A Genomic Single-Cell Map Explains Neuronal Death in Epilepsy

Summary, originally published on medicalxpress.com

A multidisciplinary team led by researchers from the Spanish Research Council (CSIC) identifies the genomic cellular map associated with hippocampal sclerosis, a major histopathological condition of temporal lobe epilepsy. The study, published in Cell Reports, identifies cell-type specific transcriptional signatures of hyper-excitability and neurodegeneration, providing grounds for improved diagnosis. While the presence of sclerosis is essential for identifying temporal lobe epilepsy (the most common form of drug-resistant epilepsy), it is also detected in some cases of dementia associated with Alzheimer’s disease.

In this work, the researchers have developed a transcriptional map that identifies the precise genetic code of all cell types specifically affected in the disease. “With these maps we seek to match different genes with specific biological elements. In the case of the brain, we aim linking expression of some specific genes with different cell types, such as neurons, astrocytes and microglia,” explains Liset Menéndez de la Prida, a scientist at the Cajal Institute of the CSIC, who lead the study together with José López-Atalaya, from the Institute of Neurosciences (CSIC-UMH) in Alicante.

Anxiety Symptoms Are the Strongest Predictor of Quality of Life in Temporal Lobe Epilepsy

Abstract, originally published in Seizure

Purpose: It is established that the severity of depressive and anxiety symptoms is associated with poorer quality of life (QOL) in persons with drug-resistant epilepsy. We aimed to verify the presence of subsyndromic depressive episodes (SDEs) and subsyndromic anxiety episodes (SAEs) in persons with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) compared to healthy controls and to determine the impact of depressive and anxiety symptoms on patients’ QOL.

Methods: We prospectively evaluated 35 persons with TLE-HS and 90 healthy controls. QOL was assessed by the Epilepsy Surgery Inventory (ESI) and QOL in Epilepsy Inventory-31 (QOLIE-31). The Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI-X) were used to assess symptoms, and SDEs and SAEs diagnosis were made considering the total scores of BDI (<9) and STAI-Trait (<49), respectively.

Results: Persons with TLE-HS had higher symptoms on BDI, STAI-S, and STAI-T. They have 3.011 greater odds of presenting SDEs and 7.056 times odds, SAEs. The depressive and anxiety symptoms, added in the model with epilepsy-related factors, accounted for a significant increase in the variance in several aspects of QOL. Anxiety-trait symptoms are the most critical individual determinant of the QOL.

Conclusion: Our results demonstrated that persons with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) had greater odds of presenting subsyndromic depressive episodes and subsyndromic anxiety episodes than healthy controls. Besides, there was a relationship between anxiety and depressive symptoms and worse quality of life in TLE-HS. It is essential to be aware of psychiatric symptoms, even though these symptoms do not meet the criteria to be considered a “disorder.”

Cognitive and Behavioral Profiles of Pediatric Surgical Candidates With Frontal and Temporal Lobe Epilepsy

Abstract, originally published in Epilepsy & Behavior

Background: We aimed to prospectively analyze memory and executive and social cognitive functioning in patients with drug-resistant frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE) with focal lesions and isolate the impact of intellectual ability on specific deficits.

Methods: A neuropsychological evaluation was performed in 23 children with FLE, 22 children with TLE, and 36 healthy pediatric controls (HCs). Patients in the epilepsy groups had a range of lesions, including low-grade epilepsy-associated tumors (LEAT), focal cortical dysplasia (FCD) type II, and mesial temporal sclerosis (MS).

Results: There were no significant differences between children with FLE and TLE regarding memory, executive, or social cognitive functioning. General Ability Index (GAI) was a predictor of memory, executive function, and social cognition scores and was influenced by age at onset, duration of epilepsy, and number of antiepileptic drugs (AEDs) prescribed at the time of assessment. Working Memory Index scores of patients with TLE, which measure verbal mnesic processing, were significantly lower than those of HCs and patients with TLE. The greatest differences in both clinical groups compared to HCs were recorded in cognitive executive functions, and patients with FLE had lower scores in this domain. Regarding behavioral executive functions, patients with TLE presented impaired emotional control and impulse inhibition and patients with FLE exhibited decreased flexibility.

Conclusion: Consistent with previous research, our findings provide further detailed evidence of small differences in cognitive performance among children with frontal lobe epilepsy and temporal lobe epilepsy. These differences emerge on analysis of the factors with which deficits are associated.

