12th International Expert Workshop 2019

12th International Expert Workshop Epilepsy and Neurodevelopmental Disorders

14 th - 15th March 2019 St Anne’s College, Oxford

epilepsy research uk

Foreword

Contents Forewords

Page 3

Programme: Day two

Page 8

Programme: Day one Speaker profiles

Speaker abstracts Delegate list

T H E OF FI C E O F

DAVID CAMERON

Former Prime Minister of the United Kingdom

Page 6

FROM THE RT HON DAVID CAMERON

Page 10 Page 14 Page 26 International Expert Workshop Epilepsy and Neurodevelopmental Disorders

Join the discussion on Twitter: Tweet us at @ERUKresearch or using the hashtag #ERUKworkshop

I joined Epilepsy Research UK in 2004 after our son, Ivan, was diagnosed with Ohtahara Syndrome. Despite the excellent care Ivan received, it was apparent how little was known about the many types of epilepsy.

During my time with the charity, there has been significant research investment into the causes, diagnosis and clinical management of epilepsy. But equally as important as funding research, is the need to bring global experts together to build the overall research capacity and accelerate breakthroughs.

This workshop brings together experts from across the world to scrutinise the wide and varied aspects of neurodevelopmental disorders. More research is fundamental to ensuring families are able to access the best possible treatments for their children. I hope this workshop will help define the key research priorities, build on international collaboration, as well as encouraging further investment.

Thank you all for your wonderful support. This comes with my and Samantha’s very best wishes for a successful and productive workshop.

Cover image:

Dr Alfredo Gonzalez-Sulser,Epilepsy Research UK Fellow, University of Edinburgh, UK 2

PO BOX 73981, LONDON, SW1P 9PN WWW.DAVIDCAMERONOFFICE.ORG The Office of David Cameron Limited. Company Registration No. 10421190

3

Foreword

Contents Forewords

Page 3

Programme: Day two

Page 8

Programme: Day one Speaker profiles

Speaker abstracts Delegate list

T H E OF FI C E O F

DAVID CAMERON

Former Prime Minister of the United Kingdom

Page 6

FROM THE RT HON DAVID CAMERON

Page 10 Page 14 Page 26 International Expert Workshop Epilepsy and Neurodevelopmental Disorders

Join the discussion on Twitter: Tweet us at @ERUKresearch or using the hashtag #ERUKworkshop

I joined Epilepsy Research UK in 2004 after our son, Ivan, was diagnosed with Ohtahara Syndrome. Despite the excellent care Ivan received, it was apparent how little was known about the many types of epilepsy.

During my time with the charity, there has been significant research investment into the causes, diagnosis and clinical management of epilepsy. But equally as important as funding research, is the need to bring global experts together to build the overall research capacity and accelerate breakthroughs.

This workshop brings together experts from across the world to scrutinise the wide and varied aspects of neurodevelopmental disorders. More research is fundamental to ensuring families are able to access the best possible treatments for their children. I hope this workshop will help define the key research priorities, build on international collaboration, as well as encouraging further investment.

Thank you all for your wonderful support. This comes with my and Samantha’s very best wishes for a successful and productive workshop.

Cover image:

Dr Alfredo Gonzalez-Sulser,Epilepsy Research UK Fellow, University of Edinburgh, UK 2

PO BOX 73981, LONDON, SW1P 9PN WWW.DAVIDCAMERONOFFICE.ORG The Office of David Cameron Limited. Company Registration No. 10421190

3

Foreword

Foreword

Dear colleagues,

Welcome to the ERUK International Expert Workshop on Epilepsy and Neurodevelopmental Disorders, organised by Professors Stuart Cobb, Oscar Marin and Sameer Zuberi.

The Expert Workshops are a flagship event in ERUK’s calendar. Occurring every two to three years, they are an opportunity to gather together experts from across the globe to critically appraise our understanding of the aetiology, pathophysiology, diagnosis and treatment of one aspect of the many faces of epilepsy. This year’s Workshop is the 12th in a series dating back to 1993, during which time the Workshops have addressed a wide range of topics including: epilepsy in pregnancy, the psychosocial burden of epilepsy, SUDEP, and tumourassociated epilepsy. The Workshops generate published proceedings in order that the material discussed at the Workshop can be shared with the wider community, with the view to promoting further investigation in that area.

This year the focus is on epilepsy associated with neurodevelopmental disorders.

The birth of a child is a momentous and joyous occasion in the lives of the parents. However, for all too many parents this joy is curtailed by the realisation that there is something wrong with their child. This earth-shattering revelation often first manifests as the appearance of epileptic seizures, for which, unfortunately, there are limited treatment options. The Workshop is thus an opportunity for the expert community to consider the basis of neurodevelopmental epilepsy, to discuss the most appropriate animal models and diagnostic approaches, and to explore the potential treatment options for afflicted children.

Given the excellent program of sessions and speakers over the next two days, I have every expectation that these issues will be given detailed and authoritative scrutiny, and that the ensuing output will be valuable resource to the community.

On behalf of ERUK, I hope you enjoy the meeting and your stay in the elegant surroundings of St Anne’s College.

Professor Bruno Frenguelli Chair, ERUK Scientific Advisory Committee

4

This Epilepsy Research UK Expert Workshop brings together an exceptional international faculty of clinicians and scientists working at the frontiers of neuroscience and epilepsy research. The presenters and discussants bring a varied range of interests and expertise, representing all the key research themes linking neurodevelopment and epilepsy.

Epilepsies with onset in childhood are associated with significant comorbidities affecting learning, motor control, cognition and behaviour. The epileptic seizure may be the presenting symptom and most dramatic expression of a brain disease, but it is the impact of the underlying condition on learning, behaviour and participation in society which results in the most disabling consequences for the child and family. Anti-seizure medications are designed to control events but disappointingly have little or no impact on the neurodevelopmental comorbidities of epilepsy.

The aim of this workshop is to present new research, introduce novel concepts and through enthusiastic debate and discussion to identify new ways forward in epilepsy research. We hope that bringing together many of the world’s leading neuroscientists and epilepsy researchers to focus on one topic from many different perspectives will spark new insights and forge new friendships and collaborations.

This meeting would not be possible without the willingness of busy people to share their ideas, expose them to critique and to travel a long way to do this. We thank all members of the faculty – presenters and discussants – for agreeing to meet in Oxford. We know that colleagues are prepared to do this for many reasons; their passion for science and intellectual discourse included but primarily because they respect and value the work of colleagues. As scientists we know that each increment in knowledge, every marginal gain, when added together can make big differences to the lives of people with epilepsy.

Finally, we would like to thank the supporters of Epilepsy Research UK whose tireless fundraising underpins all the work of the charity and the staff of ERUK, particularly Caoimhe Bennett, for their patience, support and help in developing the meeting programme.

Professor Sameer Zuberi Royal Hospital for Children & University of Glasgow

Professor Oscar Marin King’s College London

5

Professor Stuart Cobb University of Edinburgh

Foreword

Foreword

Dear colleagues,

Welcome to the ERUK International Expert Workshop on Epilepsy and Neurodevelopmental Disorders, organised by Professors Stuart Cobb, Oscar Marin and Sameer Zuberi.

The Expert Workshops are a flagship event in ERUK’s calendar. Occurring every two to three years, they are an opportunity to gather together experts from across the globe to critically appraise our understanding of the aetiology, pathophysiology, diagnosis and treatment of one aspect of the many faces of epilepsy. This year’s Workshop is the 12th in a series dating back to 1993, during which time the Workshops have addressed a wide range of topics including: epilepsy in pregnancy, the psychosocial burden of epilepsy, SUDEP, and tumourassociated epilepsy. The Workshops generate published proceedings in order that the material discussed at the Workshop can be shared with the wider community, with the view to promoting further investigation in that area.

This year the focus is on epilepsy associated with neurodevelopmental disorders.

The birth of a child is a momentous and joyous occasion in the lives of the parents. However, for all too many parents this joy is curtailed by the realisation that there is something wrong with their child. This earth-shattering revelation often first manifests as the appearance of epileptic seizures, for which, unfortunately, there are limited treatment options. The Workshop is thus an opportunity for the expert community to consider the basis of neurodevelopmental epilepsy, to discuss the most appropriate animal models and diagnostic approaches, and to explore the potential treatment options for afflicted children.

Given the excellent program of sessions and speakers over the next two days, I have every expectation that these issues will be given detailed and authoritative scrutiny, and that the ensuing output will be valuable resource to the community.

On behalf of ERUK, I hope you enjoy the meeting and your stay in the elegant surroundings of St Anne’s College.

Professor Bruno Frenguelli Chair, ERUK Scientific Advisory Committee

4

This Epilepsy Research UK Expert Workshop brings together an exceptional international faculty of clinicians and scientists working at the frontiers of neuroscience and epilepsy research. The presenters and discussants bring a varied range of interests and expertise, representing all the key research themes linking neurodevelopment and epilepsy.

Epilepsies with onset in childhood are associated with significant comorbidities affecting learning, motor control, cognition and behaviour. The epileptic seizure may be the presenting symptom and most dramatic expression of a brain disease, but it is the impact of the underlying condition on learning, behaviour and participation in society which results in the most disabling consequences for the child and family. Anti-seizure medications are designed to control events but disappointingly have little or no impact on the neurodevelopmental comorbidities of epilepsy.

The aim of this workshop is to present new research, introduce novel concepts and through enthusiastic debate and discussion to identify new ways forward in epilepsy research. We hope that bringing together many of the world’s leading neuroscientists and epilepsy researchers to focus on one topic from many different perspectives will spark new insights and forge new friendships and collaborations.

This meeting would not be possible without the willingness of busy people to share their ideas, expose them to critique and to travel a long way to do this. We thank all members of the faculty – presenters and discussants – for agreeing to meet in Oxford. We know that colleagues are prepared to do this for many reasons; their passion for science and intellectual discourse included but primarily because they respect and value the work of colleagues. As scientists we know that each increment in knowledge, every marginal gain, when added together can make big differences to the lives of people with epilepsy.

Finally, we would like to thank the supporters of Epilepsy Research UK whose tireless fundraising underpins all the work of the charity and the staff of ERUK, particularly Caoimhe Bennett, for their patience, support and help in developing the meeting programme.

Professor Sameer Zuberi Royal Hospital for Children & University of Glasgow

Professor Oscar Marin King’s College London

5

Professor Stuart Cobb University of Edinburgh

Day One Thursday 14th March 2019

TIME

PRESENTATION TITLE

SPEAKER

AFFILIATION

TIME

09:00

Welcome

Bruno Frenguelli Stuart Cobb Oscar Marin

University of Warwick, UK University of Edinburgh, UK King's College London, UK

14:30

Sameer Zuberi

Royal Hospital for Children & University of Glasgow, UK

08:15 onwards Workshop registration and coffee

Session 1: 09:10 09:15 09:35 09:55 10:15

10:35 11:10

Session 2: 11:30

11:35 11:55 12:15 12:35 12:55 13:25

What is the broad relationship between neurodevelopmental disorders and epilepsy?

Chair: Sameer Zuberi, Royal Hospital for Children & University of Glasgow.

Introduction

The link between neurodevelopmental disorders and epilepsy (own clinical and research perspective)

Lucy Raymond

Epilepsy gene discovery and its implications

Joseph Symonds

Use of epilepsy/NDD gene panels – Amy McTague does early diagnosis make a difference?

Structural aetiologies in neurodevelopment and epilepsy

Renzo Guerrini

Chaired discussion

Cambridge Institute for Medical Research, UK University of Glasgow, UK

University College London, UK University of Florence, Italy

PRESENTATION TITLE

SPEAKER

AFFILIATION

Introduction

Floor Jansen

UMC Utrecht, Netherlands

Epilepsies with sleep activation – insights from functional neuroimaging

Patrick van Bogaert

Université d’Angers, France

Influence of epilepsy surgery on developmental outcomes

Kees Braun

UMC Utrecht, Netherlands

Closing remarks for day one

Stuart Cobb Oscar Marin

University of Edinburgh, UK King's College London, UK

Session 3:

What is the relationship between genetic epilepsy and epileptic encephalopathy?

Chair: Floor Jansen, UMC Utrecht, Netherlands.

14:35

What do we mean by the concept of Ingrid Scheffer epileptic encephalopathy?

14:55 15:15

15:35 15:55

16:25-16:40

19:00

Early intervention in epileptic spasms Finbar O'Callaghan University College London, UK Chaired discussion

Drinks reception followed by dinner

Refreshment break

How well can we model neurodevelopmental epilepsy disorders in experimental systems and what can they tell us? Chair: Lieven Lagae, KU Leuven, Belgium.

Introduction

Lieven Lagae

KU Leuven, Belgium

2-D and 3-D Stem Cell Models of Epilepsy

Jack Parent

University of Michigan, US

Regulome-based computational anti-epileptic drug target discovery

Michael Johnson

Rodent models: where it all started

Imperial College London, UK

Solomon L. Moshé Albert Einstein College of Medicine, US

Epileptic networks in zebrafish - new Richard Rosch insights from a novel animal model

King's College London, UK

Chaired discussion Lunch

6

University of Melbourne, Australia

7

Day One Thursday 14th March 2019

TIME

PRESENTATION TITLE

SPEAKER

AFFILIATION

TIME

09:00

Welcome

Bruno Frenguelli Stuart Cobb Oscar Marin

University of Warwick, UK University of Edinburgh, UK King's College London, UK

14:30

Sameer Zuberi

Royal Hospital for Children & University of Glasgow, UK

08:15 onwards Workshop registration and coffee

Session 1: 09:10 09:15 09:35 09:55 10:15

10:35 11:10

Session 2: 11:30

11:35 11:55 12:15 12:35 12:55 13:25

What is the broad relationship between neurodevelopmental disorders and epilepsy?

Chair: Sameer Zuberi, Royal Hospital for Children & University of Glasgow.

Introduction

The link between neurodevelopmental disorders and epilepsy (own clinical and research perspective)

Lucy Raymond

Epilepsy gene discovery and its implications

Joseph Symonds

Use of epilepsy/NDD gene panels – Amy McTague does early diagnosis make a difference?

Structural aetiologies in neurodevelopment and epilepsy

Renzo Guerrini

Chaired discussion

Cambridge Institute for Medical Research, UK University of Glasgow, UK

University College London, UK University of Florence, Italy

PRESENTATION TITLE

SPEAKER

AFFILIATION

Introduction

Floor Jansen

UMC Utrecht, Netherlands

Epilepsies with sleep activation – insights from functional neuroimaging

Patrick van Bogaert

Université d’Angers, France

Influence of epilepsy surgery on developmental outcomes

Kees Braun

UMC Utrecht, Netherlands

Closing remarks for day one

Stuart Cobb Oscar Marin

University of Edinburgh, UK King's College London, UK

Session 3:

What is the relationship between genetic epilepsy and epileptic encephalopathy?

Chair: Floor Jansen, UMC Utrecht, Netherlands.

14:35

What do we mean by the concept of Ingrid Scheffer epileptic encephalopathy?

14:55 15:15

15:35 15:55

16:25-16:40

19:00

Early intervention in epileptic spasms Finbar O'Callaghan University College London, UK Chaired discussion

Drinks reception followed by dinner

Refreshment break

How well can we model neurodevelopmental epilepsy disorders in experimental systems and what can they tell us? Chair: Lieven Lagae, KU Leuven, Belgium.

