Pediatric State of the Art Symposium Tuberous Sclerosis ... · The American Epilepsy Society is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to

Pediatric State of the Art Symposium Tuberous Sclerosis Complex (TSC):

Understanding and Modifying Epileptogenesis

Symposium Co-Chairs: Leiven Lagae, M.D.

and

Jurriaan Peters, M.D.

Monday, December 5, 2016 Convention Center – General Assembly

5:45 – 8:15 p.m.

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EDUCATION CREDITS

American Epilepsy Society | www.AESnet.org | Houston, Texas 70th Annual Meeting | 6th Biennial North American Regional Epilepsy Congress 23

OVERVIEW In Tuberous Sclerosis Complex (TSC), at least 70 percent of the patients will develop epilepsy and in the majority, the epilepsy will start before the age of one year. Especially when epileptic spasms occur and/or when the epilepsy becomes drugresistant, the developmental and behavioral outcome will be unfavorable: Many children will develop intellectual disability and autistic behavior. Because we understand the genetic background in TSC, with the involvement of the mTOR pathway, TSC is becoming a model to study epileptogenesis at the clinical, EEG, imaging and molecular level. This will lead to earlier, better and preventive treatment of epilepsy in TSC. Also, a better and more targeted approach for the frequent behavioral problems will become possible. LEARNING OBJECTIVES Following participation in this symposium, learners should be able to:

• More rapidly diagnose epilepsy in TSC by utilizing clinical, electrophysiological, imaging and molecular biomarkers.

• Describe the preventive treatment of epilepsy in TSC. • Develop optimal treatment strategies in TSC for epilepsy and behavioral problems. • Discuss the burden of epilepsy in TSC: drug-resistant epilepsy, intellectual disability and behavioral

problems. • Describe the relationship between medical data and intellectual disability and behavioral problems. • Delineate new treatment options for behavioral problems in TSC.

TARGET AUDIENCE Intermediate: Epilepsy fellows, epileptologists, epilepsy neurosurgeons, and other providers with experience in epilepsy care (e.g., advanced practice nurses, nurses, physician assistants), neuropsychologists, psychiatrists, basic and translational researchers. Advanced: Address highly technical or complex topics (e.g., neurophysiology, advanced imaging techniques or advanced treatment modalities, including surgery.) PROGRAM Co-Chairs: Jurriaan Peters, M.D., and Lieven Lagae, M.D. Introduction Jurriaan Peters, M.D. Natural History of Epilepsy in TSC Elizabeth Thiele, M.D. Intellectual Disability and Behavior in TSC Paolo Curatolo, M.D. Current Treatment Options for Epilepsy in TSC Darcy Krueger, M.D. Imaging and EEG Biomarkers for TSC Related Epilepsy

Imaging - Jurriaan Peters, M.D. EEG - Lieven Lagae, M.D.

Molecular Biomarkers in the Epileptogenesis of TSC

Michael Wong, M.D., Ph.D. Targeting Early and Preemptive Treatment of Epilepsy in TSC to Modify Neurological Outcome Sergiusz Jóźwiak, M.D. Conclusions Lieven Lagae, M.D. Education Credit 2.5 CME Credits Nurses may claim up to 2.5 contact hours for this session.

Pharmacy Credit Pharmacists: AKH Inc., Advancing Knowledge in Healthcare approves this knowledge-based activity for 2.5 contact hours (0.25 CEUs). UAN 0077-9999-16-091-L01-P. Initial Release Date: 12/5/16.

