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Epilepsy Research UK Newsletter

Every £1 counts The summer is coming – let’s hope it hasn’t gone – and those of you who have been keeping up with us on social media will know that we have been giving out top tips for travelling with epilepsy. I recently attended the Farnell Golf Day in Leeds. It was a great day and all in all will have probably raised about £10,000 for epilepsy research. The event is now in its 15th year and looks to be going strong. Over that time more than £150,000 has been raised towards epilepsy research by the efforts of the staff and management of Farnell. But it goes further than that. Because of the “gold standard” way in which we fund research and because of our membership of the Association of Medical Research Charities, universities who we fund can claim a further 28% from the government. So this year, that £10,000 will automatically become £12,800 and the money we spend has impact. Our own research has shown that for every £1 we put into research, our researchers are able to leverage another £3.50 in funding from other sources. All of a sudden, that £10,000 donation has a value of almost £45,000 for epilepsy research. Every £1 counts. And it counts even more when you realise how effectively it can be used. That is why we continue to be so grateful to the piggy bank smashers, the runners, the cake makers and everybody else who makes a donation towards epilepsy research. It goes a long way. So thank you. Mike Rich, Chief Executive

Summer 2017

RESEARCH GRANTS AWARDED IN 2017 GeneLoop: gene therapy activated by seizures to treat epilepsy Dr Gabriele Lignani, University College London Fellowship award of £246,650

‘This project will investigate a flexible and self-regulated gene therapy approach to stop seizures. We will use seizures to stop seizures and this can potentially be a huge improvement for the treatment of intractable drug-resistant epilepsies. This fellowship will allow me to combine many years of study into the causes of network activity to develop a new treatment to stop seizures.’ Dr Gabriele Lignani

Background Gene therapy, in which the excitability of neurons is reduced via gene modification, holds promise as a treatment for drug-resistant focal epilepsy, and it could feasibly replace epilepsy surgery in the future. However, experimental gene therapies have revealed significant flaws in that they either a) have a permanent effect on neurons or b) require ‘re-administration’ each time a seizure occurs. In addition, they are unable to distinguish between neurons in the ‘treated area’ that are involved in seizures and those that are not, thus risking damage to healthy cells.

The study During this fellowship, Dr Lignani will validate a new method of gene therapy that is only activated in neurons with excessive excitability during seizures (sparing healthy neurons). The activation (in hyperexcitable neurons) increases the activity of specific ‘candidate’ genes that have been carefully chosen based on their ability to reduce neuronal excitability, and the hope is that this will restore ‘normal’ behaviour. Once seizures have stopped the therapy is designed to ‘switch off’ until seizure activity recurs. In the first instance, Dr Lignani has selected a candidate gene called KCN1A, and he fully expects to see a suppression of induced seizure activity when the gene therapy is activated. He notes that, once the new technique has been validated, it will allow the rapid screening of other candidate genes

transforming lives through research

to find out which ones, either alone or in combination, are able to stop seizure activity.

Significance This work is important, because it will help the development of a cutting-edge approach to stopping seizures. Moreover, it will enable researchers to better understand which cells in the brain are responsible for triggering seizures, and which genes should be ‘targeted’ to stop them. According to Dr Lignani, this new method of gene therapy could potentially reach clinical trials in 5-10 years. Dr Lignani’s fellowship has been supported by our memorial funds. We would like to thank all our memorial fund supporters for their tremendous commitment and generosity over the past year.

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The role of inhibitory nerve cells in seizures Dr Ivan Pavlov, University College London Project grant of £149,947

‘Surprisingly little remains known about the contribution of different cell types in the generation of seizures… Our experimental approach is beneficial for novel drug development and will help establish better targeted interventions based on gene therapy.’ Dr Ivan Pavlov

Background Epileptic seizures are caused by excessive activity of groups of neurons in the brain, and many treatments aim to suppress this by increasing inhibitory signalling. Studies in extracted brain tissue have now shown that certain inhibitory neurons that were supposed to stop pathological (disease-causing) ‘firing’ can actually promote seizure activity; however, it is not clear how this happens, or what its role in living organisms is.