Introduction

Lieven Lagae

KU Leuven, Belgium

2-D and 3-D Stem Cell Models of Epilepsy

Jack Parent

University of Michigan, US

Regulome-based computational anti-epileptic drug target discovery

Michael Johnson

Rodent models: where it all started

Imperial College London, UK

Solomon L. Moshé Albert Einstein College of Medicine, US

Epileptic networks in zebrafish - new Richard Rosch insights from a novel animal model

King's College London, UK

Chaired discussion Lunch

6

University of Melbourne, Australia

7

Day Two Friday 15th March 2019

TIME

09:00 Session 4: 09:05 09:10 09:30 09:50 10:10 10:30 11:00

Session 5: 11:20

11:25 11:45

12:05 12:25

12:45 13:15

PRESENTATION TITLE

SPEAKER

Welcome

Stuart Cobb Oscar Marin

AFFILIATION

University of Edinburgh, UK King's College London, UK

What is our understanding of underlying mechanisms linking genetic epilepsies and neurodevelopment?

Chair: Oscar Marin, King's College London, UK. Introduction

Oscar Marin

King's College London, UK

Genetic variations of NMDAR GRIN genes in epilepsy and neurodevelopmental disorders

Hongjie Yuan

Emory University, US

From rare to polygenic epilepsies

Dennis Lal

PCDH19 Girls Clustering Epilepsy, a disorder of cellular mosaics Epigenetic mechanisms and noncoding RNAs

Broad Institute of MIT and Harvard, US

Jozef Gecz

University of Adelaide, Australia

David Henshall

Royal College of Surgeons, Ireland

Chaired discussion

Refreshment break

Session 6: 14:10 14:15 14:35 14:55 15:15

Molecular therapeutic strategies in epilepsy and neurodevelopmental disorders.

What are the key questions and strategies for finding future treatments?

Chair: Dimitri Kullmann, University College London, UK. Introduction

Dimitri Kullmann

University College London, UK

Targeting defective pathways in neurodevelopmental disorders: the example of the AnkyrinG interactome

Frank Kooy

University of Antwerp, Belgium

Stuart Cobb

University of Edinburgh, UK

Scott Baraban

University of California, San Francisco, US

Stuart Cobb Oscar Marin

University of Edinburgh, UK King's College London, UK

Genetic therapies

Gene therapy in neurodevelopmental disorders Cell therapies

15:35

Chaired discussion

16.40

WORKSHOP CLOSES

16:05

Stephanie Schorge University College London, UK

Summary and closing remarks for day two

How does the link between epilepsy, behaviour and development affect current treatments?

Chair: Deb Pal, King's College London, UK. Introduction

Deb Pal

King's College London, UK

Impact of anti-epileptic drugs on mood & behaviour

Alexis Arzimanoglou

University Hospitals of Lyon, France

Concept of disease modification

Lieven Lagae

KU Leuven, Belgium

Effects of AEDs on early and in utero Gus Baker brain development Cognition, learning and AEDs in childhood epilepsy

Liam Dorris

Chaired discussion

University of Liverpool, UK

NHS Greater Glasgow and Clyde

Lunch

8

9

Day Two Friday 15th March 2019

TIME

09:00 Session 4: 09:05 09:10 09:30 09:50 10:10 10:30 11:00

Session 5: 11:20

11:25 11:45

12:05 12:25

12:45 13:15

PRESENTATION TITLE

SPEAKER

Welcome

Stuart Cobb Oscar Marin

AFFILIATION

University of Edinburgh, UK King's College London, UK

What is our understanding of underlying mechanisms linking genetic epilepsies and neurodevelopment?

Chair: Oscar Marin, King's College London, UK. Introduction

Oscar Marin

King's College London, UK

Genetic variations of NMDAR GRIN genes in epilepsy and neurodevelopmental disorders

Hongjie Yuan

Emory University, US

From rare to polygenic epilepsies

Dennis Lal

PCDH19 Girls Clustering Epilepsy, a disorder of cellular mosaics Epigenetic mechanisms and noncoding RNAs

Broad Institute of MIT and Harvard, US

Jozef Gecz

University of Adelaide, Australia

David Henshall

Royal College of Surgeons, Ireland

Chaired discussion

Refreshment break

Session 6: 14:10 14:15 14:35 14:55 15:15

Molecular therapeutic strategies in epilepsy and neurodevelopmental disorders.

What are the key questions and strategies for finding future treatments?

Chair: Dimitri Kullmann, University College London, UK. Introduction

Dimitri Kullmann

University College London, UK

Targeting defective pathways in neurodevelopmental disorders: the example of the AnkyrinG interactome

Frank Kooy

University of Antwerp, Belgium

Stuart Cobb

University of Edinburgh, UK

Scott Baraban

University of California, San Francisco, US

Stuart Cobb Oscar Marin

University of Edinburgh, UK King's College London, UK

Genetic therapies

Gene therapy in neurodevelopmental disorders Cell therapies

15:35

Chaired discussion

16.40

WORKSHOP CLOSES

16:05

Stephanie Schorge University College London, UK

Summary and closing remarks for day two

How does the link between epilepsy, behaviour and development affect current treatments?

Chair: Deb Pal, King's College London, UK. Introduction

Deb Pal

King's College London, UK

Impact of anti-epileptic drugs on mood & behaviour

Alexis Arzimanoglou

University Hospitals of Lyon, France

Concept of disease modification

Lieven Lagae

KU Leuven, Belgium

Effects of AEDs on early and in utero Gus Baker brain development Cognition, learning and AEDs in childhood epilepsy

Liam Dorris

Chaired discussion

University of Liverpool, UK

NHS Greater Glasgow and Clyde

Lunch

8

9

Speaker Profiles

Professor Alexis Arzimanoglou leads the Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology of the Hospices Civils de Lyon, France and is the Epilepsy Research coordinator for the Child Neurology Department of the Sant Joan de Déu Barcelona Hospital in Spain.

Together with Professor Helen Cross he coordinates the European Reference Network for rare and complex epilepsies, ERN EpiCARE.

therapies. He is a founding member of an international Rett syndrome gene therapy consortium and is pioneering RNA-based therapies for Rett syndrome and monogenic forms of epilepsy.

Dr Liam Dorris is a Consultant Paediatric Neuropsychologist at the Royal Hospital for Children in Glasgow, and Honorary Associate Professor at the University of Glasgow. He has published widely in developmental neuropsychology with particular interests in cognitive and psychosocial consequences of childhood epilepsy. He recently delivered a multi-centre RCT psychosocial intervention (PIE), which has changed practice in many paediatric neurosciences centres.

Professor Gus Baker is Emeritus Professor of Clinical Neuropsychology and Honorary Consultant Clinical Neuropsychologist at the University of Liverpool and the Walton Centre for Neurology and Neurosurgery.

He was the principal researcher of the UK study on the neurodevelopment effects of exposure to antiepileptic drugs and co-principal researcher on the US/UK NIH funded study. The UK group have published more than 25 papers in this field.

Professor Jozef Gécz is Channel 7 Children’s Research Foundation Chair for the Prevention of Childhood Disability at the University of Adelaide, Australia. Jozef discovered or co-discovered of >200 disease genes for various forms of neurodevelopmental disabilities (e.g. ARX, CDKL5 or PCDH19). Jozef’s research is patient centric and focuses on the application of genomics for precise diagnosis to empower early intervention and personalised treatment.

Professor Scott Baraban is the William K. Bowes Jr. Endowed Chair in Neuroscience Research at the University of California San Francisco. Dr Baraban is the recipient of awards from Klingenstein Fund, NIH (Javits), and AES (Basic Science Research Recognition). His laboratory established the (i) first interneuron-based cell transplantation strategies for intractable epilepsies, (ii) first zebrafish epilepsy models and (iii) first zebrafish-based drug screens for epilepsy.

Professor Renzo Guerrini is a Professor of Child Neurology and Psychiatry at the University of Florence, Italy. He is also Head of the Centre of Excellence for Neuroscience at Children’s Hospital A. Meyer, Florence. Professor Guerrini chaired the International League Against Epilepsy Commission on Paediatrics. In 2003, he received the ‘Ambassador of Epilepsy’ award from the International League Against Epilepsy and in 2012 the ‘Research Award for Clinical Science’ from the American Epilepsy Society (AES). He has coordinated the EU Project DESIRE on development of epilepsy.

Professor Kees Braun is Professor of Child Neurology and coordinator of epilepsy research at the University Medical Center Utrecht. He was president of the Dutch Paediatric Neurology Society from 2012-2017 and president of the 2016 ICNC world congress of child neurology. He participates in several European epilepsy consortia and is a member of the ERN EpiCARE steering committee.

His research focuses on paediatric epilepsy surgery and drug withdrawal policies.

Professor David C. Henshall is Professor of Molecular Physiology & Neuroscience and Director of the FutureNeuro Research Centre at the Royal College of Surgeons in Ireland. His research interests are cell and molecular mechanisms of epilepsy, biomarkers and novel therapies. He has authored over 175 original papers and book chapters.

Professor Stuart Cobb is a neurobiology specialist based in the Patrick Wild Centre for Neurodevelopmental Disorders at the University of Edinburgh, UK. His research focuses on the reversibility and tractability of genetic brain disorders and in the development of novel molecular 10

Dr Floor Jansen specialised in Paediatric Neurology in 2007, and in the same year she obtained her PhD degree on a thesis entitled “identification of epileptogenic sources in patients with TSC”. Her clinical and scientific areas of expertise are: refractory paediatric epilepsy, including epilepsy surgery, tuberous sclerosis, electrical status epilepticus in sleep (ESES of CSWS), and genetic epilepsy.

Dr Dennis Lal is Assistant Staff in the Genomic Medicine Institute (GMI) and the Epilepsy Center at the Cleveland Clinic as well as Visiting Scientist at the Broad Institute of Harvard & M.I.T,US. He leads a computational epilepsy genetic research group with members in Cleveland, Cambridge as well as at the Cologne Center for Genomics at the University of Cologne, Germany.

Professor Michael Johnson is Professor of Neurology and Genomic Medicine and Deputy Head of the Centre for Clinical Translation in the Division of Brain Sciences at Imperial College London, and Honorary Consultant Neurologist at Imperial College Healthcare NHS Trust. His research focuses on the systems-level integration of genetic, genomic and phenotypic data to infer causal functional pathways and their drugable regulators.

Professor Oscar Marín is Professor of Neurobiology, Director of the MRC Centre for Neurodevelopmental Disorders and the Centre for Developmental Neurobiology at King’s College London. He graduated in Biology from Universidad Complutense in Madrid, where he also obtained a PhD in Neuroscience, followed by a postdoc with John Rubenstein at UCSF. He was a group leader at the Institute of Neuroscience in Alicante prior to joining King’s in 2014.

Professor Frank Kooy is a full Professor in Cognitive Genetics at the University of Antwerp. His research successfully focuses on the identification of genetic causes of cognitive disorders, such as intellectual disability and autism and to study the defective genes with the ultimate goal of developing rational therapies.

Dr Amy McTague is a GOSH NIHR BRC Catalyst Research Fellow at the UCL Great Ormond Street Institute of Child Health and Honorary Consultant Paediatric Neurologist at Great Ormond Street Hospital, London. Dr McTague is investigating disease mechanisms and potential novel therapies in early onset genetic epilepsies.

Professor Dimitri Kullmann is a professor of neurology at UCL. He trained in medicine and physiological sciences in Oxford and London. After a post-doctoral fellowship at UCSF he completed neurology training in London. His interests include synaptic physiology, mechanisms of neurological channelopathies, and gene therapy for epilepsy. He is also the Editor of Brain.

Professor Solomon L. Moshé is the Charles Frost Chair in Neurosurgery and Neurology, and Professor of Neurology, Neuroscience, and Paediatrics at the Albert Einstein College of Medicine/Montefiore Medical Center in the Bronx, New York. He is also the Vice Chair of the Saul R. Korey Department of Neurology, Director of the Isabelle Rapin Child Neurology Division and Director of Clinical Neurophysiology.

Professor Lieven Lagae is Full Professor at the University of Leuven, Belgium (KUL), Head of the Paediatric Neurology Department of the KUL University Hospitals, and Director of the Childhood Epilepsy Program at the KUL University Hospitals.

Lieven Lagae is the immediate past President of the European Paediatric Neurology Society and serves as an elected Board Member of the International Child Neurology Association (ICNA) and the Taskforce on Medical Treatment of Childhood Epilepsy of the International League against Epilepsy (ILAE).

Dr Finbar O’Callaghan is Professor of Paediatric Neuroscience at the UCL GOS Institute of Child Health, University College London and (Hon) Consultant Paediatric Neurologist at Great Ormond Street Hospital. His research has been in the area of neuroepidemiology and clinical trials. He is Chief Investigator of the International Collaborative Infantile Spasm Study (ICISS). He is currently President of the British Paediatric Neurology Association

11

Speaker Profiles

Professor Alexis Arzimanoglou leads the Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology of the Hospices Civils de Lyon, France and is the Epilepsy Research coordinator for the Child Neurology Department of the Sant Joan de Déu Barcelona Hospital in Spain.

Together with Professor Helen Cross he coordinates the European Reference Network for rare and complex epilepsies, ERN EpiCARE.

therapies. He is a founding member of an international Rett syndrome gene therapy consortium and is pioneering RNA-based therapies for Rett syndrome and monogenic forms of epilepsy.

Dr Liam Dorris is a Consultant Paediatric Neuropsychologist at the Royal Hospital for Children in Glasgow, and Honorary Associate Professor at the University of Glasgow. He has published widely in developmental neuropsychology with particular interests in cognitive and psychosocial consequences of childhood epilepsy. He recently delivered a multi-centre RCT psychosocial intervention (PIE), which has changed practice in many paediatric neurosciences centres.

Professor Gus Baker is Emeritus Professor of Clinical Neuropsychology and Honorary Consultant Clinical Neuropsychologist at the University of Liverpool and the Walton Centre for Neurology and Neurosurgery.

He was the principal researcher of the UK study on the neurodevelopment effects of exposure to antiepileptic drugs and co-principal researcher on the US/UK NIH funded study. The UK group have published more than 25 papers in this field.

Professor Jozef Gécz is Channel 7 Children’s Research Foundation Chair for the Prevention of Childhood Disability at the University of Adelaide, Australia. Jozef discovered or co-discovered of >200 disease genes for various forms of neurodevelopmental disabilities (e.g. ARX, CDKL5 or PCDH19). Jozef’s research is patient centric and focuses on the application of genomics for precise diagnosis to empower early intervention and personalised treatment.

Professor Scott Baraban is the William K. Bowes Jr. Endowed Chair in Neuroscience Research at the University of California San Francisco. Dr Baraban is the recipient of awards from Klingenstein Fund, NIH (Javits), and AES (Basic Science Research Recognition). His laboratory established the (i) first interneuron-based cell transplantation strategies for intractable epilepsies, (ii) first zebrafish epilepsy models and (iii) first zebrafish-based drug screens for epilepsy.

Professor Renzo Guerrini is a Professor of Child Neurology and Psychiatry at the University of Florence, Italy. He is also Head of the Centre of Excellence for Neuroscience at Children’s Hospital A. Meyer, Florence. Professor Guerrini chaired the International League Against Epilepsy Commission on Paediatrics. In 2003, he received the ‘Ambassador of Epilepsy’ award from the International League Against Epilepsy and in 2012 the ‘Research Award for Clinical Science’ from the American Epilepsy Society (AES). He has coordinated the EU Project DESIRE on development of epilepsy.

