A new intranasal spray could prevent damage caused by status epilepticus, according to research published in the Proceedings of the National Academy of Sciences (PNAS).
Status epilepticus (SE) is a prolonged seizure (lasting more than five minutes) that requires urgent treatment and hospital admission. If not ended quickly, just one episode can lead to neuronal death, cognitive impairment and memory loss, and it also renders a person more susceptible to developing epilepsy if they don’t already have it.
Tranquilizing drugs such as benzodiazepines are the usual treatment for SE, but they are ineffective approximately 30% of the time. Researchers in Texas have now developed an intranasal spray that is made up of tiny sacs (vesicles) secreted by a specific type of stem cell obtained from the bone marrow. These vesicles have anti-inflammatory properties. In the current study, the researchers aimed to investigate the effects of the new treatment on SE-induced damage.
To do this the team induced SE in young rodents for 2 h, and then administered them with either the new treatment or a type of placebo twice over 24 h (both intranasally). Looking closely at the brains of the animals at different time points post-SE, the researchers found that those receiving the active treatment had decreased loss of neurons and greatly reduced inflammation in the hippocampus (an important memory structure) compared with the placebo-treated animals. They noticed that this effect was long-lasting, and that the generation of new neurons in the hippocampus was sustained (whereas in the placebo-treated animals this was abnormal). Behavioural tests showed that memory and cognitive functions were preserved in the animals that received the treatment, but not in those that received the placebo. The new treatment also appeared to protect animals from developing chronic epilepsy.
Professor Ashok Shetty, Co-Senior Author on the paper comments:
“What is remarkable is that the animal models were rescued from long-term effects of the seizure-induced brain injury by a nasal spray.”
“In fact, the vesicles were able to move to the hippocampus in six hours, and their neuroprotection was enough to prevent loss of normal cognitive and memory function as well as abnormal neurogenesis, one of the substrates involved in formation of new memories.”
“There really hasn’t been anything non-invasive like this to stop the cascade of inflammation and abnormal neuronal wiring or epileptogenesis that occurs after a status epilepticus even.”
These results are very promising, and they could have implications for a number of neurological conditions, not just epilepsy. However, the authors urge caution because a lot more research is needed before the new treatment reaches clinical trials. We look forward to receiving further updates from them in the future.
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Epileptogenic networks are defined by the brain regions involved in the production and propagation of epileptic activities. In this review we describe the historical, methodologic, and conceptual bases of this model in the analysis of electrophysiologic intracerebral recordings. In the context of epilepsy surgery, the determination of cerebral regions producing seizures (i.e., the “epileptogenic zone”) is a crucial objective. In contrast with a traditional focal vision of focal drug-resistant epilepsies, the concept of epileptogenic networks has been progressively introduced as a model better able to describe the complexity of seizure dynamics and realistically describe the distribution of epileptogenic anomalies in the brain. The concept of epileptogenic networks is historically linked to the development of the stereoelectroencephalography (SEEG) method and subsequent introduction of means of quantifying the recorded signals. Seizures, and preictal and interictal discharges produce clear patterns on SEEG. These patterns can be analyzed utilizing signal analysis methods that quantify high-frequency oscillations or changes in functional connectivity. Dramatic changes in SEEG brain connectivity can be described during seizure genesis and propagation within cortical and subcortical regions, associated with the production of different patterns of seizure semiology. The interictal state is characterized by networks generating abnormal activities (interictal spikes) and also by modified functional properties. The introduction of novel approaches to large-scale modeling of these networks offers new methods in the goal of better predicting the effects of epilepsy surgery. The epileptogenic network concept is a key factor in identifying the anatomic distribution of the epileptogenic process, which is particularly important in the context of epilepsy surgery.
