Chairmans' Report 2017 by Epilepsy Research Institute

Chairman’s report Another year, and what a momentous year it was. In 2016-17, we secured the much-prized status of ‘nominated charity’ at a national, massparticipation running event - the British 10K London Run - and also celebrated the 25th anniversary of Epilepsy Research UK with a fantastic gala ball at the Grange St Paul’s Hotel in London. I had the pleasure of participating in both and can report that the ball was marginally less exhausting! At the British 10K, the sight of hundreds of Epilepsy Research UK supporters streaming through the streets of central London in their trademark green and white running vests was incredibly uplifting and really put the charity on the map. I would to thank everyone who took

part, and everyone who turned out on the day to cheer us weary runners along, for making it such a landmark event. It was a pleasure for me to run alongside you and to hear so many inspirational stories afterwards. My thanks also go to everyone who supported the gala ball, and especially to the ball committee, volunteers and staff who put in tireless amounts of work behind the scenes, for making this yet another great evening and a huge success for Epilepsy Research UK. The money raised by these events, and also by the unstinting efforts of our incredible supporters throughout the year, has again allowed us to support an array of ground-breaking research projects. We awarded a fellowship to Dr Gabriele Lignani at University College London to explore gene therapy for

epilepsy, and a project grant to Dr Rebecca Bromley at the University of Manchester to study the development of children born to mothers with epilepsy. Other awards went to Dr Mark Wall, Dr Ivan Pavlov, Dr Dora Lozsadi, Dr Stephanie Schorge, and Prof Matthew Walker for a broad range of research covering absence seizures, status epilepticus, frontal lobe epilepsies, and exploring brain mechanisms responsible for seizure generation. We wish them all much success.

Following Leigh’s departure, we welcomed Mike Rich as our new Chief Executive. I’m grateful for the help and support of my fellow trustees at this time and am also indebted to our staff who continued to deliver through this period of change. As ever though, I sign off with my warmest appreciation for our supporters and their tireless commitment to the cause of epilepsy research. None of this would be possible without you.

The past year has witnessed some changes at Epilepsy Research UK. We bade farewell to Leigh Slocombe, our long-time Chief Executive, who led the charity for 15 years and who takes much of the credit for the healthy position we currently enjoy.

Dr Graeme Sills Chair of Trustees

Thank you so much.

transforming lives through research in 2017

Fundraising Thank you to every single one of you who supported us during our 25th anniversary year. Your drive and determination to support the cause of research into epilepsy has been an inspiration, and it is only with your generosity that we have been able to award seven new research grants this year. Whether you have set up a regular gift, made a donation of money or time, organised or taken part in an event, or supported us through a company or charitable trust, you have made a significant difference and we thank you all. During the year our supporters have been actively fundraising in so many ways: in running events, parachute jumps, challenges, obstacle races and sponsored walks. We were delighted to have so many runners in the British 10K London Run in our year as their official charity. Others gave up their time to volunteer in our cheering teams, Christmas card shops and for collections, or to organise all manner of fundraising events from a coffee morning to a ball. The time and effort involved in organising these events shows immense dedication for which we are extremely grateful. Over 200 supporters joined us at our 25th Anniversary Ball for a fantastic evening of celebration and dancing. Our thanks go to all who joined us on the evening, or donated prizes or their time, and particularly to the ball committee for their outstanding commitment in helping to organise such a successful event. People choose to support epilepsy research in many ways, and often because epilepsy has had an impact on their own lives or on

the lives of those they are close to, particularly if they have lost a loved one to epilepsy. A special mention goes to our memorial fund families for their inspirational dedication to supporting research, and in particular to those supporting the Ellen Mezzetti Memorial Fund which this year became the first of our memorial funds to raise over £100,000. Our warmest thanks go to John and Lynne Mezzetti who, together with their family, friends and local community in north Norfolk, have raised over £100,000 over the last 10 years in memory of their daughter Ellen, an exceptional achievement. We are honoured to receive the remarkable support we do from all who give through a memorial fund or in other ways in memory of a loved one. This year, the monies raised by our memorial funds will be allocated to Dr Lignani’s fellowship, described overleaf. It is only thanks to your help we are able to fund the research which will make a real difference to the lives of people with epilepsy now and in the future.

Financial summary

income

2016-17 was a successful year in fundraising terms, with total charity income from all sources of £1,402,998. This enabled us to award £629,980 in research grants. Expenditure on our other charitable activities totalled £412,070, and we continued to develop our social media activity to raise awareness of epilepsy and the need for research into the condition. We also kept our fundraising costs and expenditure under tight control.