Professor Kees Braun is Professor of Child Neurology and coordinator of epilepsy research at the University Medical Center Utrecht. He was president of the Dutch Paediatric Neurology Society from 2012-2017 and president of the 2016 ICNC world congress of child neurology. He participates in several European epilepsy consortia and is a member of the ERN EpiCARE steering committee.

His research focuses on paediatric epilepsy surgery and drug withdrawal policies.

Professor David C. Henshall is Professor of Molecular Physiology & Neuroscience and Director of the FutureNeuro Research Centre at the Royal College of Surgeons in Ireland. His research interests are cell and molecular mechanisms of epilepsy, biomarkers and novel therapies. He has authored over 175 original papers and book chapters.

Professor Stuart Cobb is a neurobiology specialist based in the Patrick Wild Centre for Neurodevelopmental Disorders at the University of Edinburgh, UK. His research focuses on the reversibility and tractability of genetic brain disorders and in the development of novel molecular 10

Dr Floor Jansen specialised in Paediatric Neurology in 2007, and in the same year she obtained her PhD degree on a thesis entitled “identification of epileptogenic sources in patients with TSC”. Her clinical and scientific areas of expertise are: refractory paediatric epilepsy, including epilepsy surgery, tuberous sclerosis, electrical status epilepticus in sleep (ESES of CSWS), and genetic epilepsy.

Dr Dennis Lal is Assistant Staff in the Genomic Medicine Institute (GMI) and the Epilepsy Center at the Cleveland Clinic as well as Visiting Scientist at the Broad Institute of Harvard & M.I.T,US. He leads a computational epilepsy genetic research group with members in Cleveland, Cambridge as well as at the Cologne Center for Genomics at the University of Cologne, Germany.

Professor Michael Johnson is Professor of Neurology and Genomic Medicine and Deputy Head of the Centre for Clinical Translation in the Division of Brain Sciences at Imperial College London, and Honorary Consultant Neurologist at Imperial College Healthcare NHS Trust. His research focuses on the systems-level integration of genetic, genomic and phenotypic data to infer causal functional pathways and their drugable regulators.

Professor Oscar Marín is Professor of Neurobiology, Director of the MRC Centre for Neurodevelopmental Disorders and the Centre for Developmental Neurobiology at King’s College London. He graduated in Biology from Universidad Complutense in Madrid, where he also obtained a PhD in Neuroscience, followed by a postdoc with John Rubenstein at UCSF. He was a group leader at the Institute of Neuroscience in Alicante prior to joining King’s in 2014.

Professor Frank Kooy is a full Professor in Cognitive Genetics at the University of Antwerp. His research successfully focuses on the identification of genetic causes of cognitive disorders, such as intellectual disability and autism and to study the defective genes with the ultimate goal of developing rational therapies.

Dr Amy McTague is a GOSH NIHR BRC Catalyst Research Fellow at the UCL Great Ormond Street Institute of Child Health and Honorary Consultant Paediatric Neurologist at Great Ormond Street Hospital, London. Dr McTague is investigating disease mechanisms and potential novel therapies in early onset genetic epilepsies.

Professor Dimitri Kullmann is a professor of neurology at UCL. He trained in medicine and physiological sciences in Oxford and London. After a post-doctoral fellowship at UCSF he completed neurology training in London. His interests include synaptic physiology, mechanisms of neurological channelopathies, and gene therapy for epilepsy. He is also the Editor of Brain.

Professor Solomon L. Moshé is the Charles Frost Chair in Neurosurgery and Neurology, and Professor of Neurology, Neuroscience, and Paediatrics at the Albert Einstein College of Medicine/Montefiore Medical Center in the Bronx, New York. He is also the Vice Chair of the Saul R. Korey Department of Neurology, Director of the Isabelle Rapin Child Neurology Division and Director of Clinical Neurophysiology.

Professor Lieven Lagae is Full Professor at the University of Leuven, Belgium (KUL), Head of the Paediatric Neurology Department of the KUL University Hospitals, and Director of the Childhood Epilepsy Program at the KUL University Hospitals.

Lieven Lagae is the immediate past President of the European Paediatric Neurology Society and serves as an elected Board Member of the International Child Neurology Association (ICNA) and the Taskforce on Medical Treatment of Childhood Epilepsy of the International League against Epilepsy (ILAE).

Dr Finbar O’Callaghan is Professor of Paediatric Neuroscience at the UCL GOS Institute of Child Health, University College London and (Hon) Consultant Paediatric Neurologist at Great Ormond Street Hospital. His research has been in the area of neuroepidemiology and clinical trials. He is Chief Investigator of the International Collaborative Infantile Spasm Study (ICISS). He is currently President of the British Paediatric Neurology Association

11

Speaker Profiles

Professor Deb Pal is Professor of Paediatric Epilepsy at King’s College London and Honorary Consultant Paediatric Neurologist at King’s Health Partners where he heads the Epilepsy Genetics service for south east England. Deb graduated in natural sciences and medicine from Cambridge University and holds a Masters in epidemiology from the London School of Hygiene and Tropical Medicine.

He completed a PhD in Neuroscience at UCL and postdoctoral training in statistical genetics and genetic epidemiology at Mount Sinai and Columbia University Medical Centers, New York. Professor Pal is interested in the genetic epidemiology and mechanisms of childhood epilepsy and its comorbidities in particular the common forms of childhood epilepsy with complex genetic inheritance.

epilepsy genetics over more than 20 years, in collaboration with Professor Samuel Berkovic and molecular geneticists. This resulted in identification of the first epilepsy gene and many more genes subsequently. Her major interests are in the genetics of the epilepsies, epilepsy syndromology and classification, and translational research. She led the first major reclassification of the epilepsies in three decades, published in March 2017, for the International League Against Epilepsy. She has received many awards, including 2007 American Epilepsy Society Clinical Research Recognition Award, ILAE Ambassador for Epilepsy Award, 2013 Australian Neuroscience Medallion, 2013 Emil Becker Prize for child neurology and the L’OréalUNESCO Women in Science Laureate for the AsiaPacific region for 2012.

Professor Jack M. Parent is the William J. Herdman Professor of Neurology and co-director of the Epilepsy Center at Michigan Medicine. He is a past Board member of the American Epilepsy Society and is Chief Editor of Epilepsy Currents. His research focuses on epileptogenic mechanisms in temporal lobe epilepsy and genetic epilepsies.

Professor Stephanie Schorge completed a PhD in Neuroscience at Brown University, and travelled to London to take on single channel biophysics. Her research quickly shifted to exploring how mutations in ion channels lead to neurological disorders, and conversely, how neurological disorders can change the regulation of ion channels. She is working with a larger collaboration to harness some of the insights gained into the altered excitability in epilepsy to a first-in-human trial for gene therapy for focal neocortical epilepsy.

Professor Lucy Raymond is Professor of Medical Genetics and Neurodevelopment at the University of Cambridge and Honorary Consultant in Medical Genetics at Cambridge University Hospital, UK. Her research interest is understanding the genetic basis of disease and leads a number of collaborative efforts to identify the rare disease genes where intellectual disability, epilepsy or neurological conditions predominate.

Professor Hongjie Yuan is Assistant Professor and Deputy Director of Center for Functional Evaluation of Rare Variants, Emory University. His work focuses on human glutamate receptor variants associated with neurological disorders by utilizing a multidisciplinary approach that combines clinical experience, training in electrophysiology, and understanding of neurophysiology to translate basic research involving NMDAR/AMPAR variants toward therapeutic use.

Professor Sameer Zuberi is Consultant Paediatric Neurologist at the Royal Hospital for Children and Honorary Professor in the University of Glasgow. His clinical and research interests are in epilepsy and neurogenetics. He is past Chair of the ILAE Commission on Classification & Terminology & is President of the European Paediatric Neurology Society. ERUK funded research by his group is helping define the incidence and outcomes of the genetic epilepsies of early childhood.

Dr Joe Symonds is a paediatric neurology trainee at the Royal Hospital for Children in Glasgow. He is currently completing a PhD at the University of Glasgow on the impact of genotype-driven precision medicine for children with epilepsy.

Dr Richard Rosch is a Sir Henry Wellcome Fellow at King’s College London and the University of Pennsylvania, Philadelphia. He is a clinically trained neuroscientist and employs a variety of computational and empirical methods across patient data and model systems to link synaptic dysfunction and whole brain abnormal dynamics.

Professor Patrick Van Bogaert is head of the department of Paediatric Neurology at CHU Angers, France, and Professor of Paediatric Neurology at the Université d’Angers, France, since 2016. Since then he has worked at the Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS), Université d’Angers, France. He has authored or coauthored 135 medical peer-reviewed articles, as well as 5 book chapters on Landau-Kleffner syndrome and epileptic encephalopathy with continuous spike-waves during slow-wave sleep.

Laureate Professor Ingrid Scheffer AO is a physician-scientist whose work as a paediatric neurologist and epileptologist at the University of Melbourne and Austin Health has led the field of

12

13

Speaker Profiles

Professor Deb Pal is Professor of Paediatric Epilepsy at King’s College London and Honorary Consultant Paediatric Neurologist at King’s Health Partners where he heads the Epilepsy Genetics service for south east England. Deb graduated in natural sciences and medicine from Cambridge University and holds a Masters in epidemiology from the London School of Hygiene and Tropical Medicine.

He completed a PhD in Neuroscience at UCL and postdoctoral training in statistical genetics and genetic epidemiology at Mount Sinai and Columbia University Medical Centers, New York. Professor Pal is interested in the genetic epidemiology and mechanisms of childhood epilepsy and its comorbidities in particular the common forms of childhood epilepsy with complex genetic inheritance.

epilepsy genetics over more than 20 years, in collaboration with Professor Samuel Berkovic and molecular geneticists. This resulted in identification of the first epilepsy gene and many more genes subsequently. Her major interests are in the genetics of the epilepsies, epilepsy syndromology and classification, and translational research. She led the first major reclassification of the epilepsies in three decades, published in March 2017, for the International League Against Epilepsy. She has received many awards, including 2007 American Epilepsy Society Clinical Research Recognition Award, ILAE Ambassador for Epilepsy Award, 2013 Australian Neuroscience Medallion, 2013 Emil Becker Prize for child neurology and the L’OréalUNESCO Women in Science Laureate for the AsiaPacific region for 2012.

Professor Jack M. Parent is the William J. Herdman Professor of Neurology and co-director of the Epilepsy Center at Michigan Medicine. He is a past Board member of the American Epilepsy Society and is Chief Editor of Epilepsy Currents. His research focuses on epileptogenic mechanisms in temporal lobe epilepsy and genetic epilepsies.

Professor Stephanie Schorge completed a PhD in Neuroscience at Brown University, and travelled to London to take on single channel biophysics. Her research quickly shifted to exploring how mutations in ion channels lead to neurological disorders, and conversely, how neurological disorders can change the regulation of ion channels. She is working with a larger collaboration to harness some of the insights gained into the altered excitability in epilepsy to a first-in-human trial for gene therapy for focal neocortical epilepsy.

Professor Lucy Raymond is Professor of Medical Genetics and Neurodevelopment at the University of Cambridge and Honorary Consultant in Medical Genetics at Cambridge University Hospital, UK. Her research interest is understanding the genetic basis of disease and leads a number of collaborative efforts to identify the rare disease genes where intellectual disability, epilepsy or neurological conditions predominate.

Professor Hongjie Yuan is Assistant Professor and Deputy Director of Center for Functional Evaluation of Rare Variants, Emory University. His work focuses on human glutamate receptor variants associated with neurological disorders by utilizing a multidisciplinary approach that combines clinical experience, training in electrophysiology, and understanding of neurophysiology to translate basic research involving NMDAR/AMPAR variants toward therapeutic use.

Professor Sameer Zuberi is Consultant Paediatric Neurologist at the Royal Hospital for Children and Honorary Professor in the University of Glasgow. His clinical and research interests are in epilepsy and neurogenetics. He is past Chair of the ILAE Commission on Classification & Terminology & is President of the European Paediatric Neurology Society. ERUK funded research by his group is helping define the incidence and outcomes of the genetic epilepsies of early childhood.

Dr Joe Symonds is a paediatric neurology trainee at the Royal Hospital for Children in Glasgow. He is currently completing a PhD at the University of Glasgow on the impact of genotype-driven precision medicine for children with epilepsy.

Dr Richard Rosch is a Sir Henry Wellcome Fellow at King’s College London and the University of Pennsylvania, Philadelphia. He is a clinically trained neuroscientist and employs a variety of computational and empirical methods across patient data and model systems to link synaptic dysfunction and whole brain abnormal dynamics.

Professor Patrick Van Bogaert is head of the department of Paediatric Neurology at CHU Angers, France, and Professor of Paediatric Neurology at the Université d’Angers, France, since 2016. Since then he has worked at the Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS), Université d’Angers, France. He has authored or coauthored 135 medical peer-reviewed articles, as well as 5 book chapters on Landau-Kleffner syndrome and epileptic encephalopathy with continuous spike-waves during slow-wave sleep.

Laureate Professor Ingrid Scheffer AO is a physician-scientist whose work as a paediatric neurologist and epileptologist at the University of Melbourne and Austin Health has led the field of

12

13

Session 1: What is the broad relationship between neurodevelopmental disorders and epilepsy?

Chair: Professor Sameer Zuberi, University of Glasgow 09:00 Thursday 14th March 2019

The link between neurodevelopmental disorders and epilepsy Professor Lucy Raymond, University of Cambridge, UK

09:15

Epilepsy gene discovery and its implications Dr Joe Symonds, University of Glasgow, UK

09:35

Use of epilepsy/NDD gene panels – does early diagnosis make a difference?

Dr Amy McTague, University College London, UK

09:55

Early brain development is extremely complex and requires the coordinated expression of thousands of genes at the required dose, location and function during development. Failure to achieve this is commonly due to constitutional abnormalities of the genome in the affected child. The majority of genetic variants arise de novo in the affected child although familial rare variants may cause disease. Over recent years large-scale analysis of genomes of children with neurodevelopmental disorders or epilpesy has revealed many new genes that cause disease. The rate of gene identification is still high in this field both due to the extreme heterogeneity of the condition and the relative rarity of individuals who have a specific gene abnormality.

The IMAGINE ID study has followed up 3,000 children diagnosed with a genetic cause of intellectual disability and identified that epilepsy is a frequent co-morbidity (30%). In children presenting with epilepsy as neonates in NICU and PICU the association with developmental delay is similarly common at 27%. The talk will focus on the range of molecular mechanisms of disease identified to date, the association of neurodevelopmental disorders and epilepsy and to put a diagnosis of epilepsy in context of other neurological features.

The development and application of next generation sequencing (NGS) technology has led to an exponential rise in the number of genes and genetic variants associated with epilepsy. The detection of highly penetrant and damaging variants in some patients can be sufficient to provide an adequate explanation for the entire disease process. Particularly high yields from such diagnostic genetic testing are observed in cohorts of children who present with early onset seizures. Obtaining a genetic diagnosis can be helpful to families in terms of informing further reproductive decisions, providing answers, and preventing further costly investigations. Evidence is emerging that certain anti-epileptic drug therapies may be more effective than others in specific genetic epilepsies. Early trials of gene-corrective therapy are now taking place. In a population-based cohort of all children presenting with epilepsy < 3 years identified a genetic cause in 29%. Genetic diagnosis is strongly associated with both early age of onset and the development of drug-resistant seizures. 84% of diagnoses involve the most frequently implicated 10 genes. Beyond the 1020 most commonly implicated genes there is a long tail of more than 1000 extremely rare genetic disorders, most of which often present also with neurodevelopmental disorders in the absence of epileptic seizures.