The study Here, Dr Pavlov and colleagues will explore the behaviour of selected inhibitory neurons during seizures, in awake rodents. They will investigate two theories about how inhibitory neurons might promote seizures: 1) that these neurons ‘fire’ so much to suppress excitation when a seizure begins that they become

unable to do so, and 2) that during a seizure their inhibitory actions progressively weaken and may even convert to excitatory activity due to activity-dependent chloride accumulation in surrounding cells. During the project the team will implant a window made from transparent film into the skulls of rodents to allow easy access to their brains. Seizures will be chemically induced and tiny electrodes will be used to record the electrical activity of individual inhibitory neurons in the rodents’ brains. The scientists will also probe the neurons’ behaviour using a cutting-edge technique called optogenetics, which allows researchers to control the activity of cells with light. To explore whether chloride is a part of the seizure-promoting activity of inhibitory

Neurodevelopment after prenatal exposure to seizures (NAPES) Study Dr Rebecca Bromley, University of Manchester Project grant of £149,963

‘Understanding whether transient maternal seizures during pregnancy are associated with poorer child neurodevelopment will aid treatment decisions for women with epilepsy and their doctors.’ Dr Rebecca Bromley Children who are exposed to certain antiepileptic drugs (AEDs) in the womb are at risk of poorer neurodevelopment, but if women with epilepsy don’t take antiepileptic drugs during pregnancy they risk having seizures. There is little evidence about how short-lasting seizures might directly affect an unborn child, however, and this makes very it difficult for women with epilepsy (and their doctors) to make informed treatment decisions for pregnancy. In this project, Dr Bromley and colleagues will investigate whether exposure to seizures in the womb has a negative effect on the neurodevelopment of the child exposed in the womb. During the study the group will recruit women with epilepsy who are either pregnant or planning a pregnancy, and are taking lamotrigine and/or levetiracetam*. They will divide the women into two groups: those who are experiencing seizures and those that aren’t (the controls), and they will follow them throughout their pregnancy for any changes in seizure status. When the children of the women are approximately 12 months old, the team will

assess their neurodevelopment using standard tests and without knowing whether the child was exposed to seizures or not. The team will analyse the neurodevelopmental scores and investigate whether there is a significant difference between children who were exposed to seizures in the womb and those who weren’t. They will categorise the seizures into convulsive and non-convulsive to assess the effects of each. The results of this project will have an immediate impact on the care of women with epilepsy who are planning a family, offering them important information to help in what can be very difficult treatment decisions. * Lamotrigine and levetiracetam pose the lowest risk to neurodevelopment, meaning that the team can assess the true effect of seizures on neurodevelopmental outcome.

transforming lives through research

neurons, the group will genetically manipulate the neurons so that they are able to pump chloride out more efficiently. They will then assess the neurons’ behaviour during seizures to see if decreasing their chloride load changes their function. The team will perform the investigations in both healthy rodents and those with chronic epilepsy. By comparing the results, they will be able to see whether inhibitory neurons change their functional role in epilepsy.

Significance This important project will help us to better understand the mechanisms that underlie epilepsy. This is crucial for the identification of new drug targets and the development of novel therapies.

Research Report 2017 In the last 10 years we have awarded some £8 million in research funding, and this is all thanks to you, our supporters. Throughout the year we closely monitor the outcomes of our grants to ensure that your donations fund the most promising epilepsy research across the UK. We are delighted to share with you our research report for 2017, which highlights some of the impact that our research has had to date. We have shown that every £1 we spend on our grants generates a further £3.50 for research into epilepsy, which is a clear demonstration of the quality of research we are supporting. The report also contains the findings of some of our recentlycompleted studies, and an introduction to our exciting new grants for 2017. To order a copy, please contact us at the Epilepsy Research UK Fundin office. Trans g Research

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Resear ch Re port 20 17

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The incidence of hospital admissions with prolonged seizures and status epilepticus in England 1990-2015 Professor Matthew Walker, University College London Pilot grant of £11,275