Commercial Support Acknowledgement Supported in part by educational grants from Lundbeck and GW Pharmaceuticals. FACULTY/PLANNER DISCLOSURES It is the policy of the AES to make disclosures of financial relationships of faculty, planners and staff involved in the development of educational content transparent to learners. All faculty participating in continuing medical education activities are expected to disclose to the program audience (1) any real or apparent conflict(s) of interest related to the content of their presentation and (2) discussions of unlabeled or unapproved uses of drugs or medical devices. AES carefully reviews reported conflicts of interest (COI) and resolves those conflicts by having an independent reviewer from the Council on Education validate the content of all presentations for fair balance, scientific objectivity, and the absence of commercial bias. The American Epilepsy Society adheres to the ACCME’s Essential Areas and Elements regarding industry support of continuing medical education; disclosure by faculty of commercial relationships, if any, and discussions of unlabeled or unapproved uses will be made. FACULTY / PLANNER BIO AND DISCLOSURES Lieven Lagae, MD, PhD, Chair and Faculty Full Professor Paediatric Neurology University Hospitals KULeuven Belgium Lieven Lagae is Full Professor at the University of Leuven, Belgium (KUL), Head of the Paediatric Neurology Department of the KUL University Hospitals. Lieven Lagae is the current President of the European Pediatric Neurology Society and serves as an elected Board Member of the International Child Neurology Association (ICNA). From 2004 to 2015, he was the Editor-in-Chief of the European Journal of Paediatric Neurology. Current epilepsy research projects include: 1. translational research in Zebrafish models of epilepsy; 2. new anti-epileptic drugs in childhood epilepsy; focus on Dravet syndorme and fenfluramine; 3. brain stimulation in childhood epilepsy; 4. preventive treatment of epilepsy in tuberous sclerosis complex; 5. EEG and non EEG based detection systems for seizures Dr. Lagae discloses receiving support for Consulting Fees (e.g., advisory boards): , Shire, UCB, Zogenix; Honoraria: , Zogenix

Jurriaan M. Peters, MD, PhD, Chair and Faculty Director of Computational Neurophysiology, Division of Epilepsy and Clinical Neurophysiology Boston Children's Hospital & Harvard Medical School Jurriaan M Peters, MD, PhD, Division of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital (BCH). Dr. Peters did his Medical School at the Catholic University in Leuven, Belgium, and pediatric neurology residency and clinical neurology fellowships at BCH. Currently he is an Assistant Professor of Neurology at Harvard Medical School, and serves as the site-director for the Clinical Neurophysiology Fellowship Program at at Boston Children’s Hospital. His research interests are computational neurophysiology, electrical source imaging, advanced imaging techniques for localization in epilepsy surgery, and Tuberous Sclerosis Complex. Dr. Peters discloses he has no financial relationships to disclose relevant to this activity. Paolo Curatolo, MD, Faculty Head Professor Tor Vergata University Hospital, Rome, Italy Paolo Curatolo is Head professor of Pediatric Neurology and Psychiatry, University of Rome Tor Vergata. His main areas of research are TSC, epilepsy, developmental disabilities, ASD, ADHD. He published over 300 articles in peer reviewed International Journals, and is on numerous editorial boards. He has been awarded with Manuel Gomez Award by Tuberous Sclerosis Alliance in 2015. He gave John Stobo Prichard Lecture at Hospital for Sick Children in Toronto in 2010. Actually responsible for the work package concerning neurodevelopmental evaluations in the EPISTOP project. He is Author of 3 monographs: Tuberous Sclerosis Complex: from basic science to clinical phenotypes, Cambridge University Press 2003; Neurocutaneous syndromes, John Libbey Eurotext, 2006; Malformations of the nervous system, Elsevier 2008. Dr. Curatolo discloses he has no financial relationships to disclose relevant to this activity. Sergiusz Jóźwiak, MD, PhD, Faculty Professor and Head, Pediatric Neurology INSTYTUT POMNIK-CENTRUM ZDROWIA DZIECKA, WARSZAWA, POLAND Sergiusz Jóźwiak, MD, PhD, Professor and Head, Pediatric Neurology, Warsaw’s Medical University, Poland Prof. Jóźwiak’s research focuses on neurocutaneous disorders and epilepsy, especially infantile spasms. In 2009 Prof. Jóźwiak received the Manuel Gomez Award established by Tuberous Sclerosis Alliance for "creative or pioneering efforts that have appreciably improved either the understanding of the disease or the clinical care available for individuals with tuberous sclerosis". He is a coordinator of the large-scale European Commission Project EPISTOP evaluating clinical and molecular biomarkers of epileptogenesis in a genetic model of epilepsy –tuberous sclerosis complex (www.EPISTOP.eu). Prof. Jóźwiak has published more than 300 papers in peer reviewed journals. Dr. Jozwiak discloses receiving support for Consulting Fees (e.g., advisory boards): UCB Pharma Darcy A. Krueger, MD, PhD, Faculty Associate Professor, Clinical Pediatrics and Neurology Cincinnati Children's Hospital Medical Center Dr. Krueger is Director of the Tuberous Sclerosis Clinic, Associate Professor of Clinical Pediatrics and Neurology, and Associate Director of Research in Neurology at Cincinnati Children’s Hospital Medical Center. He also was a founding member of the Tuberous Sclerosis Complex Clinical Research Consortium and served as its first director from 2011 to 2013 and continues as a member of its Senior Advisory Board. Active preclinical, translational, and clinical research projects are aimed at better understanding the underlying molecular mechanisms involved in TSC disease pathogenesis and treatment outcomes.

