New Insight into Brain Inflammation Inspires New Hope for Epilepsy Treatment 

Article published by The Scientist

Doctors treat epilepsy with anticonvulsants to control seizures, but some patients do not respond to these first-line therapies. For patients with drug-refractory epilepsy (DRE), whose seizures persist after treatment with two or more anticonvulsants, clinicians must surgically remove part of the brain tissue to cure the disease.

When first-line medicines fall short, scientists examine the molecular mechanisms of a disease to understand why and to develop alternatives. At Duke-NUS Medical School and KK Women’s and Children’s Hospital, clinicians and researchers teamed up to investigate how inappropriate proinflammatory mechanisms contribute to DRE pathogenesis. This work builds on evidence from animal models and resected brains of human patients that associated inflammation with epilepsy. Derrick Chan, a clinician scientist at KK Women’s and Children’s Hospital believes this research is an extension of his clinical work. “[T]his direction became really important, because we were looking for a less invasive way to try to help all the children with drug resistant epilepsy,” he said.

Chan and his team partnered with the immunology research group of fellow physician scientist, Salvatore Albani. In a study published in Nature Neuroscience, Chan and Albani described their efforts to understand the immunologic factors that contribute to DRE pathology. They examined the holistic involvement of the immune system in epileptic tissue that clinicians surgically removed from patients. The researchers used a single-cell 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 DRE lesions that resembles brain autoimmune diseases, such as multiple sclerosis (MS).

The researchers identified cell types and their functions in DRE lesions at single-cell resolution and differentiated resident brain and neurovascular cells from infiltrating immune cells. They found that the DRE microenvironment includes activated microglia and other proinflammatory immune cells, and they captured cellular interactions with additional molecular analyses. “We had not expected these interactions between microglia and other immune cells, and then how these microglia become kind of a pivot to attract all of the immune cells by starting this proinflammatory milieu inside the brain,” explained Pavanish Kumar, the first author of the study.

Patients With Epilepsy May Benefit from Muscle Relaxation Exercises, Study Finds 

Article published by AJMC

A study on the effects of progressive muscle relaxation (PMR) exercises in patients with epilepsy found a significant decrease in depressive symptoms, improved sleep, and improved quality of life.

“Progressive muscle relaxation exercise enables individuals to feel the difference between tension and relaxedness and teaches individuals to relax on their own,” wrote the authors of this study. “It also provides relaxation and peace while reducing physical and emotional tension.”

This randomized controlled intervention study was published in Seizure – European Journal of Epilepsy.

The study included a total of 70 participants diagnosed with epilepsy. The participants were divided into control and intervention groups between November 1, 2022, and April 15, 2022. The patients in the intervention group underwent 12 PMR exercise sessions, 3 days a week, for 4 weeks.

PMR exercises are mind-body practices that create relaxation through regular and voluntary relaxation of large muscles, with many benefits such as improving mental and physical states of stress, pain, and fatigue.

Risk of Sudden Unexpected Death in Epilepsy (SUDEP) with Lamotrigine (Lamictal ®) and Other Sodium Channel Modulating Antiseizure Medications

Abstract found on Wiley Online Library

Objective: In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti-seizure medication (NaM-ASM), could increase risk of sudden death in patients with structural or ischaemic cardiac disease, however its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear.

Methods: This retrospective, nested case-control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM-ASM use were compared between cases and controls at time of admission, and survival analyses from time of admission up to 16?years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors.

Results: Proportions of cases and controls prescribed lamotrigine (p=0.166), one NaM-ASM (p=0.80) or ?2NaM-ASMs (p=0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR]=0.56; p=0.054), one NaM-ASM (aHR=0.8; p=0.588) or ?2 NaM-ASMs (aHR=0.49; p=0.139) at EMU admission were not at increased SUDEP risk up to 16?years following admission. Active tonic-clonic seizures at EMU admission associated with >2-fold SUDEP risk, irrespective of lamotrigine (aHR=2.24; p=0.031) or NaM-ASM use (aHR=2.25; p=0.029). Sensitivity analyses accounting for incomplete ASM data at follow-up suggest undetected changes to ASM use are unlikely to alter our results.

Significance: This study provides additional evidence that lamotrigine and other sodium channel-modulating anti-seizure medications are unlikely to be associated with an increased long-term risk of SUDEP, up to 16?years post epilepsy monitoring unit admission.

Is the Antiparasitic Drug Ivermectin a Suitable Candidate for the Treatment of Epilepsy?