Comparison and optimization of in silico algorithms for predicting the pathogenicity of sodium channel variants in epilepsy
Variants in neuronal voltage-gated sodium channel α-subunits genes SCN1A, SCN2A, and SCN8A are common in early onset epileptic encephalopathies and other autosomal dominant childhood epilepsy syndromes. However, in clinical practice, missense variants are often classified as variants of uncertain significance when missense variants are identified but heritability cannot be determined. Genetic testing reports often include results of computational tests to estimate pathogenicity and the frequency of that variant in population-based databases. The objective of this work was to enhance clinicians’ understanding of results by (1) determining how effectively computational algorithms predict epileptogenicity of sodium channel (SCN) missense variants; (2) optimizing their predictive capabilities; and (3) determining if epilepsy-associated SCN variants are present in population-based databases. This will help clinicians better understand the results of indeterminate SCN test results in people with epilepsy.Methods
Pathogenic, likely pathogenic, and benign variants in SCNs were identified using databases of sodium channel variants. Benign variants were also identified from population-based databases. Eight algorithms commonly used to predict pathogenicity were compared. In addition, logistic regression was used to determine if a combination of algorithms could better predict pathogenicity.Results
Based on American College of Medical Genetic Criteria, 440 variants were classified as pathogenic or likely pathogenic and 84 were classified as benign or likely benign. Twenty-eight variants previously associated with epilepsy were present in population-based gene databases. The output provided by most computational algorithms had a high sensitivity but low specificity with an accuracy of 0.52–0.77. Accuracy could be improved by adjusting the threshold for pathogenicity. Using this adjustment, the Mendelian Clinically Applicable Pathogenicity (M-CAP) algorithm had an accuracy of 0.90 and a combination of algorithms increased the accuracy to 0.92.Significance
Potentially pathogenic variants are present in population-based sources. Most computational algorithms overestimate pathogenicity; however, a weighted combination of several algorithms increased classification accuracy to >0.90.
New research from the University of Liverpool, published in the Journal of Clinical Investigation, has identified a protein that could help patients with epilepsy respond more positively to drug therapies.
There is now increasing body of evidence showing that local inflammation in the brain may be important in preventing control of seizures. Inflammation refers to the process by which the body reacts to insults such as having a fit. In most cases, the inflammation settles down, but in a small number of patients, the inflammation continues.
The aim of the research, undertaken by Dr Lauren Walker while she was a Medical Research Council (MRC) Clinical Training Fellow, was to address the important question of how can inflammation be detected by using blood samples, and whether this may provide us with new ways of treating patients in the future to reduce the inflammation and therefore improve seizure control.
The research focused on a protein called high mobility group box-1 (HMGB1), which exists in different forms in tissues and bloodstream (called isoforms), as it can provide a marker to gauge the level of inflammation present.
The results showed that there was a persistent increase in these isoforms in patients with newly-diagnosed epilepsy who had continuing seizure activity, despite anti-epileptic drug therapy, but not in those where the fits were controlled.
An accompanying drug study also found that HMGB1 isoforms may predict how an epilepsy patient’s seizures will respond to anti-inflammatory drugs.
Dr Walker, said: “Our data suggest that HMGB1 isoforms represent potential new drug targets, which could also identify which patients will respond to anti-inflammatory therapies. This will require evaluation in larger-scale prospective trials.”
On Monday Epilepsy Research UK announced the recipients of its 2017 grants at a reception at the Royal Society in London. The event was attended by Epilepsy Research UK supporters and researchers and is an annual event which runs in National Epilepsy Week. As well as celebrating the new grants, the organisation was also recognising the contribution of the Fund for Epilepsy which was founded 25 years ago and was one of the organisations that merged to form Epilepsy Research UK. Many Fund for Epilepsy stalwarts were at the event and we were delighted to welcome them to this special celebration.
Epilepsy Research UK is proud and pleased to announce the appointment of Professor Helen Cross as President of the organisation. Professor Cross has long been involved in the organisation being Chair of Trustees between 2005 and 2011. We are delighted that Professor Cross has now agreed to be President of the organisation.
About Professor Cross
Professor Helen Cross is The Prince of Wales’s Chair of Childhood Epilepsy and Honorary Consultant in Paediatric Neurology at UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Trust, London, and Young Epilepsy, Lingfield.
She is currently Clinical Advisor to the Children’s Epilepsy Surgery Services (CESS) (2012-present), is Chair of the Medicines for Children Research Network Neurosciences Clinical Study Group (2012-present), Chair of the Evidence Update of the NICE Guidelines for Epilepsy (2013) and was recently elected Secretary General of the ILAE to serve 2013-2017.