Dr. Krueger discloses receiving support for Consulting Fees (e.g., advisory boards): Novartis Pharmaceuticals; Contracted Research: Novartis Pharmaceuticals, Upsher-Smith Laboratories; Honoraria: Novartis Pharmaceuticals Elizabeth A. Thiele, MD, PhD, Faculty Director, Pediatric Epilepsy Program Massachusetts General Hospital Dr. Thiele discloses receiving support for Consulting Fees (e.g., advisory boards): Eisai, GW Pharma, Zogenix; Contracted Research: GW Pharma, Zogenix Michael Wong, PhD Professor of Neurology Washington University School of Medicine My name is Jennifer Wong, Ph.D., and I am a postdoctoral research fellow at Emory University. I joined the Escayg laboratory (July 2013) shortly after receiving my doctorate in Neuroscience from the University of Georgia (May 2013). My long-term research goal is to develop more efficacious treatments for refractory forms of epilepsy and associated comorbidities. Dr. Wong discloses receiving support for Contracted Research: GW Pharma, Novartis Pharmaceuticals CME REVIEWERS Juliann Paolicchi, MD, MA, Reviewer Juliann M Paolicchi, MA, MD, FANA is the Director of Pediatric Epilepsy for New York for the Northeast Regional Epilepsy Group, a multi-disciplinary both private and academic based epilepsy group. She is a Clinical Professor of Pediatric Neurology at Rutgers University Medical Center. Dr. Paolicchi is boarded by the ABPN in Neurology with Special Qualifications in Child Neurology, Epiilepsy, and Clinical Neurophysiology. She has published extensively in research focusing on outcomes in clinical pharmacology, clinical neurogenetics, and surgical outcomes in pediatric epilepsy. She has served as the Director of several academic Pediatric Epilepsy Programs at Ohio State, Vanderbilt, and Weill Cornell Universities, and is a regular faculty speaker at the Kiffen Penry Epilepsy Program at Wake Forest University. Dr. Paolicchi discloses receiving support for Contracted Research: GW Pharma, Zogenix; Honoraria: LivaNova, Lundbeck Courtney Wusthoff, MD, MS Courtney Wusthoff, MD, MS is an Assistant Professor of Neurology and Pediatrics (Neonatal and Developmental Medicine) at Stanford University. She also is the Neurology Director of the Stanford Children’s Neuro-NICU, which provides care for newborns with or at risk for neurologic problems. Clinically, she specializes in treatment of seizures and epilepsy for newborns and infants, as well as in ICU EEG. Her research interests include neonatal seizures and EEG. Dr. Wusthoff discloses she has no financial relationships to disclose relevant to this activity. PHARMACY/NURSE PLANNERS Gigi Smith, PhD, RN, CPNP-PC: No financial relationships to disclose relevant to this activity. Dorothy Duffy, PharmD: No financial relationships to disclose relevant to this activity.

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11/28/2016

1

Tuberous Sclerosis Complex : understanding and modifying

epileptogenesis‐‐ Introduction ‐‐

Jurriaan M Peters, MD, PhDBoston Children’s Hospital & Harvard Medical School

Disclosures

None

Learning Objectives

• Obtain an overview of today’s Pediatric State of the Art Symposium

• Understand advances in rapidly changing field

Historical Note

Historical Note

1862 1880 1890

Tuberous Sclerosis ComplexRare genetic neurocutaneous disorder1 in 6,000 live births, 1 million people worldwideOver 50,000 in the United States.

Hamartomas in brain, heart, skin, eyes, kidney, lung, and liver – in brain a.k.a. tubers

Neurological involvement:1 – Epilepsy ~85% lifetime prevalence2 – Cognitive impairment3 – Autism ~ 50% ASD

Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008; 372:657–668.