THE HIPPOCAMPUS

‘Very prolonged seizures (status epilepticus) can have devastating consequences and can result in death. It is critical to understand how recent changes in the treatment of seizures and epilepsy have impacted upon status epilepticus. Funding from ERUK will enable us to determine how common status epilepticus is in the UK, how that has changed over time and what impact that has had on epilepsy deaths.’ Professor Matthew Walker Status epilepticus is a prolonged seizure (lasting more than five minutes) that requires urgent treatment and hospital admission. It is a significant cause of mortality in people with epilepsy, accounting for approximately 10% of epilepsy deaths. Since the 1990’s, a lot of work has been carried out to establish care pathways and protocols for status epilepticus/prolonged seizures, so that all hospitals in the United Kingdom have clear treatment regimens to manage them. Recent analyses suggest that the death rates for status epilepticus in England and Wales are falling, which may be due to improved/earlier treatment. However, it is impossible to know this for certain without knowing whether the frequency of status epilepticus has changed in the corresponding period (i.e. it could be that the fall in mortality rate is simply due to fewer cases of status epilepticus in that time). Currently there is no available data on the frequency of status epilepticus in England,

or indeed, whether the frequency of status epilepticus has changed over time. During this grant, Professor Walker and his colleagues hope to address this gap in knowledge. To achieve this, the team will obtain information about hospital admissions due to status epilepticus in England, for the period 1990-2015, from the Health and Social Care Information Centre (HSCIC). They will analyse the data to get an idea of the frequency of status epilepticus during this period, and find out if/how the frequency of status epilepticus changed. They will then see how their newly-acquired frequency data correlates with the mortality data that is already available. The findings of this study will help to establish why a fall in mortality rate due to status epilepticus has been seen in recent years, and whether the care pathways in hospitals are responsible for this decrease. This will allow for a more informed assessment of current treatment regimens and their effectiveness.

Modulation of glial signalling as a novel therapy for absence epilepsy Dr Mark Wall, University of Warwick Pilot grant of £29,300

‘Our work will hopefully identify a new therapeutic target to treat absence epilepsy and increase understanding of the disease.’ Dr Mark Wall

Background

The Study

Absence epilepsy is largely a childhood condition characterised by sudden, brief interruptions of consciousness. In severe cases there may be more than 200 of these episodes each day, and these can be accompanied by or develop into convulsive seizures. Many children with absence seizures don’t respond to existing antiepileptic medication, which can present numerous difficulties in daily life, particularly with schooling.

This grant focuses on brain cells called glial cells, which support neurons and are important for maintaining correct communication between them. More specifically, Dr Wall and Dr Ngomba (University of Lincoln) want to find out if a loss of glial cell function is responsible for the increased inhibition that leads to absence seizures.

On EEG, absence seizures show a specific pattern of brain activity that arises within a neuronal network called the thalamo-cortical network. The mechanisms that generate these episodes are still not fully understood, but evidence shows that enhancement of a particular type of inhibitory communication between neurons may be responsible. Attempts to develop treatments that directly reduce this inhibition have failed because of side effects, so a more targeted approach is required.

A CLOSER LOOK AT ... The hippocampus is a very important structure found deep within the temporal lobe of the brain. There are, in fact, two of them, one on each side of the brain, and they got their name because they are seahorse-shaped and hippocampus means seahorse. The hippocampi (plural of hippocampus) are involved in controlling our emotions and they are vital to our memory function. They are also one of the only regions where new nerve cells are created throughout adulthood. The hippocampus is mentioned a lot in epilepsy, because, particularly in people with temporal lobe epilepsy, it is frequently the place where seizures start. There is often damage to the hippocampus on the ‘affected’ side of the brain (and sometimes both hippocampi are involved), although it is still not clear whether this is the cause or result of seizures. Damage to the hippocampus causes loss of function and this is one of the reasons why many people with epilepsy experience memory problems. We have funded a number of grants aimed at understanding the role of the hippocampus in epilepsy (with a view to protecting it), and most recently we awarded Dr Stephanie Schorge, at University College London, a pilot grant to try and find out why the front end of the hippocampus is more likely to generate seizures than the back end. If successful, this research could help the development of exciting new epilepsy treatments that target the front part of the hippocampus with minimal side effects. You can read more about Dr Schorge’s research on p4.

