Seizure Pathways Change over Different Timescales in Individual Patients with Focal Epilepsy

Abstract, published in Proceedings of the National Academy of Sciences of the United States of America

Epilepsy is an episodic disease characterized by brief periods of abnormal brain activity, known as seizures, that often have clinical correlates. In many patients, seizures preferentially happen during certain stages of daily and multiday cycles. However, it is unclear whether and how seizures themselves change over time, even though such variability may have clinical implications.

To address this knowledge gap, this research team quantitatively analyzed the nature of within-patient variability in seizure networks using intracranial electroencephalographic (iEEG) recordings of over 500 seizures from 31 patients with focal epilepsy (average of 16.5 seizures per patient). An iEEG is a type of EEG in which electrodes are placed directly on the brain, and a focal seizure is one in which the seizures starts from a single location in the brain.

Contrary to common expectations, this study found seizure variability throughout our group of patients. Importantly, the team demonstrated that seizures do not change randomly; instead, they also appear to fluctuate over daily and slower timescales. These results suggest that various modulatory processes, operating at different timescales, appear to lead to variable seizure pathways in individual patients. Ultimately, we may improve treatments by tailoring interventions to the full range of seizures in each patient.

International Study Uncovers Three Molecules with Potential for Treating Epilepsy

Featuring the work of former CURE Grantee Dr. David Henshall

Summary, published by the Royal College of Surgeons in Ireland

The findings are an important step towards discovering new drugs for people with epilepsy whose seizures cannot be controlled with current treatments.

The study was led by researchers at FutureNeuro, the SFI Research Centre for Chronic and Rare Neurological Diseases and RCSI University of Medicine and Health Sciences. It is the result of seven years of research, involving contributions from 35 scientists, based in eight different European countries, across the fields of neuroscience, genetics, computer science and synthetic chemistry. The research is published in the current issue of Proceedings of the National Academy of Sciences (PNAS).

In one of the largest sequencing projects of its kind, researchers identified and measured levels of over a billion strands of microRNAs – small molecules that control gene activity in the brain – to investigate if they were changed in epilepsy. They discovered a small set of microRNAs which were always elevated in epilepsy and designed drug-like molecules, synthesized by chemists from the group, to target these. Three of the synthetic molecules were found to stop seizures in preclinical tests.

Computer simulations demonstrated how the potential treatments influenced molecule networks inside brain cells by changing the inflammatory response, part of the brain’s immune system which is thought to contribute to seizures.

“Our approach to drug discovery has led us to new types of molecules that can be targeted to prevent seizures with hopefully fewer side effects,” said Dr Cristina Reschke, FutureNeuro Research Fellow and Honorary Lecturer at RCSI, and Co-Lead Author. “Currently, most drugs used to treat epilepsy work by blocking the signals brain cells use to communicate. This results in many of the side effects experienced by people with epilepsy.”

Which Seizure Elements Do Patients Remember? A Comparison of History and Seizure Documentation

Abstract, published in Epilepsia

Objective: People with epilepsy (PWE) are frequently unable to recall the core manifestation of their disease, epileptic seizures. This means that seizure frequency is often underestimated by practitioners and that seizure classification based on reports of patients or their relatives is difficult because seizure symptoms remain unclear. The purpose of this study, therefore, was to prospectively explore patients’ memory regarding seizure elements and to assess the role of seizure types.

Methods: Ninety patients diagnosed with focal epilepsy undergoing diagnostic electroencephalography (EEG)–video monitoring were included. The ability to remember individual seizure elements was assessed using a questionnaire. Patient memory was then compared to the findings of subsequent seizure documentation during EEG?video monitoring. Seizure elements were categorized in four groups: subjective, motor, autonomic, and postictal (immediately after the seizure) elements.

Results: In all categories, the number of documented seizure elements during monitoring strongly exceeded the number of elements that were recalled. Only 45.6% of subjective elements, 5.4% of motor phenomena, 11.9% of autonomic findings, and 2.1% of postictal impairments were recalled. The ability to recall seizure elements varied significantly depending on seizure types (secondarily generalized tonic?clonic seizures [SGTCS] < complex partial seizures [CPS] < simple partial seizures [SPS]), but not on the relative timing of the element during the seizure.