Using Whole Genome Sequencing (WGS) in a cohort of patients with drug-resistant seizures who have already had the more common genetic diagnoses excluded we have been able to identify several new genetic causes of epilepsy. Diagnosis for these families may help provide an answer, allow them to connect with other families affected by very rare conditions, and provide useful recurrence risk estimation. Due to extreme rarity and phenotypic heterogeneity of these conditions, prognostication and precision therapy for these patients will remain a significant challenge.

Over the past decade, the use of next generation sequencing (NGS) panels has revolutionised diagnostics in early onset epilepsy and neurodevelopmental disorders. The diagnostic yield varies from 18-48%, depending on epilepsy or developmental phenotype, age at seizure onset and panel-dependent factors such as number of genes included and sequence coverage. For some genetic epilepsies, treatment choice can be guided by variants identified on NGS panels. In the SCN1A-related epilepsies this includes avoidance 14

of sodium channel blocking medications, early use of stiripentol and consideration of novel therapies such as cannabidol and fenfluramine. Conversely, in SCN2A and SCN8A related epilepsies early use of sodium channel blockers such as carbamazepine for neonatal seizures and phenytoin for status epilepticus has led to reduced seizure frequency. In some genetic aetiologies, a more specific treatment is available.

Identification of variants in SLC2A1 in an expanding range of phenotypes allows early consideration of the ketogenic diet. Repurposing of older medications such as quinidine for gain of function KCNT1 variants in epilepsy of infancy with migrating focal seizures and autosomal dominant nocturnal frontal lobe epilepsy has been successful in some, but not all, patients. Novel therapies under development include RNA-directed treatments and gene therapy and early diagnosis will allow recruitment of patients to appropriate clinical trials. The impact of an early genetic diagnosis also includes an end to the diagnostic odyssey, may avoid unnecessary invasive investigations and allows discussion of prognosis and access to patient support groups. However, the advent of NGS panels has also brought challenges including interpretation of multiple putative pathogenic variants, issues of reduced penetrance and somatic mosaicism and expansion of known phenotypes. As we move towards whole exome and whole genome sequencing and more rapid genetic diagnosis, it will be essential to prospectively monitor the impact of early diagnosis and aetiology-directed treatments on both seizures and neurodevelopmental outcome.

Structural aetiologies in neurodevelopment and epilepsy Professor Renzo Guerrini, University of Florence

10:15

The malformations of the human cerebral cortex represent a major cause of a range of developmental disabilities, severe epilepsy and reproductive disadvantage. In general, it is estimated that up to 40% of individuals with drug-resistant epilepsy have a cortical malformation visible by good quality MRI scan. Highresolution MRI techniques have identified in vivo a growing group of cortical malformation phenotypes.

Classical neuropathological studies have recently been confirmed by larger studies that have correlate abnormal cortical folding on high resolution imaging with specific neuropsychological deficits. Treatment options for associated epilepsy are deceptive since drugs are scarcely effective and only a subset of patients apply for surgical treatment. Planning of surgical options needs a comprehensive electrophysiological and functional imaging approach, in relation to both the complex representation of eloquent cortical functions in the abnormally folded cortex and to the intricate networks that usually subserve the epileptogenic area.

Intrinsic epileptogenic networks often involve the malformed cortex and distant cortical areas, as demonstrated by depth electrode explorations of the human brain and in vivo electrophysiological studies.

The concept of structural aetiologies, after all, goes well beyond that of the MRI visible abnormality. Some genetic disorders, and now even channelopathies, challenge the classic distinction between the ‘pure’ genetic epilepsies, which used to be ideally epitomized exactly by ion channel alterations versus the structural/metabolic disorders in which a separate abnormality is interposed between the genetic defect and the epilepsy. On the other hand, epilepsy in non malformation ARX phenotypes (at least in relation to some of the mutations of this gene) or in patients with STXBP1 or CDKL5 mutations/deletions is difficult to assign to either the ‘genetic’ or the ‘structural’ category as they seem to carry both labels. It seems to be a primary expression of the genetic defect: since all patients have severe seizures but no structural lesion is recognizable as far as the diagnostic dimension can be pushed. Only developmental- and molecularpathology studies can provide answers to these queries.

Chaired discussion:

10:35-11:10

15

Session 1: What is the broad relationship between neurodevelopmental disorders and epilepsy?

Chair: Professor Sameer Zuberi, University of Glasgow 09:00 Thursday 14th March 2019

The link between neurodevelopmental disorders and epilepsy Professor Lucy Raymond, University of Cambridge, UK

09:15

Epilepsy gene discovery and its implications Dr Joe Symonds, University of Glasgow, UK

09:35

Use of epilepsy/NDD gene panels – does early diagnosis make a difference?

Dr Amy McTague, University College London, UK

09:55

Early brain development is extremely complex and requires the coordinated expression of thousands of genes at the required dose, location and function during development. Failure to achieve this is commonly due to constitutional abnormalities of the genome in the affected child. The majority of genetic variants arise de novo in the affected child although familial rare variants may cause disease. Over recent years large-scale analysis of genomes of children with neurodevelopmental disorders or epilpesy has revealed many new genes that cause disease. The rate of gene identification is still high in this field both due to the extreme heterogeneity of the condition and the relative rarity of individuals who have a specific gene abnormality.

The IMAGINE ID study has followed up 3,000 children diagnosed with a genetic cause of intellectual disability and identified that epilepsy is a frequent co-morbidity (30%). In children presenting with epilepsy as neonates in NICU and PICU the association with developmental delay is similarly common at 27%. The talk will focus on the range of molecular mechanisms of disease identified to date, the association of neurodevelopmental disorders and epilepsy and to put a diagnosis of epilepsy in context of other neurological features.

The development and application of next generation sequencing (NGS) technology has led to an exponential rise in the number of genes and genetic variants associated with epilepsy. The detection of highly penetrant and damaging variants in some patients can be sufficient to provide an adequate explanation for the entire disease process. Particularly high yields from such diagnostic genetic testing are observed in cohorts of children who present with early onset seizures. Obtaining a genetic diagnosis can be helpful to families in terms of informing further reproductive decisions, providing answers, and preventing further costly investigations. Evidence is emerging that certain anti-epileptic drug therapies may be more effective than others in specific genetic epilepsies. Early trials of gene-corrective therapy are now taking place. In a population-based cohort of all children presenting with epilepsy < 3 years identified a genetic cause in 29%. Genetic diagnosis is strongly associated with both early age of onset and the development of drug-resistant seizures. 84% of diagnoses involve the most frequently implicated 10 genes. Beyond the 1020 most commonly implicated genes there is a long tail of more than 1000 extremely rare genetic disorders, most of which often present also with neurodevelopmental disorders in the absence of epileptic seizures.

Using Whole Genome Sequencing (WGS) in a cohort of patients with drug-resistant seizures who have already had the more common genetic diagnoses excluded we have been able to identify several new genetic causes of epilepsy. Diagnosis for these families may help provide an answer, allow them to connect with other families affected by very rare conditions, and provide useful recurrence risk estimation. Due to extreme rarity and phenotypic heterogeneity of these conditions, prognostication and precision therapy for these patients will remain a significant challenge.

Over the past decade, the use of next generation sequencing (NGS) panels has revolutionised diagnostics in early onset epilepsy and neurodevelopmental disorders. The diagnostic yield varies from 18-48%, depending on epilepsy or developmental phenotype, age at seizure onset and panel-dependent factors such as number of genes included and sequence coverage. For some genetic epilepsies, treatment choice can be guided by variants identified on NGS panels. In the SCN1A-related epilepsies this includes avoidance 14

of sodium channel blocking medications, early use of stiripentol and consideration of novel therapies such as cannabidol and fenfluramine. Conversely, in SCN2A and SCN8A related epilepsies early use of sodium channel blockers such as carbamazepine for neonatal seizures and phenytoin for status epilepticus has led to reduced seizure frequency. In some genetic aetiologies, a more specific treatment is available.

Identification of variants in SLC2A1 in an expanding range of phenotypes allows early consideration of the ketogenic diet. Repurposing of older medications such as quinidine for gain of function KCNT1 variants in epilepsy of infancy with migrating focal seizures and autosomal dominant nocturnal frontal lobe epilepsy has been successful in some, but not all, patients. Novel therapies under development include RNA-directed treatments and gene therapy and early diagnosis will allow recruitment of patients to appropriate clinical trials. The impact of an early genetic diagnosis also includes an end to the diagnostic odyssey, may avoid unnecessary invasive investigations and allows discussion of prognosis and access to patient support groups. However, the advent of NGS panels has also brought challenges including interpretation of multiple putative pathogenic variants, issues of reduced penetrance and somatic mosaicism and expansion of known phenotypes. As we move towards whole exome and whole genome sequencing and more rapid genetic diagnosis, it will be essential to prospectively monitor the impact of early diagnosis and aetiology-directed treatments on both seizures and neurodevelopmental outcome.

Structural aetiologies in neurodevelopment and epilepsy Professor Renzo Guerrini, University of Florence

10:15

The malformations of the human cerebral cortex represent a major cause of a range of developmental disabilities, severe epilepsy and reproductive disadvantage. In general, it is estimated that up to 40% of individuals with drug-resistant epilepsy have a cortical malformation visible by good quality MRI scan. Highresolution MRI techniques have identified in vivo a growing group of cortical malformation phenotypes.

Classical neuropathological studies have recently been confirmed by larger studies that have correlate abnormal cortical folding on high resolution imaging with specific neuropsychological deficits. Treatment options for associated epilepsy are deceptive since drugs are scarcely effective and only a subset of patients apply for surgical treatment. Planning of surgical options needs a comprehensive electrophysiological and functional imaging approach, in relation to both the complex representation of eloquent cortical functions in the abnormally folded cortex and to the intricate networks that usually subserve the epileptogenic area.

Intrinsic epileptogenic networks often involve the malformed cortex and distant cortical areas, as demonstrated by depth electrode explorations of the human brain and in vivo electrophysiological studies.

The concept of structural aetiologies, after all, goes well beyond that of the MRI visible abnormality. Some genetic disorders, and now even channelopathies, challenge the classic distinction between the ‘pure’ genetic epilepsies, which used to be ideally epitomized exactly by ion channel alterations versus the structural/metabolic disorders in which a separate abnormality is interposed between the genetic defect and the epilepsy. On the other hand, epilepsy in non malformation ARX phenotypes (at least in relation to some of the mutations of this gene) or in patients with STXBP1 or CDKL5 mutations/deletions is difficult to assign to either the ‘genetic’ or the ‘structural’ category as they seem to carry both labels. It seems to be a primary expression of the genetic defect: since all patients have severe seizures but no structural lesion is recognizable as far as the diagnostic dimension can be pushed. Only developmental- and molecularpathology studies can provide answers to these queries.

Chaired discussion:

10:35-11:10

15

Session 2: How well can we model neurodevelopmental epilepsy disorders in experimental systems and what can they tell us?

Regulome-based computational anti-epileptic drug target discovery Professor Michael Johnson, Imperial College London

Chair: Lieven Lagae, KU Leuven, Belgium 11:30 Thursday 14th March 2019

11:35

Using integrated systems biology approaches we have previously shown that rare and common variants for genetic epilepsy converge on a gene co-expression network highly expressed in interneurons, and that integration of this epilepsy gene expression signature with drug perturbation data can reveal novel opportunities for drug repositioning in epilepsy (Delahaye-Duriez A, et al. Genome Biology 2016,13;17:245263). More recently, we showed how a gene expression signature for acquired epilepsy could be leveraged to new drug target discovery using a novel gene-regulatory framework based on experimentally defined relationships between membrane receptors, transcription factors and target genes (Srivastava PK, et al.

Nature Communications, 2018;9:3561. doi: 10.1038/s41467-018-06008-4). Although this later work established proof-of-concept for antiepilepsy drug target discovery based on gene regulatory networks (GRNs, regulomes), regulomes inferred from published knowledge lack tissue specificity and are limited by the incompleteness of the scientific archive as well as publication bias. In this presentation, I show how empirical gene expression data from epileptic brain tissue can also be used to infer gene regulatory relationships for drug target discovery at a disease context specific level, providing an improved framework for the discovery of novel disease modifying therapies for epilepsy.

2-D and 3-D Stem Cell Models of Genetic Epilepsies Professor Jack Parent, University of Michigan, US

11:55

Reprogramming somatic cells to a pluripotent state via the induced pluripotent stem cell (iPSC) method offers an unparalleled approach for neurological disease modeling using patient-derived cells. Several groups, including ours, have applied the iPSC approach to model severe genetic developmental and epileptic encephalopathies (DEEs) with patient-derived cells. I will describe our findings using 2-D cultures of patient-derived neurons to model Dravet syndrome, also known as early infantile epileptic encephalopathy type 6 (EIEE6), caused by loss-of-function mutations in the SCN1A gene encoding the voltage-gated sodium channel Nav1.1. Then I will discuss similar studies of EIEE13 caused by gain-of-function mutations in the SCN8A encoding Nav1.6. Several groups are also beginning to explore epilepsy mechanisms using 3-D iPSC cultures, also known as cerebral or cortical organoids. Our laboratory and others are applying this approach to understand severe DEEs, including PMSE (Polyhydramnios, Megalencephaly and Symptomatic Epilepsy) syndrome and Rett Syndrome. Both 2-D and 3-D human iPSC models show epilepsy-relevant phenotypes and offer platforms for anti-seizure drug testing in patient-derived cells. Challenges include obtaining complete maturation of cells in vitro, and generating the complex repertoire of neuronal cell types.

Nonetheless, the field is rapidly advancing and the findings suggest that human pluripotent stem cell approaches offers great promise for modeling neurodevelopmental epilepsies and identifying novel therapies.

Rodent models: where it all started Professor Solomon L. Moshé, MD, Albert Einstein College of Medicine, US

development of multifocal seizures and lack of postictal refractoriness that allows for clustering of seizures.

These studies led to the development of a unique model of infantile spasms that replicates the human condition with recurrent spasms followed by other seizure types as the animals age. This model has been effectively used to identify new treatments for spasms. The post status epilepticus models provided insights on the extent of age-related seizure induced hippocampal injury. Nowadays, understanding the key features and possible biomarkers that may allow for the expression and consequences of seizures and related epileptogenesis taking into account the maturational patterns of the brain and gender differences will provide novel insights into creating therapeutic approaches leading to individualized treatments and precision based medicine.

Epileptic networks in zebrafish – new insights from a novel animal model Dr Richard Rosch, King’s College London, UK

Zebrafish have emerged as a promising new model in epilepsy research: This vertebrate model allows lowcost behavioural assays, provides well-established genetics, and has established lines with epilepsy-causing mutations. With advances in genetically encoded calcium indicators, fast volumetric microscopy, and improved computational image processing tools available, zebrafish now also offer a unique window into the whole-brain dynamics of a developing vertebrate brain – an aspect that’s currently less well exploited in epilepsy research. Here I will be presenting initial results from functional recordings of the larval zebrafish brain during epileptic seizures. Combining calcium imaging with computational models of neuronal population activity allows insights into the specific synaptic deficits that give rise to the abnormal dynamics observed during epileptic seizures. By modelling the recorded calcium dynamics as emerging from networks of interacting excitatory-inhibitory neuronal oscillators, we can derive a map of transitions that occur during the acute seizure, and identify the synaptic changes associated with each. These insights from these acute seizure recordings will illustrate the kind of inference that is now possible when imaging novel zebrafish models of gene-associated infantile and childhood epileptic encephalopathies, such as SCN1A and GRIN2Aassociated epilepsies. The combination of detailed functional imaging of whole-brain dynamics with (near) single cell resolution and the genetic deficits associated with human disease will allow insights into the dynamics of the epileptic brain not currently possible with other model systems.