The group will use a range of laboratory techniques to explore, in depth, how certain aspects of glial activity are altered in a rodent model of absence epilepsy. They also plan to investigate whether it is possible to reduce or even prevent absence seizures by enhancing glial cell activity.

Significance The findings from this project will give important new information about how absence seizures arise, and may reveal new targets for the development of more promising treatments.The methods used will also be useful for the screening process of anti-absence seizure drugs in the future.

transforming lives through research

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Recording brain activity using electrodes placed in the nose Dr Dora Lozsadi St George’s Hospital, London Pilot grant award of £30,000

‘Routine, low-risk access to electrical activity in deep-seated brain areas will improve not only the diagnostic yield of EEGs, but also aid our understanding of seizure subtypes and neuronal networks involved in their generation.’ Dr Dora Lozsadi

Background When someone is suspected to have epilepsy, they are usually referred for an electroencephalogram (EEG). The test records electrical activity in the brain via electrodes attached to the scalp. Though EEG is a very useful tool, it is poor at detecting focal abnormalities originating in deep brain areas (e.g. the inner, lower region of the frontal lobe), because the scalp electrodes are too far away. Current methods to bring the electrodes closer to the seizure source are invasive and sometimes require surgery.

The Study Here, Dr Lozsadi and colleagues will assess the tolerability and benefit of a minimally invasive technique in which recording electrodes are placed in the nose (the nasal cavity). During the study the team plans to recruit 30 people either with brain abnormalities affecting areas close to the top of the nasal cavity or controls. They will approach people who have

routine sleep deprived EEG planned, or who are awaiting video EEG monitoring. All subjects will undergo a standard EEG, and in addition a hair-thin EEG wire (attached to an amplifier) will be inserted into their nose. The investigations will last a maximum of 48 hours and will take place in a neurophysiology department or neurology ward. The researchers will examine the data in two stages: first routine EEGs alone and then EEGs in combination with nasal recordings. They will be interested in additional information obtained on deep brain structures using nasal electrodes.

Significance If they do find additional information, the impact on routine diagnosis and advanced management of people with frontal lobe epilepsy will be significant. The new technique will not only facilitate accurate and prompt diagnosis and earlier access to treatment, it will reduce the need for invasive follow-up investigations.

What makes some parts of the brain more seizure-prone? Dr Stephanie Schorge, University College London Pilot grant award of £12,845 ‘I have studied how different proteins change the activity of neurons for many years. More recently I realised that these same changes can be involved in epilepsy. I am now working to apply what I’ve learned about modifying neuronal activity to try and calm down the activity of neurons that trigger seizures.’ Dr Stephanie Schorge

Background Epileptic seizures often originate in the hippocampus, an important memory structure located deep within the brain. The hippocampus is curled and crescent-shaped, and while both ends look similar superficially, they are very different. For reasons that are not fully understood, the front (ventral) end is much more likely to generate seizures than the back (dorsal) end. Here, Dr Schorge and Dr Gareth Morris will explore why this is the case, so that they can better understand what makes the ventral part so likely to trigger seizures and, in contrast, why the dorsal part is protected.

The Study During the study, the team will record epileptic signals in thin tissue slices obtained from each end of the hippocampus. They will compare the behaviour and properties of individual brain

cells to see how those from the dorsal and ventral parts differ, and how these differences correlate with seizure activity. They will focus in particular on two proteins and how their function can affect the seizure threshold of brain cells. Towards the end of the grant the group will hopefully be able to use the knowledge they have gained to test ways of blocking seizures in the ventral part of the hippocampus.

Significance If successful, this project will identify specific features that make the ventral hippocampus so vulnerable to seizures and, potentially, ways of ‘protecting’ it. In the medium term, this could provide a springboard for the development of new epilepsy treatments that selectively target the ventral hippocampus with minimal side effects.

transforming lives through research

5 minutes with... ERUK Research Fellow, Alfredo GonzalezSulser Mike Rich reports

There is nothing more fascinating than being shown around a scientific laboratory. The smell of chemicals, test tubes, strange looking pieces of equipment – I love it. When I recently went to see our Research Fellow Dr Alfredo Gonzalez-Sulser at Edinburgh University I was looking forward to all of the above and I was not disappointed.