Abstract found on PubMed

There are only a few drugs that can seriously lay claim to the title of “wonder drug” and ivermectin, the world’s first endectocide and forerunner of a completely new class of antiparasitic agents, is among them. Ivermectin, a mixture of two macrolytic lactone derivatives (avermectin B1a and B1b in a ratio of 80:20), exerts its highly potent antiparasitic effect by activating the glutamate-gated chloride channel that is absent in vertebrate species. However, in mammals, ivermectin activates several other Cys-loop receptors, including the inhibitory GABAA and glycine receptors and the excitatory nicotinic acetylcholine receptor of brain neurons. Based on these effects on vertebrate receptors, ivermectin has recently been proposed to constitute a multifaceted wonder drug for various novel neurological indications, including alcohol use disorders, motor neuron diseases, and epilepsy. This review critically discusses the preclinical and clinical evidence of anti-seizure effects of ivermectin and provides several arguments why ivermectin is not a suitable candidate drug for the treatment of epilepsy. First, ivermectin penetrates the mammalian brain poorly, so it does not exert any pharmacological effects via mammalian ligand-gated ion channels in the brain unless it is used in high, potentially toxic doses or the blood-brain barrier is functionally impaired. Second, ivermectin is not selective but activates numerous inhibitory and excitatory receptors. Third, the preclinical evidence for anti-seizure effects of ivermectin is equivocal and, at least in part, ED50 s in seizure models are in the range of the LD50 . Fourth, the only robust clinical evidence of anti-seizure effects stems from the treatment of patients with onchocerciasis in which the reduction of seizures is due to a reduction in microfilariae densities but not a direct anti-seizure effect of ivermectin. We hope that this critical analysis of available data will avert that the unjustified hype associated with the recent use of ivermectin to control COVID-19 recurs also in neurological diseases such as epilepsy.

Epilepsy Research News: January 2023

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Genetic Testing for Epilepsy Improves Patient Outcomes

Genetic testing in patients with epilepsy can inform treatment and lead to better outcomes in many cases, according to a new study. The study, led and funded by the genetic testing company Invitae, included patients referred for genetic testing between 2016 and 2020 whose testing revealed a positive molecular diagnosis. The investigators asked the patient’s healthcare providers how the results of the genetic test impacted the patient’s treatment plan and outcomes. Of the 418 children and adults with epilepsy who were included in the study, nearly half saw changes in their treatment plans such as a change in medication or referral to a specialist, after genetic testing revealed new information about their condition. The study also found that of 167 patients with follow-up information available, treatment changes were associated with improved patient outcomes including a reduction or elimination of seizures. The authors concluded that results support the use of genetic testing to guide the clinical management of epilepsy to improve patient outcomes. Learn more about genetic testing for epilepsy here.

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New Tools to Map Seizures and Improve Epilepsy Treatment

A new “tool” – a statistical model – has been developed to help doctors find precisely where seizures originate in the brain to increase the possibility of treating that specific region. Localizing where seizures begin is usually a costly and time-consuming process that can often require days to weeks of invasive monitoring. In this study, researchers aimed to shorten the time it takes to locate the seizure onset zone by studying patients’ brains, both when they weren’t having seizures and when their brains were stimulated with quick electrical pulses, to quickly create maps predicting where seizures begin. In the 65 patients studied, the model predicted the location of the onset of seizures and the ultimate success of surgical intervention with 79% accuracy. The researchers noted that this tool might be used to help clinicians identify the area where seizures begin in a less time-consuming process.

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Gene Therapy for Epilepsy

A recently published study shows that a potential new treatment can prevent seizures in mice by clearing the accumulation of a protein in the brain known as the tau protein. Researchers at Macquarie University recently found that accumulation of tau protein can lead to neurons becoming hyperexcited. Hyperexcited neurons that fire continuously can result in seizures and cognitive decline. In the newly published study, the researchers developed a gene therapy that uses a brain enzyme known as p38y to prevent this accumulation. When treated with the new gene therapy, mice with uncontrolled epilepsy had a better chance of survival in addition to reduced seizure susceptibility. The researchers note that their next step is to conduct a more detailed study in the laboratory, in hopes of eventually preparing the treatment for a possible clinical trial.

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World Health Organization (WHO) Focuses on Improving the Lives of People with Epilepsy

A technical brief published by the World Health Organization (WHO) called Improving the Lives of People with Epilepsy sets out the actions required to deliver an integrated approach to epilepsy care and treatment with the goal of meeting the multifaceted needs of people with epilepsy. In summary, the brief highlights the importance of:

 

  • Integrated services across the life-course, particularly at the primary care level

  • Access to anti-seizure medicines

  • Resources and training for the health and social services workforce

  • Anti-stigma and discriminatory legislation and practices; promoting and respecting the human rights and full social inclusion of people with epilepsy, their families and caregivers.