Significance: Patients’ memory of seizure symptoms is almost always fragmentary. Although the rate of correctly remembered seizure elements depends on the seizure type, complete recall of a seizure is almost never obtained. Consequently, 89 of 90 patients in this cohort would only have had seizures classified as a seizure with “impaired awareness,” according to the new International League Against Epilepsy (ILAE) seizure classification.

Researcher Update: June 2020

In this month’s researcher update you will find information on:

Catalyst Award LOIs Monday, July 6

Request for Proposals (PDF)

The deadline is approaching to apply for CURE’s newest grant mechanism, the Catalyst Award. This award (2 years / $250,000) aims to stimulate and accelerate the discovery and development of new therapies for epilepsy, moving promising, well-supported preclinical and/or clinical research closer to clinical application.

  • Open call for Letters of Intent: Monday, June 1, 2020
  • Letter of Intent deadline: Monday, July 6, 2020, 9 PM ET
  • Full proposal invitations: Thursday, August 13, 2020
  • Full proposal deadline: Thursday, September 17, 2020, 9 PM ET
  • Awardee notification: Late-December 2020
  • Anticipated award start date: March 2021

Epilepsy & COVID-19 Survey for Healthcare Providers

Take Survey

SUDEP Action and the Oxford Epilepsy Research Group are collaborating to better understand what risks people with epilepsy and healthcare providers are facing, what support they have and how to help them live well with the condition. Particularly during the current COVID-19 pandemic, it is important to explore the changes and challenges healthcare providers and patients are facing so they can be better supported.

NINDS Career Opportunities

NINDS has positions available for Health Scientist Administrators in the Epilepsy Therapy Screening Program and the Preclinical Screening Platform for Pain. Please don’t hesitate to send this update along to anyone you think may be interested in applying!

Submit an Abstract to the PAME Conference by June 29!

Submit Abstract

The PAME Conference, which is happening December 3-4 in conjunction with AES, has extended the deadline to submit abstracts to June 29. This conference aims to improve our understanding of mortality in epilepsy, including Sudden Unexpected Death in Epilepsy (SUDEP), by bringing together health care providers, researchers, public health officials, patient advocates, caregivers, bereaved families, and patients living with epilepsy. Abstracts should be submitted through the AES portal.

NIH Request for Information: Developing an Online Educational Resource for Training in the Principles of Rigorous Research

Submit Comment

NINDS is requesting your input to better provide accessible education on the principles of rigorous biomedical research for members of the scientific community. In particular, NINDS encourages experts in training, rigorous experimental design and implementation, mentoring, education, and technology to contribute their input.

AES Offering CE and CME Credit for 2019 Sessions

View Sessions

AES is now offering CE and CME credit for 2019 AES recorded sessions. The goal of these online materials is to provide knowledge and training for professionals working the epilepsy field and provide clinicians with resources to help improve the care of those with epilepsy.

A grid of nine brains wit different portions highlighted in red, yellow, and green.

New Noninvasive Approach Maps Seizure-Generating Brain Areas

A new noninvasive method can effectively map the source and scale of seizure activity in people with epilepsy, according to a recent study. The tool could lower the number of surgeries needed to treat epilepsy. Clinicians often rely on an invasive technique to try to find the area responsible for someone’s seizures by implanting electrodes deep into the the outer layer of the brain, in one surgery before removing brain tissue in a second surgery. But these methods can lead to bleeding and infection.

The new approach couples machine learning, a type of artificial intelligence (AI), with electroencephalography (EEG) recordings from 76 electrodes placed on the scalp, to localize seizure activity in the brain. Unlike previous EEG techniques, it can also show how much brain tissue is involved. However, noninvasive imaging techniques come with trade-offs. While EEG is adept at recording activity during a seizure, it cannot always home in on a seizure’s source with precision. The layers of fluid, skull and brain tissue that lie between the electrodes and the underlying brain activity can distort the signal. And reverse-engineering the source location from that distorted signal is mathematically difficult.