Alfredo is a warm friendly man who was born in Mexico and has studied there, in the USA and now in the UK. He is a talented neurologist and his research in optogenetics excited our Scientific Advisory Committee. Optogenetics is a cutting-edge technique which uses light to control the activity of neurons in the brain. Sounds incredibly complex – and it is – but Alfredo has a knack of explaining it in a very clear and simple way. He hopes that optogenetics can be used in the treatment of temporal lobe epilepsy which is currently very hard to treat. The idea is that he can use light to control the activity of specific neurons in the hippocampus (see elsewhere in this newsletter) to block seizures. There is a long way to go, but if successful, this work could lead to effective treatments for temporal lobe epilepsy within the next 15 to 20 years. It sounds like a long time but this really is scientific work for the future. And who knows what other benefits it will bring?

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New President appointed We are delighted to report the appointment of Professor Helen Cross as the new President of Epilepsy Research UK . Professor Cross has long been involved with the charity, first joining our Scientific Advisory Committee (SAC) in 1997, then going on to chair the SAC. She served as Chair of Trustees from 2005 to 2011, and oversaw the merger of the Epilepsy Research Foundation with the Fund for Epilepsy to form Epilepsy Research UK. Professor Cross is The Prince of Wales’s Chair of Childhood Epilepsy and Honorary Consultant in Paediatric Neurology at University College London Institute of Child Health, Great Ormond Street Hospital and Young Epilepsy. She has published widely on behavioural, neuropsychological and seizure outcomes in children after epilepsy surgery, and she has done extensive research into improving outcomes for children with early-onset epilepsy. She led the first randomized controlled trial of the ketogenic diet for the treatment of children with drug resistant focal epilepsy, and she now endeavours to conduct the same in both the very young and in adults. It is with great pleasure that we welcome Professor Cross in her new role as President of Epilepsy Research UK.

Regional ‘Meet a Researcher’ evenings – open to all! We’re planning a series of ‘Meet a Researcher’ evening events around the country, starting in autumn 2017, so you can have the opportunity to hear first-hand from one of our researchers about the work they are doing – research that you have helped us to fund – and we can meet more of our supporters in person. The meetings will be open to all our supporters, as well as to others in the local area who would be interested to come along and find out more about the work of Epilepsy Research UK.

You can complete the form on our website: www.epilepsyresearch.org.uk/regionalevents/, email your name and full contact details together with your preferred location to info@ eruk.org.uk, or call the office on 020 8747 5024. We’d love to see you somewhere on our tour! Edinburgh

Norwich

Newcastle

London

Leeds

Exeter

Chester

To help us plan our programme, please register your interest in attending a ‘Meet a Researcher’ evening in any of the locations given (see right). We’ll hope to visit other areas later in 2018.

Purple Day Purple Day, the international day for epilepsy awareness held annually on 26th March, gains ever more prominence. We are always amazed by the inventive ways in which our supporters embrace Purple Day and had fantastic support again this year. Our Communications Director, Deborah Pullen, was interviewed by local TV station Chiswickbuzz.net to explain the importance of Purple Day in raising awareness and galvanising people to raise funds for epilepsy research. You can watch the interview here: www.chiswickbuzz.net/community/ purple-day-is-coming-to-chiswick

National Epilepsy Week We were delighted to announce the recipients of our 2017 research grants at our reception at the Royal Society in National Epilepsy Week (14 - 20 May). The research grants awarded are featured in detail in this newsletter. Supporters around the country organised and took part in various events to mark the week. These included coffee mornings, afternoon teas, collections and awarenessraising activities.

who are diagnosed with epilepsy. We asked our supporters to share their thoughts about why we need more research and what research means to them. Some of the responses are shown on the right.

On social media we had significant activity around our #1in103 campaign, reinforcing awareness of the 1 in 103 people in the UK

We also ran a new text appeal in our email newsletter as part of our National Epilepsy Week activity.

