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.

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Study Findings Suggest Animal Model Replicates Key Molecular Features of Human Drug-Resistant Temporal Lobe Epilepsy

Abstract, originally published in Epilepsia

Objective: Pharmacoresistance and the lack of disease-modifying actions of current antiseizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant-induced status epilepticus remain the models of choice to discover potential antiepileptogenic drugs, but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intra-amygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug?resistant temporal lobe epilepsy (TLE).

Methods: Status epilepticus was induced via intra-amygdala microinjection of kainic acid in C57BL/6 mice, and gene expression was analyzed via microarrays in hippocampal tissue at acute and chronic time-points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug-resistant TLE.

Results: Intra-amygdala kainic acid injection in mice triggered extensive dysregulation of gene expression that was ~3-fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples from patients with TLE revealed a particularly high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signaling to be highly conserved across different models of epilepsy and patients. cAMP response element-binding protein (CREB) was predicted as one of the main upstream transcription factors regulating gene expression during acute and chronic phases, and inhibition of CREB reduced seizure severity in the intra-amygdala kainic acid model.

Significance: Our findings suggest the intra-amygdala kainic acid model faithfully replicates key molecular features of human drug-resistant temporal lobe epilepsy and provides potential rational target approaches for disease-modification through new insights into the unique and shared gene expression landscape in experimental epilepsy.

College of Medicine Researcher Makes Novel Discoveries in Preventing Epileptic Seizures

Article, originally published by Florida State University News

A team of researchers from the Florida State University College of Medicine has found that an amino acid produced by the brain could play a crucial role in preventing a type of epileptic seizure.

Temporal lobe epileptic seizures are debilitating and can cause lasting damage in patients, including neuronal death and loss of neuron function.

Sanjay Kumar, an associate professor in the College of Medicine’s Department of Biomedical Sciences, and his team are paving the way toward finding effective therapies for this disease.

The research team found a mechanism in the brain responsible for triggering epileptic seizures. Their research indicates that an amino acid known as D-serine could work with the mechanism to help prevent epileptic seizures, thereby also preventing the death of neural cells that accompanies them.

The team’s findings were published in the journal Nature Communications.

CURE Discovery: Temporal Lobe Epilepsy and Memory Impairment

Key Points

Picture of the researcher

  • CURE Taking Flight grantee, Dr. Tristan Shuman and his team, in collaboration with two other research groups, used a mouse model of temporal lobe epilepsy (TLE) to examine how chronic epilepsy leads to cognitive and memory deficits.
  • The team developed innovative research tools, including a wireless miniature microscope that can “see” into the brain and analyze the exact firing patterns brain cells use to communicate with each other.
  • The team found that disrupting these firing patterns plays an important role in the development of memory deficits. Restoring these firing patterns may someday provide relief from the memory deficits and cognitive delays that accompany TLE.

Deep Dive

Temporal lobe epilepsy (TLE), which occurs in the temporal lobe of the brain, is the most common type of focal epilepsy.1,2 Unfortunately, people with TLE also often experience disabling cognitive and memory impairments.1 With support from a CURE Taking Flight award, Dr. Tristan Shuman and his team may have discovered a possible cause for these debilitating symptoms. His team at the Icahn School of Medicine at Mount Sinai in New York collaborated with Dr. Peyman Golshani’s laboratory at the University of California, Los Angeles. Together, they examined how two small areas of the brain that play key roles in memory and learning share information between each other to explore possible origins of the cognitive and memory deficits that develop in people with chronic epilepsy.

HippocampusThe temporal lobe of the brain contains a region called the hippocampus which plays a vital role in regulating learning, memory, and spatial navigation.3 Dr. Shuman and his team focused on two subregions of the hippocampus important in spatial navigation: the dentate gyrus (DG) and the CA1. Spatial information from other areas in the brain enters through the DG and leaves through the CA1.3 Dr. Shuman aimed to understand if disrupting this input/output circuit contributed to the cognitive and memory deficits observed in mice with TLE.

To study the interactions between the neurons in the DG and CA1, Dr. Shuman and colleagues first developed novel tools which enabled them to make their initial findings. They determined that in mice with chronic epilepsy, electrical impulses moving between neurons in the DG and CA1 were disrupted, indicating that these two regions were not able to process spatial information.