Chaired discussion

12:55-13:25

12:15

The immature brain is not a miniature version of the adult brain and better understanding of the discrete windows of the developmental processes may indeed provide unique insights into factors that may mediate the expression and consequences of seizures and epilepsy as a function of sex. We have been fortunate in the past 40 years to witness an amazing growth of information in the field of developmental epilepsy. A major step was to the establishment of kindling as a model of epilepsy in infant rodents, the first such model of epileptogenesis followed by studies of post status epilepticus models. Kindling in developing rats provided unique insights in the expression of seizures including specific behavioral patterns of seizures, 16

12:35

17

Session 2: How well can we model neurodevelopmental epilepsy disorders in experimental systems and what can they tell us?

Regulome-based computational anti-epileptic drug target discovery Professor Michael Johnson, Imperial College London

Chair: Lieven Lagae, KU Leuven, Belgium 11:30 Thursday 14th March 2019

11:35

Using integrated systems biology approaches we have previously shown that rare and common variants for genetic epilepsy converge on a gene co-expression network highly expressed in interneurons, and that integration of this epilepsy gene expression signature with drug perturbation data can reveal novel opportunities for drug repositioning in epilepsy (Delahaye-Duriez A, et al. Genome Biology 2016,13;17:245263). More recently, we showed how a gene expression signature for acquired epilepsy could be leveraged to new drug target discovery using a novel gene-regulatory framework based on experimentally defined relationships between membrane receptors, transcription factors and target genes (Srivastava PK, et al.

Nature Communications, 2018;9:3561. doi: 10.1038/s41467-018-06008-4). Although this later work established proof-of-concept for antiepilepsy drug target discovery based on gene regulatory networks (GRNs, regulomes), regulomes inferred from published knowledge lack tissue specificity and are limited by the incompleteness of the scientific archive as well as publication bias. In this presentation, I show how empirical gene expression data from epileptic brain tissue can also be used to infer gene regulatory relationships for drug target discovery at a disease context specific level, providing an improved framework for the discovery of novel disease modifying therapies for epilepsy.

2-D and 3-D Stem Cell Models of Genetic Epilepsies Professor Jack Parent, University of Michigan, US

11:55

Reprogramming somatic cells to a pluripotent state via the induced pluripotent stem cell (iPSC) method offers an unparalleled approach for neurological disease modeling using patient-derived cells. Several groups, including ours, have applied the iPSC approach to model severe genetic developmental and epileptic encephalopathies (DEEs) with patient-derived cells. I will describe our findings using 2-D cultures of patient-derived neurons to model Dravet syndrome, also known as early infantile epileptic encephalopathy type 6 (EIEE6), caused by loss-of-function mutations in the SCN1A gene encoding the voltage-gated sodium channel Nav1.1. Then I will discuss similar studies of EIEE13 caused by gain-of-function mutations in the SCN8A encoding Nav1.6. Several groups are also beginning to explore epilepsy mechanisms using 3-D iPSC cultures, also known as cerebral or cortical organoids. Our laboratory and others are applying this approach to understand severe DEEs, including PMSE (Polyhydramnios, Megalencephaly and Symptomatic Epilepsy) syndrome and Rett Syndrome. Both 2-D and 3-D human iPSC models show epilepsy-relevant phenotypes and offer platforms for anti-seizure drug testing in patient-derived cells. Challenges include obtaining complete maturation of cells in vitro, and generating the complex repertoire of neuronal cell types.

Nonetheless, the field is rapidly advancing and the findings suggest that human pluripotent stem cell approaches offers great promise for modeling neurodevelopmental epilepsies and identifying novel therapies.

Rodent models: where it all started Professor Solomon L. Moshé, MD, Albert Einstein College of Medicine, US

development of multifocal seizures and lack of postictal refractoriness that allows for clustering of seizures.

These studies led to the development of a unique model of infantile spasms that replicates the human condition with recurrent spasms followed by other seizure types as the animals age. This model has been effectively used to identify new treatments for spasms. The post status epilepticus models provided insights on the extent of age-related seizure induced hippocampal injury. Nowadays, understanding the key features and possible biomarkers that may allow for the expression and consequences of seizures and related epileptogenesis taking into account the maturational patterns of the brain and gender differences will provide novel insights into creating therapeutic approaches leading to individualized treatments and precision based medicine.

Epileptic networks in zebrafish – new insights from a novel animal model Dr Richard Rosch, King’s College London, UK

Zebrafish have emerged as a promising new model in epilepsy research: This vertebrate model allows lowcost behavioural assays, provides well-established genetics, and has established lines with epilepsy-causing mutations. With advances in genetically encoded calcium indicators, fast volumetric microscopy, and improved computational image processing tools available, zebrafish now also offer a unique window into the whole-brain dynamics of a developing vertebrate brain – an aspect that’s currently less well exploited in epilepsy research. Here I will be presenting initial results from functional recordings of the larval zebrafish brain during epileptic seizures. Combining calcium imaging with computational models of neuronal population activity allows insights into the specific synaptic deficits that give rise to the abnormal dynamics observed during epileptic seizures. By modelling the recorded calcium dynamics as emerging from networks of interacting excitatory-inhibitory neuronal oscillators, we can derive a map of transitions that occur during the acute seizure, and identify the synaptic changes associated with each. These insights from these acute seizure recordings will illustrate the kind of inference that is now possible when imaging novel zebrafish models of gene-associated infantile and childhood epileptic encephalopathies, such as SCN1A and GRIN2Aassociated epilepsies. The combination of detailed functional imaging of whole-brain dynamics with (near) single cell resolution and the genetic deficits associated with human disease will allow insights into the dynamics of the epileptic brain not currently possible with other model systems.

Chaired discussion

12:55-13:25

12:15

The immature brain is not a miniature version of the adult brain and better understanding of the discrete windows of the developmental processes may indeed provide unique insights into factors that may mediate the expression and consequences of seizures and epilepsy as a function of sex. We have been fortunate in the past 40 years to witness an amazing growth of information in the field of developmental epilepsy. A major step was to the establishment of kindling as a model of epilepsy in infant rodents, the first such model of epileptogenesis followed by studies of post status epilepticus models. Kindling in developing rats provided unique insights in the expression of seizures including specific behavioral patterns of seizures, 16

12:35

17

Session 3: What is the relationship between genetic epilepsy and epileptic encephalopathy?

What do we mean by the concept of epileptic encephalopathy?

Professor Ingrid E Scheffer, University of Melbourne, Austin Health and Royal Children’s Hospital, Florey and Murdoch Institutes, Melbourne, Australia

Chair: Dr Floor Jansen, UMC Utrecht, The Netherlands 14:30 Thursday 14th March 2019

14:35

The concept of epileptic encephalopathy underpins the group of diseases known as the Developmental and Epileptic Encephalopathies (DEEs). Many infants and young children presenting with seizures develop an epileptic encephalopathy. This means that they have very frequent, often virtually continual, epileptiform activity. This epileptiform activity may be generalized, bilaterally synchronous, unifocal or multifocal. Patients typically have frequent seizures and multiple seizure types, but this is not universal. The third key component of an epileptic encephalopathy is that there is developmental slowing, arrest or regression. Why does an epileptic encephalopathy matter? Largely because there may be a remediable component if the process can be arrested. Such an improvement may be evident by simply changing anti-epileptic therapy from one that exacerbates seizures and epileptiform activity to optimal treatment for a DEE, ideally based on understanding the neurobiology. For example, in Dravet syndrome, typically due to SCN1A haploinsufficiency, sodium channel blockers such as carbamazepine increase both seizures and epileptiform activity. Often families will comment that the child is learning and more alert when the process is ameliorated. Many of the children with epileptic encephalopathies, which include a large number of epilepsy syndromes (eg Lennox-Gastaut syndrome, West syndrome, Epilepsy of Infancy with Migrating Focal Seizures), have a genetic basis for their disease, most commonly a de novo dominant pathogenic variant.

The new terminology of ‘developmental and epileptic encephalopathy (DEE)’ was coined because many children with these diseases have developmental impairment due to the underlying mutation with the epileptic encephalopathy process superimposed on the underlying disorder. This means that suppressing the epileptic encephalopathy does not cure the disorder but understanding these two related but distinct components influences treatment approaches, providing the opportunity to optimise long term outcome.

Epilepsies with sleep activation – insights from functional neuroimaging Professor Patrick Van Bogaert, MD, PhD. Université d’Angers. France

14:55

Epilepsies with sleep activation are epileptic encephalopathies in which intense interictal epileptiform activity during sleep is though to play a major role in the cognitive and behavioural disturbances that occur in these children. This hypothesis is supported by studies showing an association between long duration of the continuous spike and waves during slow-wave sleep (CSWS) pattern on EEG and cognitive outcome.

However, other possible contributing factors are the underlying etiology, which is likely to be genetic in patients with the absence of structural brain lesion on MRI, and side effects of anti-epileptic drugs. The aims of functional imaging in these epilepsies are to identify brain networks involved respectively in epileptogenicity and in cognitive dysfunction, to understand the functional dynamics between these two networks, and to study the impact of treatments on these networks. Studies performed at rest at the awake state using either PET with FDG or EEG-fMRI have shown relative hypermetabolism (or increased perfusion) in regions that belong to the epileptogenic network and hypometabolism (or decreased perfusion) in functionally connected regions that belong to the default mode network. These abnormalities may be reversible in patients who respond to antiepileptic treatments, evidencing the place of functional imaging as a biomarker of therapeutic response. Functional neuroimaging approaches combining the excellent temporal resolution of EEG and MEG with a good spatial resolution through sources reconstruction and coregistration with structural MRI, i.e. electrical and magnetic source imaging, are relevant to study the dynamics of these networks at the level of the millisecond.

18

Early intervention in epileptic spasms Professor Finbar O’Callaghan, University College London, UK

15:15

Influence of epilepsy surgery on developmental outcome Professor Kees Braun, UMC Utrecht, The Netherlands

15:35

Infantile spasms are the classic example of an epileptic encephalopathy. There are multiple reports describing the arrest or regression of development coincident with the onset of epileptic spasms and hypsarrhythmia. If the spasms themselves are causing developmental damage then the logical corollary is that rapid resolution of the epileptic encephalopathy with effective treatment should lead to improved cognitive and developmental outcomes compared to those children who are exposed to the encephalopathy for longer periods. Lead-time to treatment i.e. the interval between onset of spasms and the initiation of treatment, is a significant component in the total duration of exposure to the epileptic encephalopathy. Whether treatment is effective and and how fast it works are two other factors influencing the duration of exposure to the encephalopathy. In this talk, drawing on data from ICISS and UKISS and other published clinical studies, I will discuss the effect of lead-time to treatment, speed of response and type of therapy on epilepsy and developmental outcomes. Infantile spasms may have many different underlying aetiologies. There have been suggestions in the literature that specific aetiologies may have specific responses to therapy. I will explore whether different aetiologies have different responses to treatment and different developmental outcomes and I will also discuss the inter-relationship between aetiology, lead-time and therapy on outcomes.

Cognitive development of paediatric epilepsy surgery candidates is determined by many variables, including their genetic and environmental “background”, the epileptogenic pathology, the seizure disorder itself – varying in severity from status epilepticus, epileptic encephalopathy, frequent seizures, to interictal EEG discharges – and the use of antiepileptic drugs. The majority of children with refractory epilepsy have cognitive impairments. Intellectual disability has been considered a contraindication for surgery in the past, whereas the child’s developmental capacity nowadays is an important perspective in surgical decision making. Cognitive functioning of the youngest surgical candidates, particularly those who undergo hemispherotomy, is almost always severely affected (with an IQ or DQ <55), and these children often have an arrest or regression of development due to an epileptic encephalopathy. Although a quantifiable postoperative increase of >8-15 DQ/IQ points is only seen in around 30%, mental age increases in almost all children, and their development seems to restart; one of the most gratifying experiences in paediatric epilepsy surgery. Eventual cognitive outcome after surgery, and the postoperative change in cognitive functioning, depend on etiology, contralateral MRI abnormalities, parental education, age at onset and surgery, presurgical IQ, and on seizure outcome. Most importantly, shorter epilepsy duration has been shown to not only increase the chance of reaching seizure-freedom, it also predicts better postoperative cognitive outcome and more cognitive improvement. Finally, AED withdrawal – which can be safely considered early after surgery in many children – is an independent predictor of eventual IQ and of postoperative IQ increase. Therefore, children with focal lesional epilepsy should be referred for presurgical evaluation early after diagnosis. Epilepsy surgery is an early treatment option, rather than a last resort.

Chaired discussion 15:55-16:25

Closing remarks for day one 16:25-16:40

19

Session 3: What is the relationship between genetic epilepsy and epileptic encephalopathy?

What do we mean by the concept of epileptic encephalopathy?

Professor Ingrid E Scheffer, University of Melbourne, Austin Health and Royal Children’s Hospital, Florey and Murdoch Institutes, Melbourne, Australia

Chair: Dr Floor Jansen, UMC Utrecht, The Netherlands 14:30 Thursday 14th March 2019

14:35

The concept of epileptic encephalopathy underpins the group of diseases known as the Developmental and Epileptic Encephalopathies (DEEs). Many infants and young children presenting with seizures develop an epileptic encephalopathy. This means that they have very frequent, often virtually continual, epileptiform activity. This epileptiform activity may be generalized, bilaterally synchronous, unifocal or multifocal. Patients typically have frequent seizures and multiple seizure types, but this is not universal. The third key component of an epileptic encephalopathy is that there is developmental slowing, arrest or regression. Why does an epileptic encephalopathy matter? Largely because there may be a remediable component if the process can be arrested. Such an improvement may be evident by simply changing anti-epileptic therapy from one that exacerbates seizures and epileptiform activity to optimal treatment for a DEE, ideally based on understanding the neurobiology. For example, in Dravet syndrome, typically due to SCN1A haploinsufficiency, sodium channel blockers such as carbamazepine increase both seizures and epileptiform activity. Often families will comment that the child is learning and more alert when the process is ameliorated. Many of the children with epileptic encephalopathies, which include a large number of epilepsy syndromes (eg Lennox-Gastaut syndrome, West syndrome, Epilepsy of Infancy with Migrating Focal Seizures), have a genetic basis for their disease, most commonly a de novo dominant pathogenic variant.

The new terminology of ‘developmental and epileptic encephalopathy (DEE)’ was coined because many children with these diseases have developmental impairment due to the underlying mutation with the epileptic encephalopathy process superimposed on the underlying disorder. This means that suppressing the epileptic encephalopathy does not cure the disorder but understanding these two related but distinct components influences treatment approaches, providing the opportunity to optimise long term outcome.

Epilepsies with sleep activation – insights from functional neuroimaging Professor Patrick Van Bogaert, MD, PhD. Université d’Angers. France

14:55

Epilepsies with sleep activation are epileptic encephalopathies in which intense interictal epileptiform activity during sleep is though to play a major role in the cognitive and behavioural disturbances that occur in these children. This hypothesis is supported by studies showing an association between long duration of the continuous spike and waves during slow-wave sleep (CSWS) pattern on EEG and cognitive outcome.