#1in103 “I live with 3 of the #1in103 and my older daughter makes the 4th. That’s why research and fundraising is so important to me” Nick Davidson

“More research hopefully means a cure and that my son won’t have to grow up with a Mummy who has seizures” Faye Waddams

“As research makes progress we will discover more effective treatments and many more will be able to become seizure-free” Tom Jensen

transforming lives through research

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Fundraisers in action Simon Osborn’s Thames Path Walk Simon walked the entire 184 miles of the Thames Path back in April. His good friend’s son was born with severe epilepsy and was having seizures from only a few weeks old. After being diagnosed in 2015 with epilepsy himself Simon found this to become more of an incentive to help fund vital research.

Simon walked 184 miles in 12 days, from the source of the Thames in the Cotswold hills to the Thames Barrier in Woolwich. He walked most of the path on his own, carrying just a 25kg rucksack of essentials, apart from three days where friends, work colleagues and Jo from ERUK walked stages alongside him.

Simon says, “The walk itself was very tough both physically and mentally. I knew it would be hard but way tougher then I had anticipated. Despite all the aches and pains, I enjoyed the scenic views of the country side as well as the iconic landmarks in places like Windsor Castle and in around London. Most days I was literally crawling to the hotels at the end of the stages as I am known for being more mixed grills than Bear Grylls!!”. You can read the full account of Simon’s challenge in the Focus on Fundraiser’s section on our website.

“I had a great time and actually enjoyed it! Completed in 22 hours 6 minutes and will do it again!”

“Thank you for everything. The t-shirts were great, we were known as the green team on the walk. Alex and I both feel privileged to have raised money for such a wonderful, attentive charity.”

“Most importantly I raised over £600 for ERUK in the process which I hope will go some way to solving the challenge of epilepsy.”

transforming lives through research

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Sporting events

“The sense of achievement at the end and knowing we had raised money for such a great cause were definitely worth it.”

“Copious amounts of mud, even more water and some Gladiators-inspired obstacles were all that stood in our way from powering up the Travelator at the end of the course.” It’s not too late to join Team ERUK and there are plenty of opportunities to get involved in our sporting calendar:

Thames Bridges Trek - 9 September Big Fun Run Series – July – October Bournemouth Marathon Festival - 7-8 October

transforming lives through research

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Reception at the Royal Society During National Epilepsy Week we held an evening reception at the Royal Society to announce the seven new research grants we are funding in 2017. Supporters and fundraisers of the charity were able to meet those researchers whose projects have been selected this year and hear first-hand about the projects that they have been helping to fund through all their fundraising efforts. We also celebrated 25 years since the founding of the Fund for Epilepsy and were delighted to welcome both the founders, former trustees and long-standing supporters for all they achieved since setting up the charity 25 years ago. Looking to the future, we were delighted to welcome Professor Helen Cross as the newly appointed President of Epilepsy Research UK (see p5). We would like to thank everyone who came for their contribution to such an informative and enjoyable evening.

Christmas card shop volunteers needed We’re looking for volunteers to help in charity Christmas card shops later in the year in Durham, Ealing, central London, Stamford and York. If you would like to join our team of volunteers and could spare a regularly morning or afternoon each week from mid-October through to mid-December to help, please contact Shona for more information on 020 8747 5024 or email shona@eruk.org.uk.

Thank you to all our supporters for your generous donations in recent months. Our particular thanks go to all who have chosen to remember their loved ones by supporting our research. Names of those in whose memory we have recently received donations are given on our website: www.epilepsyresearch.org.uk/support-us/given-in-memory/

“Research into epilepsy is the only way that things will get better for those who live with it.” Mark Blackshaw

The application process for our 2018 research grant awards has just begun. You can help us now to fund even more promising research next year and beyond by making a regular monthly donation to Epilepsy Research UK. If you would like to support us with a regular donation, or a single gift, please complete and return the donation form enclosed or donate online at: www.epilepsyresearch.org.uk.

Thank you.

PO Box 3004, London W4 4XT T: 020 8747 5024 E: info@eruk.org.uk W: www.epilepsyresearch.org.uk • Registered charity number: 1100394 Designed and printed by Eclipse Creative Ltd: 01252 517341 www.eclipse-creative.co.uk

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Focus Newsletter - Summer 2017  

Focus Newsletter - Summer 2017