Previous EEG methods could “pinpoint the center of gravity” of the recorded seizure activity, says lead investigator Bin He, professor of biomedical engineering at Carnegie Mellon University in Pittsburgh, Pennsylvania. But knowing where seizure activity is centered is not enough for surgical treatment of epilepsy.

To circumvent this problem, Bin Hee and his colleagues developed a new algorithm, called “fast spatio-temporal iteratively reweighted edge sparsity (FAST-IRES)”. Rather than just localizing the source, their algorithm provides information about the extent of the brain network that gives rise to the EEG signal. FAST-IRES also uses machine learning to calculate the thresholds at which signals are deemed significant. As a proof of concept, Hee and his colleagues tested FAST-IRES on EEG recordings from 36 people with epilepsy who were pursuing surgery as treatment. The researchers found that their method was as successful as implanted electrodes at finding the location and extent of the seizure source and would have produced similar surgical outcomes.

Efficacy and Tolerability of Intravenous Brivaracetam (Briviact®) for Status Epilepticus: A Systematic Review

Abstract, published in Journal of the Neurological Sciences

Background & Objectives: Status epilepticus (SE) is an emergent neurologic condition that carries a high risk of morbidity and mortality. Intravenous brivaracetam (IV BRV) may be an alternative anticonvulsant against SE, although the sparseness of controlled studies on the topic limits its recommendation for this indication. This systematic review aimed to determine the efficacy and safety of IV BRV in the treatment of SE.

Results: From a total of 34 studies identified in a comprehensive literature search, 5 uncontrolled studies with 77 patients were included in this review. Thirty-seven out of 77 patients (48%) with SE responded to IV BRV. Reported time to seizure cessation may be immediate from a few minutes to several hours after IV BRV treatment.

Conclusions: Limited evidence from 5 uncontrolled studies involving a limited number of patients suggests that IV BRV may be efficacious and safe in terminating seizures among patients with SE or refractory SE. Further studies employing either prospective, controlled trials or registry-based study designs are essential to determine the definitive role of IV BRV in patients with status epilepticus.

A black and white digital rendering of a brain with colorful dots showing seizure localization and spread.

Novel Approach is Helping to Explain Epileptic Seizures

Many patients with treatment-resistant epilepsy seek surgical resection, a procedure that removes part of the brain where seizures begin. Although resection can greatly reduce the number of seizures a person experiences, and in some cases, can eliminate seizures completely, the surgery is most successful when a surgeon can first pinpoint the exact spot in the brain where seizures begin, a challenging feat that has not yet been perfected in the clinic. New research from Boston University (BU) neuroscientists and statisticians, published in the journal Nature Communications, could someday improve the success of resections and, therefore, the quality of life for people with epilepsy.

Mark Kramer, a BU professor of mathematical neuroscience, says that “seizures evolve within the extraordinarily complicated and three-dimensional network of the brain’s cells and tissues such that the slightest change within that network can lead to sudden explosions or reductions in seizure spread”. But, during a resection, the clinical team which places a grid with individual electrodes directly on the brain’s surface, views each electrode as a separate data point instead of as a network.

Being able to represent the brain’s collective behavior would represent a big step forward. To accomplish this task, the researchers came up with a new way to analyze the brain activity data gathered by the electrodes. Specifically, they developed an algorithm that finds patterns of connectivity in these brain networks that can be traced as they evolve through time before, during, and after a seizure.

Results suggest that patients with fewer, shorter-lasting dynamic communities during seizure have improved surgical outcomes. Importantly, researchers believe that if they can track the seizure back to the point where it ignites, it may be possible to extinguish the seizure before it ever has the opportunity to spread.

Whose Seizures Last Longest? Impact of Clinical and Demographic Factors

Abstract, published in Epilepsia

Objective: To investigate the impact of clinical and demographic parameters on the duration of seizures starting at a single place in the brain (focal onset), with and without secondary spread, using precise duration measurements from intracranial electroencephalographic (iEEG) recordings. These recordings are made with electrodes placed directly on the brain.