However, other possible contributing factors are the underlying etiology, which is likely to be genetic in patients with the absence of structural brain lesion on MRI, and side effects of anti-epileptic drugs. The aims of functional imaging in these epilepsies are to identify brain networks involved respectively in epileptogenicity and in cognitive dysfunction, to understand the functional dynamics between these two networks, and to study the impact of treatments on these networks. Studies performed at rest at the awake state using either PET with FDG or EEG-fMRI have shown relative hypermetabolism (or increased perfusion) in regions that belong to the epileptogenic network and hypometabolism (or decreased perfusion) in functionally connected regions that belong to the default mode network. These abnormalities may be reversible in patients who respond to antiepileptic treatments, evidencing the place of functional imaging as a biomarker of therapeutic response. Functional neuroimaging approaches combining the excellent temporal resolution of EEG and MEG with a good spatial resolution through sources reconstruction and coregistration with structural MRI, i.e. electrical and magnetic source imaging, are relevant to study the dynamics of these networks at the level of the millisecond.

18

Early intervention in epileptic spasms Professor Finbar O’Callaghan, University College London, UK

15:15

Influence of epilepsy surgery on developmental outcome Professor Kees Braun, UMC Utrecht, The Netherlands

15:35

Infantile spasms are the classic example of an epileptic encephalopathy. There are multiple reports describing the arrest or regression of development coincident with the onset of epileptic spasms and hypsarrhythmia. If the spasms themselves are causing developmental damage then the logical corollary is that rapid resolution of the epileptic encephalopathy with effective treatment should lead to improved cognitive and developmental outcomes compared to those children who are exposed to the encephalopathy for longer periods. Lead-time to treatment i.e. the interval between onset of spasms and the initiation of treatment, is a significant component in the total duration of exposure to the epileptic encephalopathy. Whether treatment is effective and and how fast it works are two other factors influencing the duration of exposure to the encephalopathy. In this talk, drawing on data from ICISS and UKISS and other published clinical studies, I will discuss the effect of lead-time to treatment, speed of response and type of therapy on epilepsy and developmental outcomes. Infantile spasms may have many different underlying aetiologies. There have been suggestions in the literature that specific aetiologies may have specific responses to therapy. I will explore whether different aetiologies have different responses to treatment and different developmental outcomes and I will also discuss the inter-relationship between aetiology, lead-time and therapy on outcomes.

Cognitive development of paediatric epilepsy surgery candidates is determined by many variables, including their genetic and environmental “background”, the epileptogenic pathology, the seizure disorder itself – varying in severity from status epilepticus, epileptic encephalopathy, frequent seizures, to interictal EEG discharges – and the use of antiepileptic drugs. The majority of children with refractory epilepsy have cognitive impairments. Intellectual disability has been considered a contraindication for surgery in the past, whereas the child’s developmental capacity nowadays is an important perspective in surgical decision making. Cognitive functioning of the youngest surgical candidates, particularly those who undergo hemispherotomy, is almost always severely affected (with an IQ or DQ <55), and these children often have an arrest or regression of development due to an epileptic encephalopathy. Although a quantifiable postoperative increase of >8-15 DQ/IQ points is only seen in around 30%, mental age increases in almost all children, and their development seems to restart; one of the most gratifying experiences in paediatric epilepsy surgery. Eventual cognitive outcome after surgery, and the postoperative change in cognitive functioning, depend on etiology, contralateral MRI abnormalities, parental education, age at onset and surgery, presurgical IQ, and on seizure outcome. Most importantly, shorter epilepsy duration has been shown to not only increase the chance of reaching seizure-freedom, it also predicts better postoperative cognitive outcome and more cognitive improvement. Finally, AED withdrawal – which can be safely considered early after surgery in many children – is an independent predictor of eventual IQ and of postoperative IQ increase. Therefore, children with focal lesional epilepsy should be referred for presurgical evaluation early after diagnosis. Epilepsy surgery is an early treatment option, rather than a last resort.

Chaired discussion 15:55-16:25

Closing remarks for day one 16:25-16:40

19

Session 4: What is our understanding of underlying mechanisms linking genetic epilepsies and neurodevelopment?

From rare to polygenic epilepsies Dr Dennis Lal, Broad Institute of MIT and Harvard, US

09:10

Genetic Variations of NMDAR GRIN Genes in Epilepsy and Neurodevelopmental Disorders Professor Hongjie Yuan, Emory University School of Medicine, US

09:30

By accumulating a massive amount of genomic data, scientists have identified >100 genes associated with generalized, focal epilepsies and neurodevelopmental disorders with seizures. Part 1: The translation of these findings into the development of novel drugs or improved patient management is challenging, and the process is slow. Our group has developed a computational infrastructure for exploration of genetic variants on 3D protein structures to facilitate variant interpretation and drug target discovery, which will be presented at the meeting. Part 2: Recent research illustrates that genetic factors significantly contribute to the early onset and severe forms of epilepsy; they represent only one part of the puzzle. In the second part of the talk, recent data we will present new data on common risk variants and their role in the etiology of epilepsy.

N-methyl-D-aspartate receptors (NMDAR), ligand-gated ionotropic glutamatergic receptors, mediate a slow component of excitatory synaptic transmission in the brain that plays a key role in brain development and function. Genetic variations in multiple NMDAR subunits gene GRIN are implicated in a spectrum of neurodevelopmental disorders, including epileptic encephalopathy. There is a mismatch between the high volume of genetic information from sequencing and functional information about variants, which precludes understanding disease mechanism and treatment options. This presentation will focus on a set of GRIN missense variants identified in patients with developmental and epileptic encephalopathy (DEE). These variants are located in pre-M1, pre-M4, and M3/SYTANLAAF motif, critical regions for the channel gating and intolerant to genetic variation. Functional evaluation revealed that these variants influence NMDAR function in multiple ways with enhanced agonist potency, reduced sensitivity to negative modulators (Mg2+, Zn2+, H+), prolonged synaptic response time course, and/or increased single channel probability, leading to NMDAR hyperactivity and neuroexcitotoxicity. Overall, the data suggest these GRIN variants have complex influence on NMDAR function, which may underlie the patients’ phenotypes. A number of FDAapproved NMDAR drugs were assessed for their ability to rectify the altered NMDAR function to explore the potential for rescue pharmacology and clinical opportunity.

Fundings: HY’s research was supported by the NICHD/NIH (HD082373), UDP/NIH, ACTSI/URC, and Emory+Children’s Paediatrictric Center.

Competing interests: HY is PI on a research grant from Sage Therapeutics to Emory University School of Medicine.

PCDH19 Girls clustering epilepsy, a disorder of cellular mosaics.

Professor Josef Gecz, Adelaide Medical School, University of Adelaide, Australia

09:50

Chair: Professor Oscar Marin, King's College London, 09:00 Friday 15th March 2019

PCDH19 variants using in vitro functional assays, in silico prediction and crystal structure modelling. We subsequently tested 25 variants; known disease-causing, VOUS as well as select, frequent population PCDH19 variants with high success rate. Our systematic review of 271 published cases showed that the penetrance of PCDH19 GCE is about 80%, much less than >90% we estimated from family studies in 2008.

The review also showed significant behavioural comorbidities (60%) and significant association between age at seizure onset, before or after 12 months of age and disease severity. Subsequently we performed an online survey focusing on neurocognitive and neuropsychiatric aspects of PCDH19 GCE for which we received 111 completed responses, 33% from unpublished cases. The explanation of variable penetrance between e.g., mothers and daughters or discordant MZ twins, have been challenging to address. In this regard, we studied cellular and electrophysiological aspects of PCDH19 GCE using CRISPR/Cas9 modified mouse models with both, wt and KO PCDH19 alleles visualised. Only the heterozygous females showed altered brain EEG activity (altered SWDs). These mice also showed highly specific sorting and distribution of PCDH19 wt and PCDH19 KO neurons in their developing cortices (14.5dpc). We postulate that individually and tissue specific levels of cellular mosaicism, determined by either X-inactivation or somatic mutation timing, together with altered gene expression of the mutant PCDH19 cells, are the underlying forces of PCDH19 GCE. Epigenetic mechanisms and noncoding RNAs Professor David Henshall, Royal College of Surgeons, Ireland

Epigenetics refers broadly to processes that influence the medium- to long-term expression of genes through changes to the readability and accessibility of the genetic code. The mediators include biochemical modifications to DNA and the histones around which DNA is wrapped, as well as non-coding RNAs. This talk will provide an overview of these processes and how they promote open and closed states of chromatin and regulate transcription. Next, key examples of epigenetic processes found to be altered in models and patients with epilepsy will be reviewed with attention to how these influence gene expression, including mutations in genes with epigenetic functions. The talk will consider practical applications of this emerging area of research, including epigenetic marks as biomarkers for tissue- and biofluid-based diagnostics and precision medicine-based epigenetic editing of specific sites in the genome, as well as global approaches that might offer novel ways to correct dysregulated gene expression and treat or prevent epilepsy. Last, the talk will review the research gaps and the next challenges. In summary, epigenetic processes modulate brain excitability and epileptogenesis, shaping the transcriptional environment which together provides novel insight into patho-mechanisms, biomarkers and novel therapies for epilepsy.

Chaired discussion

10:30-11:00

Co-authors: Kolc K, Homan C, Sharma R, Scheffer IE, Sadleir L, Pitman M, Petrovski S, Pitson S, Roberts R, Jolly L, Pederick D, Thomas P, Pham D

We have implicated PCDH19 in girls clustering epilepsy (GCE) in 2008. Hundreds of heterozygous females and >12 males with somatic mosaic PCDH19 mutations have been reported since. In addition to cell-cell adhesion function we found that PCDH19 protein acts as an intracellular signalling molecule with e.g. estrogen receptor alpha, ESR1, which leads to unexpected, but consistent deregulation of neurosteroid hormone levels in these GCE girls. We have developed a multidimensional pathogenicity assessment tool for 20

10:10

21

Session 4: What is our understanding of underlying mechanisms linking genetic epilepsies and neurodevelopment?

From rare to polygenic epilepsies Dr Dennis Lal, Broad Institute of MIT and Harvard, US

09:10

Genetic Variations of NMDAR GRIN Genes in Epilepsy and Neurodevelopmental Disorders Professor Hongjie Yuan, Emory University School of Medicine, US

09:30

By accumulating a massive amount of genomic data, scientists have identified >100 genes associated with generalized, focal epilepsies and neurodevelopmental disorders with seizures. Part 1: The translation of these findings into the development of novel drugs or improved patient management is challenging, and the process is slow. Our group has developed a computational infrastructure for exploration of genetic variants on 3D protein structures to facilitate variant interpretation and drug target discovery, which will be presented at the meeting. Part 2: Recent research illustrates that genetic factors significantly contribute to the early onset and severe forms of epilepsy; they represent only one part of the puzzle. In the second part of the talk, recent data we will present new data on common risk variants and their role in the etiology of epilepsy.

N-methyl-D-aspartate receptors (NMDAR), ligand-gated ionotropic glutamatergic receptors, mediate a slow component of excitatory synaptic transmission in the brain that plays a key role in brain development and function. Genetic variations in multiple NMDAR subunits gene GRIN are implicated in a spectrum of neurodevelopmental disorders, including epileptic encephalopathy. There is a mismatch between the high volume of genetic information from sequencing and functional information about variants, which precludes understanding disease mechanism and treatment options. This presentation will focus on a set of GRIN missense variants identified in patients with developmental and epileptic encephalopathy (DEE). These variants are located in pre-M1, pre-M4, and M3/SYTANLAAF motif, critical regions for the channel gating and intolerant to genetic variation. Functional evaluation revealed that these variants influence NMDAR function in multiple ways with enhanced agonist potency, reduced sensitivity to negative modulators (Mg2+, Zn2+, H+), prolonged synaptic response time course, and/or increased single channel probability, leading to NMDAR hyperactivity and neuroexcitotoxicity. Overall, the data suggest these GRIN variants have complex influence on NMDAR function, which may underlie the patients’ phenotypes. A number of FDAapproved NMDAR drugs were assessed for their ability to rectify the altered NMDAR function to explore the potential for rescue pharmacology and clinical opportunity.

Fundings: HY’s research was supported by the NICHD/NIH (HD082373), UDP/NIH, ACTSI/URC, and Emory+Children’s Paediatrictric Center.

Competing interests: HY is PI on a research grant from Sage Therapeutics to Emory University School of Medicine.

PCDH19 Girls clustering epilepsy, a disorder of cellular mosaics.

Professor Josef Gecz, Adelaide Medical School, University of Adelaide, Australia

09:50

Chair: Professor Oscar Marin, King's College London, 09:00 Friday 15th March 2019

PCDH19 variants using in vitro functional assays, in silico prediction and crystal structure modelling. We subsequently tested 25 variants; known disease-causing, VOUS as well as select, frequent population PCDH19 variants with high success rate. Our systematic review of 271 published cases showed that the penetrance of PCDH19 GCE is about 80%, much less than >90% we estimated from family studies in 2008.

The review also showed significant behavioural comorbidities (60%) and significant association between age at seizure onset, before or after 12 months of age and disease severity. Subsequently we performed an online survey focusing on neurocognitive and neuropsychiatric aspects of PCDH19 GCE for which we received 111 completed responses, 33% from unpublished cases. The explanation of variable penetrance between e.g., mothers and daughters or discordant MZ twins, have been challenging to address. In this regard, we studied cellular and electrophysiological aspects of PCDH19 GCE using CRISPR/Cas9 modified mouse models with both, wt and KO PCDH19 alleles visualised. Only the heterozygous females showed altered brain EEG activity (altered SWDs). These mice also showed highly specific sorting and distribution of PCDH19 wt and PCDH19 KO neurons in their developing cortices (14.5dpc). We postulate that individually and tissue specific levels of cellular mosaicism, determined by either X-inactivation or somatic mutation timing, together with altered gene expression of the mutant PCDH19 cells, are the underlying forces of PCDH19 GCE. Epigenetic mechanisms and noncoding RNAs Professor David Henshall, Royal College of Surgeons, Ireland

Epigenetics refers broadly to processes that influence the medium- to long-term expression of genes through changes to the readability and accessibility of the genetic code. The mediators include biochemical modifications to DNA and the histones around which DNA is wrapped, as well as non-coding RNAs. This talk will provide an overview of these processes and how they promote open and closed states of chromatin and regulate transcription. Next, key examples of epigenetic processes found to be altered in models and patients with epilepsy will be reviewed with attention to how these influence gene expression, including mutations in genes with epigenetic functions. The talk will consider practical applications of this emerging area of research, including epigenetic marks as biomarkers for tissue- and biofluid-based diagnostics and precision medicine-based epigenetic editing of specific sites in the genome, as well as global approaches that might offer novel ways to correct dysregulated gene expression and treat or prevent epilepsy. Last, the talk will review the research gaps and the next challenges. In summary, epigenetic processes modulate brain excitability and epileptogenesis, shaping the transcriptional environment which together provides novel insight into patho-mechanisms, biomarkers and novel therapies for epilepsy.

Chaired discussion

10:30-11:00

Co-authors: Kolc K, Homan C, Sharma R, Scheffer IE, Sadleir L, Pitman M, Petrovski S, Pitson S, Roberts R, Jolly L, Pederick D, Thomas P, Pham D

We have implicated PCDH19 in girls clustering epilepsy (GCE) in 2008. Hundreds of heterozygous females and >12 males with somatic mosaic PCDH19 mutations have been reported since. In addition to cell-cell adhesion function we found that PCDH19 protein acts as an intracellular signalling molecule with e.g. estrogen receptor alpha, ESR1, which leads to unexpected, but consistent deregulation of neurosteroid hormone levels in these GCE girls. We have developed a multidimensional pathogenicity assessment tool for 20

10:10

21

Session 5: How does the link between epilepsy, behaviour, and development affect current treatments?