She is on the Editorial Board of Epileptic Disorders, Epilepsy Research, Developmental Medicine Child Neurology and European Journal of Paediatric Neurology.
Professor Cross qualified from Birmingham University in 1984, trained in paediatrics in Birmingham and subsequently in paediatric neurology in London, obtaining her PhD in 1998.
Her former roles include:
- Chair of the ILAE Commission for Paediatrics (2005 – 2009)
- Assistant Secretary to the Board of the European Paediatric Neurology Society (2005 – 2009)
- Chair of the Trustees of Epilepsy Research UK (2005 – 2011)
- President of the British Paediatric Neurology Association (2008 – 2011)
- Clinical Advisor to the update of the NICE guidelines on diagnosis and management of the epilepsies in adults and children (2009 – 2012)
- International League Against Epilepsy (ILAE) Commission for European Affairs, (2009 – 2013)
- ILAE Co-Chair of the sub-committee for ILAE Task Force for Global Outreach (2009 – 2013)
- Chair of the Task Force for Paediatric Epilepsy Surgery (2001-2013).
Professor Cross has published widely on seizure, neuropsychological and behavioural outcomes in children who have undergone surgical resection for treatment of their epilepsy. Her research has focused on improving outcomes for children with early onset epilepsy. Her early research was into improving imaging techniques to determine areas of likely seizure onset in children with drug resistant focal epilepsy and has developed an epilepsy surgery programme based on her research.
She conducted the first randomized controlled trial of the ketogenic diet in the treatment of children with drug resistant focal epilepsy and is endeavouring to conduct the same in the very young and adults. Recognising there was little in the way of control data with regard to neurodevelopmental progress, she initiated the North London Epilepsy in Infancy study, where a cohort of children was recruited at diagnosis in the first two years of life, and has been followed to at least three years. She is now aiming to conduct a similar study over a wider geographical area, also examining phenotypes and genotypes.
She is also endeavouring to examine mechanisms of cognitive impairment – in particular examining the relationship of sleep to memory consolidation.
BGG492 as an adjunctive treatment in patients with partial-onset seizures: A 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study with an open-label extension
To evaluate dose–response relationship of BGG492 as add-on therapy to 1–3 antiepileptic drugs in patients with partial-onset seizures and to investigate safety and tolerability of BGG492.Methods
This was a 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study (core study) with a 30-week, flexible-dose, open-label extension. In the core study, patients were randomized (1:2) to placebo or BGG492 100 mg t.i.d. in cohort 1, and in cohort 2 patients were randomized (1:4) to placebo or BGG492 150 mg t.i.d. On completion of the core study, eligible patients entered the extension study. Primary outcome measures were total partial seizure frequency per 28 days (core study) and safety and tolerability (extension study).Results
Overall, 93 patients were randomized (150 mg [n = 44]; 100 mg [n = 24]; placebo [n = 25]), and 81 (87.1%) completed the core study. Fifty-one patients entered and 43 (84.3%) completed the extension study. In the core study, no statistically significant dose–response trend among the BGG492 treatment groups (100 and 150 mg) was observed at the 4-week double-blind maintenance period (weeks 7–10); however, there was higher percent reduction in total partial seizure frequency in the BGG492 150 mg over placebo groups (37.32%; 95% confidence interval [CI] −18.90, 66.95). Dizziness, somnolence, and fatigue were the most common adverse events (AEs), higher in the BGG492 150 mg group than in the 100 mg and placebo groups (dizziness: 14 [31.8%] vs. 3 [12.5%] and 1 [4.0%]; somnolence: 7 [15.9%] vs. 1 [4.2%] and 1 [4.0%]; fatigue: 5 [11.4%] vs. 1 [4.2%] and 1 [4.0%]). During the open-label extension study, 39 (76.5%) patients on BGG492 had AEs, and the most commonly experienced AEs were dizziness (14 [27.5%]) and somnolence (9 [17.6%]).Significance
There was no significant dose–response trend in the BGG492 treatment groups (100 and 150 mg); however, higher percent reduction over placebo was observed in the BGG492 150 mg group. Safety and tolerability data were consistent with the known safety profile for BGG492, and no new safety risks were identified.
A new study has investigated why it is that some images can cause seizures in people with photosensitive epilepsy while other images don’t.