Epilepsy Research UK, PO Box 3004, London W4 4XT. The annual accounts were approved by the trustees on 15th June 2017 and the annual report and accounts have been submitted to the Charity Commission. The accounts have been audited and have been given an unqualified report by our auditors. Judith Spencer-Gregson Honorary Treasurer

Officers of the charity PRESIDENT Professor Helen Cross OBE TRUSTEES Dr Graeme Sills (Chairman) Mr Barrie Akin The Rt Hon Mr David Cameron Ms Mary Gavigan (appointed December 2016) Dr Yvonne Hart Dr John Hirst CBE Professor Michael Kerr (resigned August 2016) Mr Simon Lanyon Mrs Mary Manning (resigned September 2016) Professor Mark Rees Professor Mark Richardson Mr Harry Salmon Miss Judith Spencer-Gregson Professor Matthew Walker

Donations

£417,469

Fundraising events

£429,641

Legacies

£403,881

Other trading income

£31,438

Investment income

£16,115

Research grants not required

SCIENTIFIC ADVISORY COMMITTEE

30%

29%

£104,454 31%

£1,402,998

expenditure

Trustees’ statement The financial information included in this report are summaries extracted from the accounts of Epilepsy Research UK for the year ending 31st March 2017. The summarised accounts may not contain sufficient information for a full understanding of the financial affairs of the charity. For further information, the full annual accounts, the auditors’ report on those accounts and the trustees’ annual report should be consulted. Copies of these can be obtained from

22% 47%

Research grants

£629,980

Other charitable activities

£412,070

Fundraising

£299,202

£1,341,252

31%

Financial summary for the year ended 31st March 2017 Unrestricted Restricted Funds (£) Funds (£)

Total Funds 2017 (£)

Total Funds 2016 (£)

INCOME Donations & gifts

407,469

10,000

417,469

394,216

429,641

328,704

Professor Mark Richardson (Chairman)

Fundraising events Legacies

403,881

426,045

Mr Alasdair Ball

Interest

16,115

24,818

104,454

62,426

31,438

1,392,998

10,000

1,402,998

1,236,209

Mrs Anne Coxon Dr Mark Cunningham Professor Bruno Frenguelli Dr John Livingston

Research grants not required Other trading activities TOTAL INCOME EXPENDITURE Research grants committed

629,980

687,179

Dr Adam Noble

Other charitable activities

409,820

2,250

412,070

369,437

Dr Stephanie Schorge

Fundraising

299,202

205,082

1,339,002

2,250

1,341,252

1,261,698

Dr Graeme Sills (as Chair of Trustees) Dr Amanda Wood VICE-PRESIDENTS Mr John Bowis OBE Dr John Mumford Mr Paul Newman Dr Jolyon Oxley Lord Stevenson of Coddenham CBE

TOTAL EXPENDITURE

12,487

Net gains on investments

12,487

Net incoming/(outgoing) resources

66,483

7,750

74,233

(25,489)

Transfer between funds

10,000

(10,000)

Net incoming/(outgoing) resources after transfer

76,483

(2,250)

74,233

(25,489)

Balance brought forward at 1 April 2016

686,942

33,449

720,391

745,880

Total funds at 31 March 2017

763,425

31,199

794,624

720,391

3,128,720

31,199

3,159,919

3,298,013

(2,365,295)

(2,577,622)

763,425

31,199

794,624

720,391

Total assets Total liabilities NET ASSETS AT 31 MARCH 2017

PO Box 3004 London W4 4XT 020 8747 5024 info@eruk.org.uk w www.epilepsyresearch.org.uk @EpilepsyResearchUK @EpilepsyRUK t

Registered in England charity no.1100394 Registered office: Chiswick Town Hall, Heathfield Terrace, London W4 4JN Epilepsy Research UK is a member of the Association of Medical Research Charities

Epilepsy is one of the most common neurological conditions.

Epilepsy Research UK is the only organisation that is dedicated to funding research into all aspects of epilepsy, across the UK.

32,000 people in the

The only national charity in the UK that is exclusively dedicated to funding independent research into epilepsy, Epilepsy Research UK supports and promotes basic and clinical scientific research into the causes, treatments and prevention of epilepsy. We support the best quality research through an annual grant round, and every year fund new research projects at universities and hospitals around the UK, with scientists and clinicians investigating many aspects of epilepsy in both adults and children.

Over 600,000 people in the UK have a diagnosis of epilepsy - 1 in every 103 people.

UK are newly diagnosed with epilepsy each year – that’s about 87 people every day.

1,100

Even with controlled seizures, life for people with epilepsy can be unpredictable and restricted. Only through research will more effective therapies be discovered, seizures more safely controlled and quality of life for those with epilepsy improved. New research is key to achieving this vision, and we look forward to greater advances being made in the near future.