Effects of AEDs on early and in utero brain development Professor Gus A Baker, University of Liverpool, UK

Chair: Professor Deb Pal, King’s College London, UK 11:20 Friday 15th March 2019

11:25

The last two decades have witnessed a growing concern over the treatment of epilepsy in women of childbearing age, with an increased risk of major congenital malformations and possible cognitive difficulties associated with certain antiepileptic drugs. Increasing evidence suggests that exposure to certain antiepileptic drugs (AEDs) during critical periods of development may induce transient or long-lasting neurodevelopmental deficits across cognitive, motor and behavioural domains. The developing nervous system may endure prolonged chronic exposure to AEDs during pregnancy (in utero) or during childhood, which can lead to neurodevelopmental defects such as congenital neural tube defects, lower IQ, language deficits, autism and ADHD. Despite the methodological shortfalls of some of the research in this area, there is an accumulation of evidence highlighting an increased risk for cognitive and behavioural difficulties in children exposed to sodium valproate in utero. However, children exposed to carbamazepine were not found by the majority of studies to have poorer early development, although there is a lack of evidence regarding specific cognitive skills later in childhood and adolescence. Research regarding lamotrigine was limited to a small number of studies but suggests early global development or school aged IQ does not differ from control children, but less is known about specific cognitive skills. Evidence for the other AEDs including levetiracetam and topiramate were significantly limited. Recent research has suggested that there may also be risks associated with phenobarbital and phenytoin exposure. The aim of this presentation here is to review the literature regarding the possible cognitive and behavioural impact of exposure to antiepileptic drugs in utero and to summarize our current understanding of the neurodevelopmental effects of AEDs. Impact of anti-epileptic drugs on mood & behaviour Professor Alexis Arzimanoglou, University Hospitals of Lyon, France. Hospital Sant Joan de Déu, Universitat de Barcelona, Spain

11:45

Epilepsy is a rather complex major public health disease, encompassing a large spectrum of epilepsy syndromes of variable aetiology. In addition to recurrent and unpredictable seizures, abnormalities in psychiatric status, cognition and social adaptive behaviours are potential major sources of disability in children and adults with epilepsy disorders. In children with epilepsy, findings have unequivocally documented a higher rate of neurobehavioral and attention deficit disorders, as well as psychiatric comorbidities, particularly emotional regulation disorders such as depression, anxiety, bipolar disorders, compared with both the general population and children with other medical disorders, neurological and non-neurological. For psychiatric comorbidities, a prevalence of 12% to 35% has been reported, compared to 3-8% in the general population. The link between an underlying brain disorder and psychiatric comorbidities has also emerged in recent literature, with evidence based on studies in adults, suggesting a bidirectional relationship between epilepsy and neurobehavioral comorbidities. Emotional regulation disorders can follow the onset of epilepsy; however, they can also precede it, thus serving as a possible risk factor. The clinical implication of such a bidirectional association is that neurobehavioral comorbidities might be present at diagnosis and even before epilepsy onset.

The bidirectional relationship between psychopathology and epilepsy may also be unrelated to the severity of epilepsy, epilepsy syndrome, or type of mood or anxiety disorder. Nevertheless, controlled studies are relatively scarce and evidence-based data to strongly support such a statement are still lacking. Disparate findings are reported due to: small sample sizes, heterogeneous epilepsy syndromes, and often inclusion of children suffering from established, chronic, epilepsy rather than newly diagnosed patients. According to certain neurobiological models, the occurrence of mood/emotional disorders is linked to a biological and/or genetic susceptibility, which is influenced by stress factors. These elements may, in turn, potentially be 22

affected by epilepsy; the repetition and propagation of seizures, disrupting or merely modifying the organization of specific neural networks. The pharmacological management of the epilepsies, particularly when frequent changes or polytherapy are necessary, further complicates a better understanding of the above. Up to 8% of patients with drug-resistant epilepsy develop treatment-emergent psychiatric adverse events of AED regardless of the mechanism of action of the drug and this is probably related to an underlying predisposition given by the previous psychiatric history. On the other hand, while some AEDs are successfully used for the treatment of mood disorders outside epilepsy, the same AEDs may be associated with paradoxical mood deterioration in people with epilepsy. The therapeutic challenges in clinical practice will be discussed.

Social cognition, learning and AEDs in childhood epilepsy Dr Liam Dorris, NHS Glasgow and Clyde, UK

12:05

Concept of disease modification Professor Lieven Lagae, University of Leuven, Belgium

12:25

Recent evidence indicates that young children with genetic generalised epilepsy may have impairments in cognitive and affective empathy, and that these deficits correlate with everyday social problems. There is also limited evidence that higher dosages of AEDs may be related to cognitive empathy deficits in adults with temporal lobe epilepsy. This talk will consider the latest insights from ‘big data’ lifespan studies on cognitive empathy abilities, and will consider how early neurological disorders such as epilepsy may constrain the normal development of social cognitive abilities. This presentation will also cover the latest evidence for learning, memory and cognitive difficulties in childhood epilepsy and the potential impact of epilepsy treatments on cognition and behaviour.

In neurological disorders such as epilepsy and neurodevelopmental disorders, disease modification refers to any therapeutic intervention which can substantially change the final outcome of the disease. It is indeed still frustrating that for many neurological disorders, we still need to rely on symptomatic treatment options (which nevertheless can be successful to some extent). In epilepsy, for example, except perhaps for epilepsy surgery, our treatment arsenal with more than 25 anti-epileptic drugs, ketogenic diet and VNS, remains largely symptomatic. Adequate disease modification requires in most cases early and perhaps presymptomatic diagnosis. In a second stage, an adequate intervention should be given which should be more directed towards the etiology of the disease than to the accompanying symptoms. However, different challenges arise. The most important one is the need for other research designs. Placebo controlled trials will be almost impossible and the benefits of active intervention should clearly outweigh the possible side effects of the intervention. Research into disease modification will also need long-term follow up trials. Two examples of disease modification in paediatric neurology illustrate the potentials of disease modification.

The very successful early treatment in SMA with nusinersen shows how the natural evolution in SMA1 completely changes. This SMA story also indicates that real disease modification will happen through genetic modulatory interventions. Another possible success story is the preclinical treatment with AEDs in children with TSC. Early pre-clinical treatment with AEDs significantly changes the developmental outcome in these children. In addition, earlier use of specific mTOR inhibitors might change not only the neurological outcome but all related morbidities in TSC patients.

Chaired discussion

12:45-13:15

23

Session 5: How does the link between epilepsy, behaviour, and development affect current treatments?

Effects of AEDs on early and in utero brain development Professor Gus A Baker, University of Liverpool, UK

Chair: Professor Deb Pal, King’s College London, UK 11:20 Friday 15th March 2019

11:25

The last two decades have witnessed a growing concern over the treatment of epilepsy in women of childbearing age, with an increased risk of major congenital malformations and possible cognitive difficulties associated with certain antiepileptic drugs. Increasing evidence suggests that exposure to certain antiepileptic drugs (AEDs) during critical periods of development may induce transient or long-lasting neurodevelopmental deficits across cognitive, motor and behavioural domains. The developing nervous system may endure prolonged chronic exposure to AEDs during pregnancy (in utero) or during childhood, which can lead to neurodevelopmental defects such as congenital neural tube defects, lower IQ, language deficits, autism and ADHD. Despite the methodological shortfalls of some of the research in this area, there is an accumulation of evidence highlighting an increased risk for cognitive and behavioural difficulties in children exposed to sodium valproate in utero. However, children exposed to carbamazepine were not found by the majority of studies to have poorer early development, although there is a lack of evidence regarding specific cognitive skills later in childhood and adolescence. Research regarding lamotrigine was limited to a small number of studies but suggests early global development or school aged IQ does not differ from control children, but less is known about specific cognitive skills. Evidence for the other AEDs including levetiracetam and topiramate were significantly limited. Recent research has suggested that there may also be risks associated with phenobarbital and phenytoin exposure. The aim of this presentation here is to review the literature regarding the possible cognitive and behavioural impact of exposure to antiepileptic drugs in utero and to summarize our current understanding of the neurodevelopmental effects of AEDs. Impact of anti-epileptic drugs on mood & behaviour Professor Alexis Arzimanoglou, University Hospitals of Lyon, France. Hospital Sant Joan de Déu, Universitat de Barcelona, Spain

11:45

Epilepsy is a rather complex major public health disease, encompassing a large spectrum of epilepsy syndromes of variable aetiology. In addition to recurrent and unpredictable seizures, abnormalities in psychiatric status, cognition and social adaptive behaviours are potential major sources of disability in children and adults with epilepsy disorders. In children with epilepsy, findings have unequivocally documented a higher rate of neurobehavioral and attention deficit disorders, as well as psychiatric comorbidities, particularly emotional regulation disorders such as depression, anxiety, bipolar disorders, compared with both the general population and children with other medical disorders, neurological and non-neurological. For psychiatric comorbidities, a prevalence of 12% to 35% has been reported, compared to 3-8% in the general population. The link between an underlying brain disorder and psychiatric comorbidities has also emerged in recent literature, with evidence based on studies in adults, suggesting a bidirectional relationship between epilepsy and neurobehavioral comorbidities. Emotional regulation disorders can follow the onset of epilepsy; however, they can also precede it, thus serving as a possible risk factor. The clinical implication of such a bidirectional association is that neurobehavioral comorbidities might be present at diagnosis and even before epilepsy onset.

The bidirectional relationship between psychopathology and epilepsy may also be unrelated to the severity of epilepsy, epilepsy syndrome, or type of mood or anxiety disorder. Nevertheless, controlled studies are relatively scarce and evidence-based data to strongly support such a statement are still lacking. Disparate findings are reported due to: small sample sizes, heterogeneous epilepsy syndromes, and often inclusion of children suffering from established, chronic, epilepsy rather than newly diagnosed patients. According to certain neurobiological models, the occurrence of mood/emotional disorders is linked to a biological and/or genetic susceptibility, which is influenced by stress factors. These elements may, in turn, potentially be 22

affected by epilepsy; the repetition and propagation of seizures, disrupting or merely modifying the organization of specific neural networks. The pharmacological management of the epilepsies, particularly when frequent changes or polytherapy are necessary, further complicates a better understanding of the above. Up to 8% of patients with drug-resistant epilepsy develop treatment-emergent psychiatric adverse events of AED regardless of the mechanism of action of the drug and this is probably related to an underlying predisposition given by the previous psychiatric history. On the other hand, while some AEDs are successfully used for the treatment of mood disorders outside epilepsy, the same AEDs may be associated with paradoxical mood deterioration in people with epilepsy. The therapeutic challenges in clinical practice will be discussed.

Social cognition, learning and AEDs in childhood epilepsy Dr Liam Dorris, NHS Glasgow and Clyde, UK

12:05

Concept of disease modification Professor Lieven Lagae, University of Leuven, Belgium

12:25

Recent evidence indicates that young children with genetic generalised epilepsy may have impairments in cognitive and affective empathy, and that these deficits correlate with everyday social problems. There is also limited evidence that higher dosages of AEDs may be related to cognitive empathy deficits in adults with temporal lobe epilepsy. This talk will consider the latest insights from ‘big data’ lifespan studies on cognitive empathy abilities, and will consider how early neurological disorders such as epilepsy may constrain the normal development of social cognitive abilities. This presentation will also cover the latest evidence for learning, memory and cognitive difficulties in childhood epilepsy and the potential impact of epilepsy treatments on cognition and behaviour.

In neurological disorders such as epilepsy and neurodevelopmental disorders, disease modification refers to any therapeutic intervention which can substantially change the final outcome of the disease. It is indeed still frustrating that for many neurological disorders, we still need to rely on symptomatic treatment options (which nevertheless can be successful to some extent). In epilepsy, for example, except perhaps for epilepsy surgery, our treatment arsenal with more than 25 anti-epileptic drugs, ketogenic diet and VNS, remains largely symptomatic. Adequate disease modification requires in most cases early and perhaps presymptomatic diagnosis. In a second stage, an adequate intervention should be given which should be more directed towards the etiology of the disease than to the accompanying symptoms. However, different challenges arise. The most important one is the need for other research designs. Placebo controlled trials will be almost impossible and the benefits of active intervention should clearly outweigh the possible side effects of the intervention. Research into disease modification will also need long-term follow up trials. Two examples of disease modification in paediatric neurology illustrate the potentials of disease modification.

The very successful early treatment in SMA with nusinersen shows how the natural evolution in SMA1 completely changes. This SMA story also indicates that real disease modification will happen through genetic modulatory interventions. Another possible success story is the preclinical treatment with AEDs in children with TSC. Early pre-clinical treatment with AEDs significantly changes the developmental outcome in these children. In addition, earlier use of specific mTOR inhibitors might change not only the neurological outcome but all related morbidities in TSC patients.

Chaired discussion

12:45-13:15

23

Session 6: Molecular therapeutic strategies in epilepsy and neurodevelopmental disorders. What are the key questions and strategies for finding future treatments?

Genetic therapies Professor Stephanie Schorge, University College London, UK

Chair: Dimitri Kullmann, University College London, UK 14:10 Friday 15th March 2019 14:15

Gene therapy offers the potential to change the expression of any gene in targeted cells. The potential for treatments to restore functional copies of genes in people who have mutations disrupting those genes is increasingly well-recognised. In epilepsy, which is frequently characterised by an imbalance between excitation and inhibition, there is a different opportunity for gene therapy. That is to alter expression of genes to restore this balance, even in individuals with no known causative mutation. This allows gene therapy to move from a focus on rare monogenetic epilepsies to more common epilepsies, and the wealth of neurophysiological and molecular data revealing how neuronal excitability is modulated during epileptogenesis and epilepsy, means there are many potential target genes to investigate. This talk focuses on three different strategies in our collaboration that are aimed at reducing the likelihood of seizures: over expression of potassium channels, use of designer receptors exclusively activated by designer drugs (DREADDs), and glutamate-gated chloride channels. The focus is on the technical and translational challenges and advantages of each approach and an analysis of how these approaches may be progressed to clinical trials, and how those clinical trials might be designed, using the strategy with the original potassium channel construct as a worked example.

Genetic variation in the AnkyrinG interactome causes a range of neurological disorders Professor Frank Kooy, University of Antwerp, Antwerp, Belgium

Co-authors: Ilse M. van der Werf1, Sandra Jansen2, Bert B. A. de Vries2, Geert Vandeweyer1 1 Department of Medical Genetics, University of Antwerp, Antwerp, Belgium 2 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

14:35

Numerous genes are involved in the pathogenesis of neurodevelopmental disorders. Several studies showed that a significant proportion of all putative disease genes converge on a relatively limited number of molecular pathways or protein networks. Thus far, the identification of the disease-networks followed the identification of the individual genes. To what extend this type of selection bias affects the detection of the disease-related pathways is unknown. We here took an unbiased approach by selecting a well-defined protein-protein interaction network and investigating the mutational load therein in a large cohort of patients with various neurodevelopmental disorders along with their parents. For our study, we selected the AnkyrinG PPI network. The AnkyrinG protein binds simultaneously to the spectrin cytoskeleton as well as to multiple membrane proteins. ANK3 encodes the AnkyrinG protein that is enriched at the axon initial segment and the nodes of Ranvier of myelinated neurons in the central nervous system. Mutations in ANK3 have been implicated in many neurodevelopmental disorders, including ID, epilepsy, ASD and behavioral problems, whereas multiple SNPs have confirmed associations with bipolar disorder, schizophrenia and post-traumatic stress disorder. Upon an extensive literature search, we identified a total of 17 proteins that interact with AnkG. Direct interactors include cell adhesion molecules, cytoskeleton-component β4-spectrin and specific sodium and potassium channel components. The other proteins in this PPI network are specific sodium and potassium channels as well as components of Casein kinase 2.