Deep Brain Stimulation Prevents Epileptic Seizures in Mouse Model

Summary, originally published in EurekAlert!

Scientists led by neurobiologist Prof. Dr. Carola Haas, head of the research group at the Department of Neurosurgery at Medical Center – University of Freiburg and the BrainLinks-BrainTools research center, have investigated a new therapeutic approach to prevent epileptic seizures in temporal lobe epilepsy. They showed in mice that low-frequency stimulation of specific brain areas could completely stop epileptic activity. Instead of using electric current, the researchers stimulated the cells with light. To do this, they had previously introduced a light-sensitive molecule into the cells that allows particularly precise stimulation. They published the results in December 2020 in the scientific journal elife.

“As soon as we stimulated the brain region with a frequency of one hertz, the epileptic seizures disappeared. This effect was stable over several weeks,” Haas says. Habituation, which can occur with drug therapy, did not take place. The brain region was stimulated for one hour daily.

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.

Learn More

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

Epilepsy Research News: December 2020

This month’s research news includes announcements about the Curing the Epilepsies 2021 Conference, and a reminder about the Cure Epilepsy and Taking Flight grant letters of intent (LOIs).

We also share that the Health Disparities Research Institute will be accepting applications, and that the TESS Research Foundation is hiring.

These news items are summarized below.

Research Highlights

Curing the Epilepsies 2021 Conference–January 4-6, 2021

Please join the epilepsy community from around the world to discuss the progress made in understanding the biological mechanisms underlying the epilepsies, and the inroads being made towards potential cures.

The main outcome and priority of the meeting will be to identify transformative research priorities that will accelerate development of cures and improve outcomes for people with epilepsy. The meeting takes place from January 4-6, 2021. It will be open to the public and freely available via livestream.

Learn more

Understanding & Treating Temporal Lobe Epilepsy
A team of researchers has found that an amino acid produced by the brain could play a crucial role in preventing cell loss and seizures associated with temporal lobe epilepsy. Utilizing an animal model of temporal lobe epilepsy, the research team found that administration of the amino acid D-serine prevented cell loss characteristic of temporal lobe epilepsy and reduced the number and severity of seizures.

Learn More

CURE Epilepsy and Taking Flight Grant Timeline–Letter of Intent (LOI) due January 11, 2021 9 PM EST
Reminder, CURE Epilepsy is accepting LOIs for both the CURE Epilepsy and Taking Flight grant awards now through Monday, January 11, 2021 at 9 PM ET. Don’t miss your opportunity to be considered!

  • CURE Epilepsy Award, $250,000 over two years: This award reflects CURE Epilepsy’s continued focus on scientific advances that have potential to truly transform the lives of those affected by epilepsy.
  • Taking Flight Award, $100,000 for one year: This award seeks to promote the careers of young epilepsy investigators, allowing them to develop a research focus independent of their mentors.
  • Research areas: Sudden unexpected death in epilepsy (SUDEP), acquired epilepsy, treatment-resistant epilepsy, pediatric epilepsy, and sleep and epilepsy

Learn More

2021 Health Disparities Research Institute–Accepting Applications February 1-March 8, 2021The next Health Disparities Research Institute–featuring lectures on minority health and health disparities research, mock grant review, seminars and more–will be held virtually August 9-13, 2021.

The program’s intent is to support early-career minority health/health disparities research scientists and stimulate research in the disciplines supported by health disparities science. Admission to this program is by application only. The application cycle is open February 1-March 8, 2021.

Learn More

Job Opportunity: Research Program Manager Position with TESS Research Foundation
Looking for an opportunity to make a difference in the area of rare epilepsies? The TESS Research Foundation is seeking a Research Program Manager to oversee all scientific research focused on SLC13A5 Epilepsy, including research coordination, grant program oversight, community outreach, and scientific communication and cultivation.

Learn More

Epilepsy Research News: December 2020

In this month’s news, we spotlight a publication describing CURE Epilepsy’s Infantile Spasms (IS) Initiativea collaborative research program that brought a team science approach to understanding the causes and potential treatments for IS. Running from 2013-2016, this program led to numerous advances in understanding the pathways in the brain involved in IS. 