Every year 1,100 people die as a result of epilepsy-related causes.

Epilepsy Research UK funding is crucial to making these future advances, which is only made possible by the generosity of our supporters. Together we can transform lives.

60%

This year we awarded seven new grants, details of which are given below.

Epilepsy can take many forms, from a momentary blank spell to a dramatic major convulsion.

Epilepsy can be caused by a stroke, a head injury or an inherent genetic defect, but in over 60% of cases there is no known cause.

transforming lives through research in 2017

Research grants awarded in 2016/17 GeneLoop: gene therapy activated by seizures to treat epilepsy

The role of inhibitory nerve cells in seizures

Neurodevelopment after prenatal exposure to seizures (NAPES) Study

“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.”

“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.”

“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 Gabriele Lignani University College London Fellowship award of £246,650

‘normal’ behaviour. Once seizures have stopped the therapy is designed to ‘switch off’ until seizure activity recurs.

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

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 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.

The incidence of hospital admissions with prolonged seizures and status epilepticus in England 1990-2015 “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 University College London Pilot grant of £11,275 Background 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 1990s, 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. The study 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 has changed. They will then see how their newly-acquired frequency data correlates with the mortality data that is already available. Significance 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.

What makes some parts of the brain more seizure-prone? “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 University College London Pilot grant award of £12,845 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.

Dr Ivan Pavlov University College London Project grant of £149,947 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 activitydependent 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 seizurepromoting activity of inhibitory 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.

Dr Rebecca Bromley University of Manchester Project grant of £149,963 Background 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 it very difficult for women with epilepsy (and their doctors) to make informed treatment decisions for pregnancy. The study 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. 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. Significance 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.

Modulation of glial signalling as a novel therapy for absence epilepsy

Recording brain activity using electrodes placed in the nose

“Our work will hopefully identify a new therapeutic target to treat absence epilepsy and increase understanding of the disease.”

“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 Mark Wall University of Warwick Pilot grant of £29,300 Background 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. 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.

The study 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.

Dr Dora Lozsadi St George’s Hospital, London Pilot grant award of £30,000 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 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.

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.

Other research activities and outcomes Current funding

A good investment

We are currently funding 31 projects at institutes around the country, with researchers investigating new methods of diagnosing and treating epilepsy, studying ways to prevent SUDEP, exploring techniques to improve surgical outcomes and developing tools to improve the quality of life for people with epilepsy.

Each year, alongside most other medical research charities in the UK, we ask our grant holders, past and present, to report on the outcomes of their projects via an online platform called Researchfish. Outcomes include: influence on clinical practice, follow-on funding, public engagement events (where scientists share their work with members of the public), and publications.

1 Glasgow

Edinburgh

1 Newcastle-upon-Tyne

Research areas funded Manchester

SUDEP 2 Co-morbidities of epilepsy 5

Causes of epilepsy 12

Birmingham

2 Cardiff

Diagnosis and treatment of epilepsy 12

Sheffield

Exeter

2 Bath

Warwick Oxford

14 London

Using Researchfish we have recently tracked the successes of research we funded between 2009 and 2015. During this period we spent £3,305,372 on research grants and these have leveraged a further £11,568,068 in follow-on funding from other sources. Every pound invested by Epilepsy Research UK has therefore generated a further £3.50 for epilepsy research. This huge return on our investment demonstrates our ability to identify innovative research at an early stage that will ultimately benefit everyone with epilepsy. Another indicator of the quality of the research we fund is the number of publications that arise from the work. A total of 89 journal publications have resulted from ERUK grants during the 2009-2015 period, 15 of which were in very high impact journals such as Brain, Nature or Journal of Physiology.

The Association of Medical Research Charities (AMRC) collates Researchfish data from its member organisations and produces a report demonstrating the phenomenal impact of research charity funding. In this report, the AMRC highlights case studies from members that have ‘achieved’ exceptionally for a particular outcome. Last year, Epilepsy Research UK was recognised by the AMRC for follow-on funding generated by a grant awarded in 2009. This £99,397 project, entitled ‘Potassium channels in epilepsy’, was led by Professor Matthew Walker, at University College London, and its findings helped to secure an incredible £2.5 million (for continued research) from the Medical Research Council. We are immensely proud of Professor Walker for this achievement, and greatly encouraged to see this level of further funding for epilepsy research leveraged by our investment. The AMRC impact report is available to read on the AMRC website, www.amrc.org.uk. You can read more about our research impact along with the latest grant results and thoughts from our grant holders, in our Research Report 2017. This can be downloaded from our website, www.epilepsy.org.uk, or copies are available on request from the Epilepsy Research UK office.