MIP sequencing of all genes in the ANK3 PPI network was performed for over 1009 patient-parent trios. For this cohort, all nonsynonymous de novo variants that passed quality parameters, were selected for Sanger sequencing validation. A total number of 14 confirmed de novo variants were identified in multiple ANK3 PPI network members. Considering the average rate of base-substitutional mutations and size of the encoded genomic region by the network genes, a priori only one to two de novo mutations are expected in our screen assuming no selective pressure on the included genes. Thus our cohort, we detected a significant 24

overrepresentation of de novo mutations in the AnkyrinG PPI network (p=0.007, Fisher’s exact test). Our finding stresses the importance of the AnkyrinG PPI network in neurodevelopmental disorders and suggests it as a potential target for future therapies.

Gene therapy in neurodevelopmental disorders Professor Stuart Cobb, University of Edinburgh, UK

14:55

Interneuron-based cell therapy for intractable epilepsies Professor Scott Baraban, University of California, San Francisco, US

15:15

The potential for gene therapy in neurological disorders is finally being realised. Advances in diagnostic gene panels and sequencing technologies are giving earlier / definitive molecular diagnoses and identifying patient populations. At the same time, AAV vector-mediated gene therapy can target the root-cause in neurodevelopmental disorders (NDD) and genetic epilepsies. Importantly, gene therapy can attack genetic targets that are not readily ‘druggable’ by conventional therapeutic modalities. In the presentation, Rett syndrome will be given as an exemplar of translational progress in gene therapy. Rett syndrome is caused by loss-of-function mutations in the X-linked MECP2 gene and leads to seizures and lifelong cognitive, motor and other disabilities. It was the first genetic neurodevelopmental disorder to have been shown to respond to genetic rescue and these findings and others marked a paradigmatic change in the way we view and envision treating NDDs. Studies in accurate genetic models of the disorder have demonstrated the concept gene therapy and led to commercial and clinical development programmes NDDs. There are however many challenges and significant obstacles to translational success in NDD and genetic epilepsies. Many of the genes underlying the disorders are highly dosage sensitive and achieving appropriate control of levels and patterns of expression are as important as are the delivery, spread and distribution of the vector within the nervous system. As a result, ongoing efforts aim to make a new generation of gene therapy reagents with improved efficacy and safety necessary for clinical translation.

Nearly 3 million Americans suffer from epilepsy. In one third of these patients, available antiepileptic drugs or invasive surgical procedures are not effective. With an increased understanding of the role of inhibitory GABAergic interneurons in the healthy and epileptic brain, hope for a cure emerges. During the past decade, transplantation of neuronal precursors into the CNS has shown great promise for the treatment of neurological diseases and epilepsy (often viewed as a deficit in inhibition) more specifically. Reports of neural progenitor cells with the ability to disperse and differentiate into neurons following transplantation have further raised expectations that defective brain circuits can be repaired. Using transplanted neural progenitors derived from the embryonic medial ganglionic eminence (or MGE) we are exploring the possibility that these cells will influence synaptic function in the host brain and reduce spontaneous seizures.

Our work takes advantage of the unique ability of MGE progenitor cells to migrate and integrate as inhibitory GABAergic interneurons following transplantation. Here I will describe our on-going efforts to characterize these cells in vitro and in vivo – at morphological, molecular, immunohistochemical, and functional levels – following transplantation. Data will also be presented to demonstrate the efficacy of these transplanted GABA progenitor cells in ameliorating spontaneous seizures and behavioral co-morbidities in a wide variety of rodent epilepsy models. Finally, the initial steps we are taking to translate these rodent studies to larger species will be discussed. Overall, these efforts provide proof-of-principle for the development of an interneuron-based cell transplantation therapy.

Chaired discussion 12:55-13:25

Closing remarks for day two 16:05-16:40

25

Session 6: Molecular therapeutic strategies in epilepsy and neurodevelopmental disorders. What are the key questions and strategies for finding future treatments?

Genetic therapies Professor Stephanie Schorge, University College London, UK

Chair: Dimitri Kullmann, University College London, UK 14:10 Friday 15th March 2019 14:15

Gene therapy offers the potential to change the expression of any gene in targeted cells. The potential for treatments to restore functional copies of genes in people who have mutations disrupting those genes is increasingly well-recognised. In epilepsy, which is frequently characterised by an imbalance between excitation and inhibition, there is a different opportunity for gene therapy. That is to alter expression of genes to restore this balance, even in individuals with no known causative mutation. This allows gene therapy to move from a focus on rare monogenetic epilepsies to more common epilepsies, and the wealth of neurophysiological and molecular data revealing how neuronal excitability is modulated during epileptogenesis and epilepsy, means there are many potential target genes to investigate. This talk focuses on three different strategies in our collaboration that are aimed at reducing the likelihood of seizures: over expression of potassium channels, use of designer receptors exclusively activated by designer drugs (DREADDs), and glutamate-gated chloride channels. The focus is on the technical and translational challenges and advantages of each approach and an analysis of how these approaches may be progressed to clinical trials, and how those clinical trials might be designed, using the strategy with the original potassium channel construct as a worked example.

Genetic variation in the AnkyrinG interactome causes a range of neurological disorders Professor Frank Kooy, University of Antwerp, Antwerp, Belgium

Co-authors: Ilse M. van der Werf1, Sandra Jansen2, Bert B. A. de Vries2, Geert Vandeweyer1 1 Department of Medical Genetics, University of Antwerp, Antwerp, Belgium 2 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

14:35

Numerous genes are involved in the pathogenesis of neurodevelopmental disorders. Several studies showed that a significant proportion of all putative disease genes converge on a relatively limited number of molecular pathways or protein networks. Thus far, the identification of the disease-networks followed the identification of the individual genes. To what extend this type of selection bias affects the detection of the disease-related pathways is unknown. We here took an unbiased approach by selecting a well-defined protein-protein interaction network and investigating the mutational load therein in a large cohort of patients with various neurodevelopmental disorders along with their parents. For our study, we selected the AnkyrinG PPI network. The AnkyrinG protein binds simultaneously to the spectrin cytoskeleton as well as to multiple membrane proteins. ANK3 encodes the AnkyrinG protein that is enriched at the axon initial segment and the nodes of Ranvier of myelinated neurons in the central nervous system. Mutations in ANK3 have been implicated in many neurodevelopmental disorders, including ID, epilepsy, ASD and behavioral problems, whereas multiple SNPs have confirmed associations with bipolar disorder, schizophrenia and post-traumatic stress disorder. Upon an extensive literature search, we identified a total of 17 proteins that interact with AnkG. Direct interactors include cell adhesion molecules, cytoskeleton-component β4-spectrin and specific sodium and potassium channel components. The other proteins in this PPI network are specific sodium and potassium channels as well as components of Casein kinase 2.

MIP sequencing of all genes in the ANK3 PPI network was performed for over 1009 patient-parent trios. For this cohort, all nonsynonymous de novo variants that passed quality parameters, were selected for Sanger sequencing validation. A total number of 14 confirmed de novo variants were identified in multiple ANK3 PPI network members. Considering the average rate of base-substitutional mutations and size of the encoded genomic region by the network genes, a priori only one to two de novo mutations are expected in our screen assuming no selective pressure on the included genes. Thus our cohort, we detected a significant 24

overrepresentation of de novo mutations in the AnkyrinG PPI network (p=0.007, Fisher’s exact test). Our finding stresses the importance of the AnkyrinG PPI network in neurodevelopmental disorders and suggests it as a potential target for future therapies.

Gene therapy in neurodevelopmental disorders Professor Stuart Cobb, University of Edinburgh, UK

14:55

Interneuron-based cell therapy for intractable epilepsies Professor Scott Baraban, University of California, San Francisco, US

15:15

The potential for gene therapy in neurological disorders is finally being realised. Advances in diagnostic gene panels and sequencing technologies are giving earlier / definitive molecular diagnoses and identifying patient populations. At the same time, AAV vector-mediated gene therapy can target the root-cause in neurodevelopmental disorders (NDD) and genetic epilepsies. Importantly, gene therapy can attack genetic targets that are not readily ‘druggable’ by conventional therapeutic modalities. In the presentation, Rett syndrome will be given as an exemplar of translational progress in gene therapy. Rett syndrome is caused by loss-of-function mutations in the X-linked MECP2 gene and leads to seizures and lifelong cognitive, motor and other disabilities. It was the first genetic neurodevelopmental disorder to have been shown to respond to genetic rescue and these findings and others marked a paradigmatic change in the way we view and envision treating NDDs. Studies in accurate genetic models of the disorder have demonstrated the concept gene therapy and led to commercial and clinical development programmes NDDs. There are however many challenges and significant obstacles to translational success in NDD and genetic epilepsies. Many of the genes underlying the disorders are highly dosage sensitive and achieving appropriate control of levels and patterns of expression are as important as are the delivery, spread and distribution of the vector within the nervous system. As a result, ongoing efforts aim to make a new generation of gene therapy reagents with improved efficacy and safety necessary for clinical translation.

Nearly 3 million Americans suffer from epilepsy. In one third of these patients, available antiepileptic drugs or invasive surgical procedures are not effective. With an increased understanding of the role of inhibitory GABAergic interneurons in the healthy and epileptic brain, hope for a cure emerges. During the past decade, transplantation of neuronal precursors into the CNS has shown great promise for the treatment of neurological diseases and epilepsy (often viewed as a deficit in inhibition) more specifically. Reports of neural progenitor cells with the ability to disperse and differentiate into neurons following transplantation have further raised expectations that defective brain circuits can be repaired. Using transplanted neural progenitors derived from the embryonic medial ganglionic eminence (or MGE) we are exploring the possibility that these cells will influence synaptic function in the host brain and reduce spontaneous seizures.

Our work takes advantage of the unique ability of MGE progenitor cells to migrate and integrate as inhibitory GABAergic interneurons following transplantation. Here I will describe our on-going efforts to characterize these cells in vitro and in vivo – at morphological, molecular, immunohistochemical, and functional levels – following transplantation. Data will also be presented to demonstrate the efficacy of these transplanted GABA progenitor cells in ameliorating spontaneous seizures and behavioral co-morbidities in a wide variety of rodent epilepsy models. Finally, the initial steps we are taking to translate these rodent studies to larger species will be discussed. Overall, these efforts provide proof-of-principle for the development of an interneuron-based cell transplantation therapy.

Chaired discussion 12:55-13:25

Closing remarks for day two 16:05-16:40

25

Delegate list

Laura Andreae Alexis Arzimanoglou Gus Baker Torsten Baldeweg Scott Baraban Caoimhe Bennett Kees Braun Andreas Brunklaus Stuart Cobb Mike Cousin Helen Cross Liam Dorris Kate Elliott Jo Finnerty Bruno Frenguelli Jozef Gecz Alfredo Gonzalez-Sulser Kathleen Gorman Renzo Guerrini David Henshall Floor Jansen Michael Johnson Rajvinder Karda Lorcan Kenny Katja Kobow Frank Kooy Manju Kurian Dimitri Kullmann Dennis Lal Gabriele Lignani Christine Linehan Massimo Mantegazza Oscar Marin Amy McTague Rikke Moller Solomon L Moshe Amy Muggeridge Finbar O'Callaghan Deb Pal Jack Parent Lucy Raymond Mark Richardson Richard Rosch Ingrid Scheffer Stephanie Schorge Arjune Sen Sanjay Sisodiya Maxine Smeaton Joe Symonds Rhys Thomas Patrick van Bogaert Simon Waddington Sukhvir Wright Hongjie Yuan Sameer Zuberi

King’s College London University Hospitals University of Liverpool University College London University of California, San Francisco Epilepsy Research UK University Medical Centre Utrecht NHS Greater Glasgow and Clyde University of Edinburgh University of Edinburgh University College London University of Glasgow University of Oxford Epilepsy Research UK University of Warwick University of Adelaide University of Edinburgh University College Dublin University of Florence Royal College of Surgeons in Ireland University Medical Centre Utrecht Imperial College London University College London Autistica Universitätsklinikum Erlangen University of Antwerp University College London University College London Broad Institute of MIT and Harvard University College London University College Dublin Institut de Pharmacologie Moléculaire et Cellulaire King’s College London University College London University of Southern Denmark Albert Einstein College of Medicine Young Epilepsy University College London King’s College London University of Michigan University of Cambridge King’s College London King’s College London University of Melbourne University College London University of Oxford University College London Epilepsy Research UK NHS Greater Glasgow and Clyde Newcastle University Université d’Angers University College London Aston University Emory University NHS Greater Glasgow and Clyde 26

Notes

27

Delegate list

Laura Andreae Alexis Arzimanoglou Gus Baker Torsten Baldeweg Scott Baraban Caoimhe Bennett Kees Braun Andreas Brunklaus Stuart Cobb Mike Cousin Helen Cross Liam Dorris Kate Elliott Jo Finnerty Bruno Frenguelli Jozef Gecz Alfredo Gonzalez-Sulser Kathleen Gorman Renzo Guerrini David Henshall Floor Jansen Michael Johnson Rajvinder Karda Lorcan Kenny Katja Kobow Frank Kooy Manju Kurian Dimitri Kullmann Dennis Lal Gabriele Lignani Christine Linehan Massimo Mantegazza Oscar Marin Amy McTague Rikke Moller Solomon L Moshe Amy Muggeridge Finbar O'Callaghan Deb Pal Jack Parent Lucy Raymond Mark Richardson Richard Rosch Ingrid Scheffer Stephanie Schorge Arjune Sen Sanjay Sisodiya Maxine Smeaton Joe Symonds Rhys Thomas Patrick van Bogaert Simon Waddington Sukhvir Wright Hongjie Yuan Sameer Zuberi

King’s College London University Hospitals University of Liverpool University College London University of California, San Francisco Epilepsy Research UK University Medical Centre Utrecht NHS Greater Glasgow and Clyde University of Edinburgh University of Edinburgh University College London University of Glasgow University of Oxford Epilepsy Research UK University of Warwick University of Adelaide University of Edinburgh University College Dublin University of Florence Royal College of Surgeons in Ireland University Medical Centre Utrecht Imperial College London University College London Autistica Universitätsklinikum Erlangen University of Antwerp University College London University College London Broad Institute of MIT and Harvard University College London University College Dublin Institut de Pharmacologie Moléculaire et Cellulaire King’s College London University College London University of Southern Denmark Albert Einstein College of Medicine Young Epilepsy University College London King’s College London University of Michigan University of Cambridge King’s College London King’s College London University of Melbourne University College London University of Oxford University College London Epilepsy Research UK NHS Greater Glasgow and Clyde Newcastle University Université d’Angers University College London Aston University Emory University NHS Greater Glasgow and Clyde 26

Notes

27

epilepsy research uk

Epilepsy Research UK is the only UK-based charity exclusively dedicated to funding independent research into epilepsy. Our mission is to drive investment into research, inspire collaboration across clinical, scientific and academic disciplines, and transform the lives of people living with epilepsy and their families and carers.

Epilepsy Research UK CAN Mezzanine, 7-14 Great Dover Street, London, SE1 4YR t 020 3096 7887 e info@eruk.org.uk w www.epilepsyresearch.org.uk Registered Charity 1100394 UK Company Number 4873718

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