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Memory Impairment in Those with Epilepsy

People with chronic epilepsy often experience impaired memory. Researchers have now found a mechanism using a mouse model of epilepsy that could explain this impairment. Porous channels called ion channels within the brain allow electrically charged particles (ions) to flow into neurons, allowing neurons to communicate with each other. However, the researchers found changes in sodium ion channels within neurons of the hippocampus – an area of the brain important in learning and memory – that could lead to changes in the activity of these neurons and affect their normal function. When the researchers administered substances to restore the normal function of these channels, the firing properties of the neurons normalized, and the animals were better able to remember places they had visited. The study provides insight into the processes involved in memory retrieval. In addition, it provides support for the idea that the development of new drugs may improve the memory of epilepsy patients.

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Can Diet Combined with Drugs Reduce Seizures?

Article found on Science Daily

Following a modified Atkins diet high in fat and low in carbohydrates plus taking medication may reduce seizures in people with tough-to-treat epilepsy, according to a study published in the January 4, 2023, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“For people with drug-resistant epilepsy, or those who have been unable to find effective treatment to reduce seizures, it’s encouraging to see that there are lifestyle changes that can be combined with standard drug therapy to reduce the number of seizures,” said study author Manjari Tripathi, MD, DM, of All India Institute of Medical Sciences in New Delhi. “Our study found that this combination may reduce the chance of seizures by more than half.”

The modified Atkins diet is a combination of the Atkins diet and a ketogenic diet that includes food items such as soy products, heavy cream, butter and oils, leafy green vegetables, and animal protein including eggs, chicken, fish, and bacon. While the ketogenic diet has been shown to be effective in reducing seizures, its stringent requirements and restrictions can make it difficult to follow.

The study involved 160 adults and adolescents who had epilepsy for more than 10 years on average and had at least 27 seizures per month despite trying an average of four antiseizure medications at the maximum tolerated dose. They were randomly assigned to receive either standard drug therapy alone or drugs plus the modified Atkins diet over six months.

The study also looked at quality of life, behavior and side effects at six months. The group that had drug therapy and followed the modified Atkins diet showed an improvement in all areas compared to the group that had drug therapy alone.

Tripathi noted that 33% of the participants did not complete the study due to poor tolerance of the diet, lack of benefit or the inability to follow-up in part due to COVID-19. However, Tripathi said tolerance of the modified Atkins diet was better than what is seen with the ketogenic diet.

Spain-Based Study: Epidyolex Safely Helps Prevent Seizures

Article published by Dravet Syndrome News

The efficacy and safety of Epidiolex, an oral cannabidiol, in children and adults with Dravet syndrome and Lennox-Gastaut syndrome (LGS) were supported in a real-world setting, with benefits similar to those seen in previous clinical trials and expanded access programs (EAPs), a Spanish EAP study reported.

EAPs are designed to make promising therapies available to eligible patients in the real-world setting before their regulatory approval.

The study, “Outcomes from a Spanish Expanded Access Program on cannabidiol treatment in pediatric and adult patients with epilepsy,” was published in the journal Epilepsy & Behavior.

Long-Term Efficacy and Safety of Cannabidiol (Epidiolex®) in Patients with Treatment-Resistant Epilepsies: 4-Year Results from the Expanded Access Program

Abstract found on PubMed

Objective: Cannabidiol (CBD) expanded access program (EAP), initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsy (TRE) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019.

Methods: Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/mL oral solution), increasing from 2-10 mg/kg/d to tolerance or maximum 25-50 mg/kg/d dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ?50%, ?75%, and 100% responder rates across 12-week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit.

Results: Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the most commonly reported primary reasons for withdrawal. Median (range) age was 11.8 years (0-74.5), and patients were taking a median (range) 3 (0-10) antiseizure medications (ASMs) at baseline; most common ASMs were clobazam (47%), levetiracetam (34%), and valproate (28%). Median top CBD dose was 25 mg/kg/d; median exposure duration was 694 days. Median percentage reduction from baseline ranged from 50%-67% for convulsive seizures and 46%-66% for total seizures. Convulsive seizure responder rates (?50%, ?75%, and 100% reduction) ranged from 51%-59%, 33%-42%, and 11%-17% of patients across visit windows, respectively. AEs were reported in 88% of patients and serious AEs in 41%; 8% withdrew because of an AE. There were 20 deaths during the study deemed unrelated to treatment by the investigator. Most common AEs (?20% of patients) were diarrhea (33%), seizure (24%), and somnolence (23%).

Significance: Add-on CBD was associated with sustained seizure reduction up to 192 weeks with an acceptable safety profile and can be used for long-term treatment of treatment-resistant epilepsies.