Methods: Patients with focal epilepsy syndromes and iEEG recordings were retrospectively identified from the database of the local epilepsy center (2006-2016). Seizure duration was defined as the time between seizure onset and end, according to the iEEG. The specific seizure symptoms were classified based on video recordings. Clinical and demographic data were extracted from patient reports.

Results: In total, 69 adults were included, and 654 focal onset seizures were analyzed. Those that spread throughout the brain and involved violent convulsing (98/654 [~15%]) were significantly longer than without secondary spread (556/654 [~85%]). Most focal seizures (545/654 [83.3%]) ended within 2 minutes. The duration of focal seizures was prolonged with increasing age of the patients and was significantly shortened by secondary spread. Furthermore, seizures with secondary spread that were also preceded by an aura, began at the front of the brain, or occurred during sleep were shorter.

Significance: The identified modifiers of seizure duration are of great relevance for clinical risk evaluation, especially in the aging epilepsy patient suffering from epilepsy with secondary generalized seizures.

Report on a Psychoeducational Intervention for Psychogenic Non-Epileptic Seizures in Argentina

Published in Seizure

Highlights

  • Group psychoeducation in Argentina included patients with PNES and caregivers.
  • Psychoeducation could have a positive impact in patients with PNES in Argentina.
  • Patients who participated in the group reported improved emotional functioning.
  • “Group” and “psychoeducational” modality was rated as positive by most participants.

Abstract

Purpose: To examine the effects of a three-session psychoeducational intervention on patients diagnosed with psychogenic non-epileptic seizures (PNES) in an Argentinian public hospital. PNES are involuntary episodes that look and feel similar to epileptic seizures but have psychological rather than neurological causes. It was hypothesized that patients would experience improvements in their understanding of PNES, illness perception, and affective scores but might not necessarily experience a significant change in post-traumatic and dissociative symptoms and in seizure frequency.

Results: This psychoeducational intervention produced results that were similar to interventions reported in US and European studies with regard to changes on psychological measures. Moreover, many patients also reported (on the final day of the intervention) a decrease in seizure frequency. All patients reported that participating in the intervention was a positive experience. Also, all but one patient referred that the participation in the group would have a positive impact on their quality of life.

Conclusions: Psychoeducational interventions appear to have had positive results in Argentinian patients with PNES. This is initial step in the design of empirically based psychoeducational/supportive initiatives for patients in South America.

Epileptic Spasms in Individuals with Down Syndrome: a Review of the Current Literature

Critical review, published in Epilepsia Open

Epilepsy can occur in individuals with Down syndrome (DS), with epileptic spasms representing the most frequent seizure type in this population. Epileptic spasms are brief seizures characterized by bending of the trunk and bending/extension of the limbs. These types of seizures can have devastating consequences on the development of individuals with the condition. This review sought to explore the lifetime prevalence and underlying mechanism of epileptic spasms in this population. We also aimed to review the response rate to various treatments, the relapse rate, and the development of subsequent epilepsy or autism in this population.

A comprehensive literature search was conducted for articles discussing the lifetime prevalence, diagnosis, treatment, outcomes, or underlying cause of epileptic spasms in animal models or individuals with DS. According to available literature, the global clinic-based lifetime prevalence of epilepsy in individuals with DS ranged from 1.6% to 23.1%, with epileptic spasms representing 6.7% to 66.7% of these cases.

Response rate to treatment with a specific steroid hormone was highest (81%) and has the most literature supporting its use, with other treatments, including vigabatrin (Sabril®) and other antiepileptic drugs, having lower response rates. Epileptic spasms occur more frequently in children with DS than in the general population, though more studies are needed to determine the true lifetime prevalence of epileptic spasms in this population. Generally, children with DS and epileptic spasms tend to be more responsive to treatment and have better outcomes than children with epileptic spasms of unknown cause, in terms of response and relapse rates, as well as the development of intractable epilepsy.