Also, this month we feature news from the EPISTOP study showing that preventative treatment with the drug vigabatrin decreased the number of days with seizures as well as the severity of epilepsy in infants with tuberous sclerosis complexWe also highlight recent work from CURE Epilepsy Grantee Dr. Jeffrey Loeb, whose team identified a protein found in healthy brain tissue that may work to prevent the spread of seizures. 

These studies and more are summarized below. 

Research Highlights

Infantile Spasms
This recent publication highlights CURE Epilepsy’s Infantile Spasms (IS) Initiative, established in 2013 to support collaborative, team science-based and milestone-driven effort to advance the understanding of causes of and potential treatments for IS. The combined efforts of the research team led to numerous advances in understanding the causes of IS. It also brought together a diverse group of investigators–who otherwise would not have collaborated–to study therapies for IS.

Learn more

Preventing the Spread of Seizures
New research may explain what prevents seizures in certain areas of the brain from spreading to other areas of the brain. In a study funded by the National Institutes of Health/American Epilepsy Society, CURE Epilepsy Grantee Dr. Jeffrey Loeb and his colleagues found that a protein called DUSP4 was increased in healthy brain tissue directly next to epileptic brain tissue. The research suggests that DUSP4 may work to prevent the spread of epilepsy in the brain and that boosting levels of DUSP4 could be a novel way of preventing or treating epilepsy.

Learn More

Tuberous Sclerosis Complex Treatment
Preventive treatment with vigabatrin effectively decreased the risk and severity of epilepsy in infants with tuberous sclerosis complex who were enrolled in the EPISTOP multi-center study. Vigabatrin resulted in a significantly longer time to first clinical seizure compared with conventional treatment as well as a lower proportion of days with seizures until age 2, according to the study findings. The EPISTOP study has shown that it may be possible to change the natural history of severe infantile epilepsy through early intervention with antiepileptic therapy,” the researchers wrote.

Learn More

Epilepsy and Dementia
Late-onset epilepsy has been linked to a substantially increased risk of subsequent dementia. Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a threefold increased risk of subsequent dementia versus their counterparts without epilepsy. “We are finding that just as the risk of seizures is increased in neurodegenerative diseases, the risk of dementia is increased after late-onset epilepsy and seizures,” study investigator Emily L. Johnson, MD, assistant professor of neurology at Johns Hopkins University, Baltimore, said in an interview. “Several other on-going studies are finding similar results,” she added.

Learn More

Epilepsy Treatment Expansion Approval
The FDA expanded its approval of lacosamide, marketed as Vimpat, to include add-on therapy for primary generalized tonic-clonic seizures as well as an IV formulation for patients aged 4 years and older.

Learn More

Diagnosing Cognitive Disorders in Older Adults With Epilepsy

Abstract, originally published in Epilepsia

Objective: To characterize the nature and prevalence of cognitive disorders in older adults with temporal lobe epilepsy (TLE) and compare their cognitive profiles to patients with amnestic mild cognitive impairment (ie, aMCI).

Methods: Seventy-one older patients with TLE, 77 aMCI, and 69 normal aging controls (NACs), all 55-80 years of age, completed neuropsychological measures of memory, language, executive function, and processing speed. An actuarial neuropsychological method designed to diagnose MCI was applied to individual patients to identify older adults with TLE who met diagnostic criteria for MCI (TLE-MCI). A linear classifier was performed to evaluate how well the diagnostic criteria differentiated patients with TLE-MCI from aMCI. In TLE, the contribution of epilepsy-related and vascular risk factors to cognitive impairment was evaluated using multiple regression.

Results: Forty-three TLE patients (60%) met criteria for TLE-MCI, demonstrating marked deficits in both memory and language. When patients were analyzed according to age at seizure onset, 63% of those with an early onset (<50 years) versus 56% of those with late onset (≥ 50 years) met criteria for TLE-MCI. A classification model between TLE-MCI and aMCI correctly classified 81.1% (90.6% specificity, 61.3% sensitivity) of the cohort based on neuropsychological scores. Whereas TLE-MCI showed greater deficits in language relative to aMCI, patients with aMCI showed greater rapid forgetting on memory measures. Both epilepsy-related risk factors and the presence of leukoaraiosis on MRI contributed to impairment profiles in TLE-MCI.

