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.
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.”
A recent study at the University of Sydney has looked into the prevalence of depression and anxiety disorders in people with epilepsy. The study carried out by Dr. Louise Sharpe and her colleagues was a meta-analysis and looked at 27 previously published research papers on the subject.
Dr. Sharpe said: “It is often thought that depression is more common than anxiety in people with epilepsy. Our results suggest that in clinical practice depression is more often diagnosed than anxiety disorders. However, in studies using structured interviews, depression and anxiety were equally common.”
The researchers found that 20% percent of people with epilepsy had anxiety disorders while 23% suffered from depression. However, the severity of people’s epilepsy did not seem to effect the prevalence of anxiety or depression.
The big difference came with how the anxiety disorder had been diagnosed. Unstructured clinician assessments resulted in a prevalence of 8%, while a structured clinical interview gave a prevalence of 27%.
“This suggests that people with epilepsy who have anxiety may be under-diagnosed in practice,” said Dr Sharpe. “We need to understand more about anxiety in epilepsy so that it can be identified more readily and effective treatments can be developed.”
The study’s findings also challenge the assumption that psychiatric disorders are more common in people with drug-resistant epilepsy. Researchers said the detection and management of such disorders — particularly anxiety disorders — among people with remains neglected.
Two recently published studies show just how important the use of computer technology and modelling have become in the study of epilepsy.
A study being carried out at Newcastle University is using a brain model to explore the cause of different epileptic seizure onset patterns. According to the study, at the onset of an epileptic seizure, differing characteristics of brain tissue surrounding the seizure’s origin site may determine which of two main patterns of brain activity will be seen. Electrical activity in the brain at the start of an epileptic seizure typically follows either a “low amplitude fast” pattern or a “high amplitude slow” pattern. Patients whose seizures follow the high amplitude slow pattern have a higher risk of continuing seizures after surgical treatment. However, the mechanisms underlying these different patterns are unclear.
To better understand the onset patterns, Yujiang Wang of Newcastle University, UK, and colleagues used a previously developed computer model that can simulate brain activity at the start of a seizure. The model output suggested that the onset pattern of a seizure may be determined not by brain tissue at the site where the seizure originates, but by characteristics of the surrounding “healthy” brain tissue.
The simulation showed that the high amplitude slow pattern occurs when surrounding brain tissue has higher excitability; that is, the brain cells have a stronger response to stimulation and can react immediately to the initiation of a seizure. Meanwhile, the low amplitude fast pattern is associated with tissue of lower excitability, which is only slowly penetrated by seizure activity.
These findings suggest why the different onset patterns are associated with different treatment outcomes. Surgical removal of seizure-triggering brain tissue may be enough to prevent seizure activity in nearby low-excitability tissue. However, high-excitability tissue may still be stimulated by alternative trigger sites after surgery, providing a possible explanation for the worse outcomes experienced by patients whose seizures follow the high amplitude slow pattern.
Next, the researchers plan to study seizure onset patterns in greater detail. “We hope to contribute towards the overall goal of associating patterns seen in seizures with an understanding of the underlying mechanism,” Wang says. “This would not only help our understanding of seizures in general, but may be useful for patient stratification in terms of treatment options.”
In a second study being carried out at Boston Children’s Hospital could enable more patients with epilepsy to benefit from surgery when medications do not help. The approach streamlines the seizure monitoring process required for surgical planning, making surgery a more feasible and less risky option for patients.
Currently, for some patients, pinpointing the diseased brain areas where their seizures originate requires invasive surgery to place grids of electrodes on the brain’s surface. This is followed by long-term electroencephalography (EEG) monitoring – typically for a week – while doctors wait for a seizure to happen. Then, patients must undergo a second brain operation to remove the diseased tissue.
The new technology, developed by Joseph Madsen, MD, Director of Epilepsy Surgery at Boston Children’s Hospital, and Eun-Hyoung Park, PhD, a computational biophysicist in the Department of Neurosurgery, could allow patients to be monitored in one short session, without the need to observe an actual seizure. Patients could then proceed directly to surgery, avoiding a second operation.
Effective use of this technology could cut the cost and risk by more than half by reducing the current two-stage procedure to one-stage, the researchers say. “We know that the diseased brain network responsible for the seizures is there all along,” says Madsen. “So rather than wait for the patient to have a seizure, we set out to find patterns of interaction between various points in the brain that might predict where seizures would eventually start.”
To identify the brain areas causing the seizures, Madsen and Park applied a special algorithm to analyze patients’ interictal EEG data – data captured between their seizures. They randomly selected 25 patients with hard-to-treat epilepsy who previously had long-term EEG monitoring at Boston Children’s, and analyzed data from the first 20 seizure-free minutes of the patients’ EEGs.
Their algorithm, known as Granger causality analysis, is based on a statistical approach developed Sir Clive Granger (for which he won the Nobel Prize in Economics in 2003). Madsen and Park adapted the Granger method, originally used for economic forecasting, to calculate the probability that activity at one brain location predicts subsequent activity at other brain locations strongly enough to be considered causative. Their analysis generated a map of the causal relations in each patient’s epileptogenic network, which Park and Madsen superimposed over images of the brain.
They then showed that the brain regions predicted to be causing seizures strongly correlated with actual causative regions on seizure EEGs – as read by ten board-certified epileptologists, usually many days later.
Madsen and Park have shown that their calculations can be done quickly enough to allow data obtained in the operating room to potentially influence surgical decision-making. They now are investigating how the Granger causality method can best augment readings of EEGs by trained neurophysiologists. “We still need to validate and refine our approach before it can be used clinically,” notes Madsen. “But we are hopeful that these advanced computer applications can help us treat more children with epilepsy – with less risk and lower cost.”
Article: Granger Causality Analysis of Interictal iEEG Predicts Seizure Focus and Ultimate Resection, Eun-Hyoung Park, PhD Joseph R. Madsen, MD, Neurosurgery, doi: 10.1093/neuros/nyx195, published 2 May 2017.
Article: Mechanisms underlying different onset patterns of focal seizures, Wang Y, Trevelyan AJ, Valentin A, Alarcon G, Taylor PN, Kaiser M, PLOS Computational Biology, doi: 10.1371/journal.pcbi.1005475, published 4 May 2017.
Following a very successful Lady Captain’s Charity Evening on 11th March, a cheque for £4,858 was presented to Dr. Graeme Sills, Chairman of Epilepsy Research UK last weekend at the West Lancashire Golf Club.
Last year’s Ladies’ Captain Jackie Bickerstaffe introduced Dr. Sills to some of the main helpers at the fundraising event and presented the cheque totalling £4,858. She thanked everyone who had given so generously and Dr. Sills for coming to accept the Club’s donation.
Dr. Sills was delighted to attend and accept the cheque on behalf of Epilepsy Research UK and explained the work he does at Liverpool University into the understanding and treatment of epilepsy, a condition which affects a huge number of the population.
We in the Fundraising Office add our thanks to that of Dr. Sills to all at West Lancashire Golf Club, especially Jackie Bickerstaffe for nominating us as a beneficiary for such fantastic support of Epilepsy Research UK.
Pictured L to R are:
Paula Morris, Kiran Sharma, Linda Foy, Dr. Sills, Immediate Past Ladies’ Captain Jackie Bickerstaffe, Wayne Arands Asst. Catering Manager, Margaret McDowell and Immediate Past Captain Dr. Anil Sharma.