Hippocampus

The researchers then examined how each individual neuron fired as the mice ran along a track. To accomplish this, the mice were fitted with a wireless, mouse-sized mini microscope, created by Dr. Shuman and his collaborators, that can “see” into the brain and record the activity of hundreds of neurons. They discovered that in the brains of mice with epilepsy, the number of place cells, a specific type of CA1 neuron that gathers and relays information about the position of objects in space, was reduced when compared to normal mice. In normal mice, these place cells were stable and active in the same location every day that the animals ran on the track. However, in the mice with TLE, the place cells changed their firing patterns every few minutes, indicating that the mice could not remember their location.

To further his research, Dr. Shuman collaborated with Dr. Panayiota Poirazi at the Foundation for Research and Technology Hellas in Greece to confirm his findings using a computer model. Using this approach, the team confirmed that by changing the timing of electrical inputs into the hippocampus, they could disrupt processing of spatial information.

Understanding how individual neuronal circuits are disturbed in epilepsy is a first step in creating future therapies to target disrupted firing patterns in people with epilepsy. By continuing to explore this promising avenue of research, scientists may one day be able to design therapeutic interventions that restore neuronal firing patterns, reducing seizures and improving cognitive function for people with chronic epilepsy.

Literature Cited

1Bell, B. et al. The neurobiology of cognitive disorders in temporal lobe epilepsy. Nat. Rev. Neurol. 2011; 7(3): 154-164.
2 Téllez-Zenteno, J.F. & Hernández-Ronquillo, L. A review of the epidemiology of temporal lobe epilepsy. Epilepsy Res. Treat. 2012; 2012: 630853.
3 Saniya, K. et al. Neuroanatomical changes in brain structures related to cognition in epilepsy: an update. J. Nat. Sci. Biol. Med. 2017; 8(2): 139-143.

Probable Reasons for the Underutilization of Neurosurgery for Drug Resistant Epilepsy (DRE): A Literature Review

Abstract, published in Epilepsia

Patients with drug-resistant epilepsy (DRE) rarely achieve seizure freedom with medical therapy alone. Despite being safe and effective for select patients with DRE, epilepsy surgery remains heavily underutilized. Multiple studies have indicated that the overall rates of surgery in patients with DRE have stagnated in recent years and may be decreasing, even when hospitalizations for epilepsy-related problems are on the rise. Ultimately, many patients with DRE who might otherwise benefit from surgery continue to have intractable seizures, lacking access to the full spectrum of available treatment options.

In this article, researchers review the various factors accounting for the persistent underutilization of epilepsy surgery and uncover several key themes, including the persistent knowledge gap among physicians in identifying potential surgical candidates, lack of coordinated patient care, patient misconceptions of surgery, and socioeconomic disparities impeding access to care. Moreover, factors such as the cost and complexity of the preoperative evaluation, a lack of federal resource allocation for the research of surgical therapies for epilepsy, and difficulties recruiting patients to clinical trials all contribute to this multifaceted dilemma.

Temporal Lobe Surgery and Memory: Lessons, Risks, and Opportunities

Careful study of the clinical outcomes of temporal lobe epilepsy (TLE) surgery has greatly advanced our knowledge of the neuroanatomy of human memory. After early cases resulted in profound amnesia, the critical role of the hippocampus and associated medial temporal lobe (MTL) structures to declarative memory became evident. Surgical approaches quickly changed to become unilateral and later, to be more precise, potentially reducing cognitive morbidity.

Neuropsychological studies following unilateral temporal lobe resection (TLR) have challenged early models, which simplified the lateralization of verbal and visual memory function. Diagnostic tests, including intracarotid sodium amobarbital procedure (WADA), structural magnetic resonance imaging (MRI), and functional neuroimaging (functional MRI (fMRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT)), can more accurately lateralize and localize epileptogenic cortex and predict memory outcomes from surgery. Longitudinal studies have shown that memory may even improve in seizure-free patients.

From 70 years of experience with epilepsy surgery, science now has a richer understanding of the clinical, neuroimaging, and surgical predictors of memory decline-and improvement-after TLR.