Epilepsy Research News: December 2022

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

 

Increased Seizures After COVID Compared to the Flu

Researchers have found that the risk of seizures or epilepsy following a COVID infection is significantly higher than after being infected with the flu. The team looked at the health records of people who had been infected with COVID and matched them (so that they were similar in characteristics such as age, sex, and medical conditions) with a group of people who had been infected with the flu. The team then compared the incidence of epilepsy and seizures between the two groups over a six-month period following the initial infection. The rate of new cases of epilepsy or seizures was 0.94% in the people who had COVID, compared with 0.6% in those who had the flu. The team indicated that while the overall risk of seizures was very low, people who had COVID were 55% more likely to develop epilepsy or seizures over the next six months than people who had the flu.

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New Statistical Tool to Understand Seizures

A new study seeks to understand how some people’s seizures change over time in what is known as a seizure ‘cycle’ and understand how certain triggers might increase or decrease seizure risk, perhaps giving people with epilepsy a better idea of how and why their seizures happen, and to better recognize the early warning signs. The study found that aging itself, as well as common triggers, may be contributing factors to how the medical condition affects those prone to seizures. The researchers studied the seizure diaries of more than 1,000 patients ages 2 months to 80 years and developed a new statistical model to explicitly capture the effect of factors that may drive transitions in seizure risk, looking at factors like antiseizure medications, illness, and menstrual cycles. In examining the way seizure cycles vary in people with epilepsy, the researchers found that individuals in older age groups had shorter “calm” stretches between seizures, while younger age groups had longer stretches. This work paves the way for future studies to further examine seizure cycles.

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Identification of a Possible Molecule to Treat Temporal Lobe Epilepsy (TLE)

Researchers have recently identified and developed a small molecule called D4 with the potential to treat TLE by suppressing neuroinflammation. The findings suggest that D4 strongly suppresses TLE-induced neuroinflammation, curbs TLE seizures, and increases survival rate in an animal model of TLE. D4 works by blocking “hemichannels” in the brain, which are channels that act as pathways for neuroinflammatory molecules. The researchers note that their findings bring forward a possible new pathway for drug development for epilepsy and also highlight the involvement of neuroinflammation in epilepsy.

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Pinpointing Brain Areas Involved in GLUT1 Deficiency Syndrome Seizures

A small group of brain cells linked to a circuit in the brain is responsible for setting off whole-brain seizures in a rare form of epilepsy affected by blood sugar levels, a new study suggests. This rare genetic disorder is known as GLUT1 deficiency syndrome. Researchers used a combination of electroencephalography (EEG) as well as brain imaging in humans to show that the seizures started from brain areas called the thalamus and somatosensory cortex. When blood sugar levels dipped, abnormal electrical activity in the circuit formed by these areas spread throughout the brain. The researchers also used an animal model of GLUT1 deficiency syndrome to further investigate this circuit and pinpoint the cell types important in causing an imbalance in inhibitory brain activity compared to excitatory brain activity (which can lead to seizures). The researchers suggested these results could point to a mechanism for seizures in GLUT1 deficiency syndrome that might be targeted as a potential treatment for seizures related to GLUT1 Deficiency syndrome.

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A Randomized, Open-Label, Two-Treatment Crossover Study to Evaluate the Effect of Food on the Pharmacokinetics of Diazepam Nasal Spray (Valtoco ®) in Healthy Adult Subjects

Abstract found on Wiley Online Library

Objective: The pharmacokinetics of oral diazepam are affected by food, but food effect studies have not been conducted for diazepam nasal spray because it is believed that most absorption occurs via the nasal mucosa. However, gastrointestinal side effects reported with nasal diazepam suggest that at least a portion of the drug may be absorbed enterally and thus subject to food effects. The objective of this study was to evaluate the possible effects of food on the pharmacokinetics of diazepam nasal spray in healthy adults.

Methods: This randomized, open-label crossover study compared equal doses of diazepam nasal spray after an overnight fast and after a standardized high-fat, high-calorie breakfast. Each subject served as their own control, and there was a washout period of at least 21?days between treatments.

Results: Twenty-four healthy adults enrolled in this study. Two subjects withdrew consent, and two subjects had pre-dose diazepam concentrations that exceeded the protocol-defined minimum after the washout period and were excluded from the final analysis population of 20 subjects. Under fed conditions, the mean maximum plasma diazepam concentration was decreased by 48% (P <0.0001) and the overall diazepam exposure during the first four hours was reduced by 57% (P <0.0001) compared with fasted conditions. The time to maximum plasma concentration was 4.0 hours in the fed state compared with 2.0 hours in the fasted state (P <0.0001). At two hours post-dose, diazepam concentrations were ?150 ng/mL for 100% of subjects when fasted and 30% when fed. Significantly more subjects experienced adverse events when fasted (83.3%) than when fed (54.5%; P =?0.0340).

Significance: This study in healthy volunteers demonstrated that food significantly decreases and delays the absorption of diazepam dosed via nasal spray. Patients using diazepam nasal spray after eating may obtain diazepam concentrations that are below those needed for seizure control.