study was conducted. Consecutive adolescent patients with epilepsy aged 11-17 years with partial or generalized seizures, treated with either levetiracetam or valproic acid for at least 6 months, and healthy controls were recruited. The Affective Reactivity Index parent report and self-report, Strengths and Difficulties Questionnaire, and Pediatric Quality of Life Inventory-Psychosocial subscale were utilized to assess irritability, psychosocial symptoms, and functioning.

Results: A total of 120 participants were analyzed; 33 patients in the LEV group, 45 patients in the VPA group, and 42 healthy controls. Both self and parent report irritability levels of the LEV group were found to be significantly higher than those of healthy controls. The irritability levels of the LEV and VPA groups were not statistically different, but still the LEV group had higher irritability levels on both scales. In the LEV group, irritability was positively correlated with behavioral, emotional, and attention/hyperactivity problems, and also negatively correlated with psychosocial quality of life.

Conclusion: Adolescents with epilepsy using LEV have a high level of irritability and this is associated with some psychosocial symptoms and poor quality of life.

AI Model May Help Epilepsy Patients Become Seizure-Free

Article published by Medical Xpress

A study led by Monash University and believed to be a world first has demonstrated that an Artificial Intelligence (AI) model can potentially predict the best personalized, anti-seizure medication for patients with newly diagnosed epilepsy.

The predictive model, once fully developed, would spare these patients the uncertainty of not knowing when their lives would be returned to normal by taking anti-seizure medications, and possibly the harmful side-effects associated with some drugs.

Professor Patrick Kwan, a neurologist and researcher from the Monash Central Clinical School’s Department of Neuroscience is leading an international collaboration that is “training” the deep-learning prediction model (deep learning is a type of machine learning).

Their study is published in the influential JAMA Neurology.

“If the patient doesn’t respond to the first treatment, quite a few will respond to the second or third one, meaning that they might have become seizure-free sooner if the ‘right’ drug was chosen at the outset,” he said. “But if they get the wrong medication they still have seizures and may also get side-effects from it—they’re not getting the benefit and are getting harm from the drug.”