We know that in people with photosensitive epilepsy, flashing lights can cause seizures. The impact of such provocative visuals can be quite staggering. In 1997, for example, a certain Pokémon episode triggered seizures in 685 people in Japan, and in 2012, the promotional video for the Olympics had to be taken down from the website because it caused seizures in multiple epileptic patients.
However, seizures can also be caused by static images, with no motion or flicker. New research set out to examine why that is. A team of international researchers reviewed the literature available in the field of neurophysiology to see if the neural responses in a healthy visual cortex can predict how people with photosensitive epilepsy might respond to static images.
The study, led by Dora Hermes, of the University Medical Center (UMC) Utrecht in the Netherlands, and published in the journal Current Biology, has looked into the role of gamma oscillations in the brain.
Their review focused on gamma oscillations induced by the spatial features of some static images, such as those depicting black and white bars.
The repetitive pattern of brain activity of gamma oscillations takes place when people are exposed to these images. In fact, the authors note that these images can cause headaches and migraines in photosensitive people as well as discomfort in perfectly healthy people.
“Our findings imply that in designing buildings, it may be important to avoid the types of visual patterns that can activate this circuit and cause discomfort, migraines, or seizures. Even perfectly healthy people may feel modest discomfort from the images that are most likely to trigger seizures in photosensitive epilepsy.” Said Dr Hermes.
Gamma brain oscillations can be measured with the help of a simple electroencephalogram, and they have been known to scientists since the 1980s. However, researchers have not yet agreed on the role that these oscillations play in perception, thought, or generally in neural processing.
Gamma oscillations occur in the brain only upon viewing certain images, however, which runs counter to the hypothesis that they may be key to neural processing. For instance, images of grating patterns cause strong gamma oscillations, but images of clouds or natural landscapes do not. Why this happens remains largely unknown.
The authors conclude that these grating patterns are most likely to induce seizures, and they suggest various ways in which the images can be adjusted so as to avoid producing gamma oscillations in the brain.
“The likelihood that a [photosensitive seizure] is induced by viewing a grating can be reduced by decreasing the size of the grating [pattern], by reducing the contrast, by superimposing a second grating [pattern] to create a plaid or checkerboard, or by superimposing noise. Both sine and square wave gratings are provocative whereas chromatic contrast alone […] is not.”
Erratum to “Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: A post-hoc study” [Epilepsy Res. 131 (2017) 70–75]
Child- and parent-reported quality of life trajectories in children with epilepsy: A prospective cohort study
To describe the developmental trajectories of quality of life (QoL) in a large cohort of children with epilepsy, and to assess the relative contribution of clinical, psychosocial, and sociodemographic variables on QoL trajectories.Methods
Five assessments during a 28-month prospective cohort study were used to model trajectories of QoL. Participants were recruited with their parents from six Canadian tertiary centers. A convenience sample of 506 children aged 8–14 years with epilepsy and without intellectual disability or autism spectrum disorder were enrolled. A total of 894 children were eligible and 330 refused participation. Participating children were, on average, 11.4 years of age, and 49% were female. Nearly one third (32%) had partial seizures. At baseline, 479 and 503 child- and parent-reported questionnaires were completed. In total, 354 children (74%) and 366 parents (73%) completed the 28-month follow-up. QoL was measured using the child- and parent-reported version of the Childhood Epilepsy QoL scale (CHEQOL-25).Results
Child-reported QoL was fitted best by a six-class model and parent-reported QoL by a five-class model. In both models, trajectories remained either stable or improved over 28 months. Of these children, 62% rated their QoL as high or moderately high, defined as at least one standard deviation above the average CHEQOL-25 score. Greater family, classmate, and peer social support, fewer symptoms of child and parent depression, and higher receptive vocabulary were identified as the most robust predictors of better QoL (all p < 0.001).Significance
Most children with epilepsy and their parents reported relatively good QoL in this first joint self- and proxy-reported trajectory study. Findings confirm the heterogeneous QoL outcomes for children with epilepsy and the primary importance of psychosocial factors rather than seizure and AED-specific factors in influencing QoL. These predictors that are potentially amenable to change should now be the focus of specific intervention studies.