Significance: Cognitive impairment is a common comorbidity in epilepsy and it presents in a substantial number of older adults with temporal lobe epilepsy (TLE). Although the underlying etiologies are unknown in many patients, the TLE-mild cognitive impairment phenotype may be secondary to an accumulation of epilepsy and vascular risk factors, signal the onset of a neurodegenerative disease, or represent a combination of factors.

 

Advances in the Surgical Management of Epilepsy: Drug-Resistant Focal Epilepsy in the Adult Patient

ABSTRACT, originally published in Neurologic Clinics

Pharmacoresistant seizures occur in nearly one-third of people with epilepsy. Medial temporal lobe and lesional epilepsy are the most favorable surgically remediable epileptic syndromes. Successful surgery may render the patient seizure-free, reduce antiseizure drug(s) adverse effects, improve quality of life, and decrease mortality. Surgical management should not be considered a procedure of “last resort.” Despite the results of randomized controlled trials, surgery remains an underutilized treatment modality for patients with drug-resistant epilepsy (DRE). Important disparities affect patient referral and selection for surgical treatment. This article discusses the advances in surgical treatment of DRE in adults with focal seizures.

Epilepsy Research News: November 2020

This month’s research news includes a study that highlights the importance of adherence to antiepileptic drug regimens and controlling seizures to reduce the risk of sudden unexplained death in epilepsy (SUDEP). We also highlight an advancement in understanding and preventing temporal lobe epilepsy, utilizing an animal model.

Additionally, we share a study that highlights the difficulty that can be faced in diagnosing sometimes subtle seizures associated with focal epilepsy, and we present findings on the development of a new tool to help ease what can be a challenging transition from pediatric/adolescent to adult care for individuals with epilepsy.

In other news, a new FDA alert was issued to avoid the use of lamotrigine/Lamictal in people with cardiac conduction disorders, ventricular arrhythmias, or cardiac disease or abnormality.

These studies and the FDA alert are summarized below.

Research Highlights

Preventing SUDEP
Polytherapy, especially the use of three or more antiepileptic drugs, is correlated with a substantially decreased risk for SUDEP according to a nationwide study conducted in Sweden. The study also demonstrated a link between statin use and a decreased risk for SUDEP. “These results provide support for the importance of medication adherence and intensified anti-epileptic drug treatment for patients with poorly controlled generalized tonic-conic seizures in the efforts to reduce SUDEP risks and suggest that comedication with statins may reduce risks,” the researchers wrote.

Learn more

Understanding & Treating Temporal Lobe Epilepsy
A team of researchers has found that an amino acid produced by the brain could play a crucial role in preventing cell loss and seizures associated with temporal lobe epilepsy. Utilizing an animal model of temporal lobe epilepsy, the research team found that administration of the amino acid D-serine prevented cell loss characteristic of temporal lobe epilepsy and reduced the number and severity of seizures.

Learn More

Focal Epilepsy & Delayed Diagnosis
A new study shows that it can take on average two years for physicians to recognize the early signs of focal epilepsy, particularly in patients with seizures that do not involve uncontrolled movements of their arms and legs. Subtler cases are often not diagnosed until they have progressed to disruptive “motor” seizures, say the study authors, which can cause the unrestrained, whole-body spasms often portrayed in popular culture. Researchers believe the impact of earlier diagnosis in focal epilepsy patients goes beyond more timely treatment of patients; some study participants reported having one or more car accidents before their diagnosis. The researchers estimate that for every 13 early diagnoses, one car accident, equating to an estimated 1,816 annually worldwide, could be prevented.

Learn More

Transitioning to Adulthood with Epilepsy
Clinicians at Michigan Medicine have developed an assessment tool to help doctors ensure adolescents and young adults with epilepsy have the skills and confidence they need to take control of seizures and health care. Through a customized screening tool for 16 to 26-year-olds, doctors are effectively able to monitor their patients’ development of knowledge and self-management skills regarding their condition. This tool allows providers to proactively address gaps in readiness that may impact long term health outcomes.

Learn More

FDA Alert for Lamotrigine
The FDA has issued a new warning advising against the use of lamotrigine/Lamictal in people with cardiac conduction disorders, ventricular arrhythmias, or cardiac disease or abnormality. People currently taking lamotrigine should consult their healthcare provider. Do not stop taking lamotrigine without talking to your healthcare provider as doing so can cause serious problems.

Learn More