11/28/2016

2

TSC Pathway

AMP

AMPK

Energy Level

TSC2

TSC1

Akt

Growth Factors

S6 Protein synthesis

Cell growth

mTOR S6K

rheb

Slide adapted from Mustafa Sahin

Line up

Elizabeth Thiele: Natural history of epilepsy in TSC

Paolo Curatolo: Intellectual disability, epilepsy and behavior in TSC

Darcy Krueger: Current treatment options for epilepsy in TSC

Lieven Lagae EEG and imaging biomarkers for TSC related epilepsy& Jurriaan Peters:

Michael Wong: Molecular biomarkers in the epile ptogenesis of TSC

Sergiusz Jozwiak: Targeted, early and preemptive treatment of epilepsy in TSCto modify neurological outcome

How does it all come together?

Molecular deficits Animal models

Imaging

Neurophysiology

DevelopmentAggressive, early & targeted drug interventions

Human biomarkers: risk stratification, predictionand monitoring

VigabatrinmTOR inhibitors

EpilepsyAutism

BehaviorCognition

Patients with TSC

#AES2016

TSC: The natural history of epilepsy

Elizabeth A. Thiele, MD, PhDDirector, Herscot Center for Tuberous Sclerosis Complex

Director, MGH Pediatric Epilepsy Program

Professor of Neurology, Harvard Medical School

TSC: The natural history of epilepsy

• Overview of TSC» TSC and the brain

• Natural history of epilepsy in TSC

• And how does the epilepsy relate to other aspects of neurologic phenotype?» Cognitive profiles in TSC

» Autism in TSC

» TSC associated neuropsychiatric disease (TAND)

TSC: What we know….

• Incidence of 1: 5500 (not rare)

• Autosomal dominant disorder; 2/3 cases sporadic

• 2 genes: TSC1 (hamartin) and TSC2 (tuberin)

• Identifiable TSC1 or TSC2 mutation in 85% with TSC» TSC2 mutations are more common (6:1)

» TSC2 mutations have a more severe phenotype

• Multisystem disorder; affects most organ systems

• Wide phenotypic variability, including within families

• Gender somehow matters: e.g. LAM in women

• TSC1/TSC2 components of mTOR signaling pathway

TSC and the brain

• CNS involvement is a hallmark of the disease, and is seen in 95% of affected individuals

• Pathologic features» cortical tuber

» subependymal nodule (SEN)

» subependymal giant cell tumor (SGCT)

» radial glial lines

TSC: CNS pathology TSC CNS involvement: Cortical tubers

• Located at the gray white junction

• Vary widely in size and distribution

• Histology:» Marked distortion of cortical lamination

» Dysplastic, hypomyelinated aggregates of abnormal glial and neural elements

» Glial derived cells and astrocytes predominate

» Giant cells: enlarged, bizarre-appearing neurons or large cells with both neuronal and glial characteristics

» Neurons lack axons and normal dendrites (but stain for neuronal markers)

TSC: Cortical tuberTuberous Sclerosis ComplexNatural history of epilepsy

• MGH Herscot Center retrospective review:» 85% of population with history of seizure (249/291)

– all but 2 developed epilepsy

» 63% with seizure onset first year of life

» 54% develop multiple seizure types

» 6% with definite Lennox Gastaut syndrome; 21% probable– 63% with h/o infantile spasms

Chu-Shore et al, Epilepsia2009

Tuberous Sclerosis ComplexEpilepsy overview

• “Natural history” of epilepsy in TSC at Herscot Center» 63% with medically refractory epilepsy (155/291)

» 34% (81/242) achieved remission (range 12 mo-51.6yr)– 1/3 of these with prior refractory epilepsy

– 38% of these off ACD at last visit

Chu-Shore et al, Epilepsia 2009

Tuberous Sclerosis ComplexNatural history of epilepsy

• Herscot Center retrospective review: Infantile spasms» 38% with history of infantile spasms(110/291)

– 2 with IS as only seizure phenotype

– 75% with subsequent refractory epilepsy

Chu-Shore et al, Epilepsia2009

Tuberous Sclerosis ComplexInfantile spasms

• Herscot Center retrospective review: Infantile spasms» 45 patients with h/o TSC, IS, available EEG

» 24% with IQ>70

» Lower IQ associated with:– Higher hypsarrhythmia score on EEG

– EEG background disorganization

– Absence of normal sleep EEG patterns

– Lack of treatment success with vigabatrin

» Detection and successful treatment important variables in favorable outcome

»Muzykewicz et al Epilepsia 2009

Tuberous Sclerosis ComplexInfantile spasms

• Herscot Center retrospective review: Epileptic spasms» 19/391 (4.8%) patients with TSC with epileptic spasms

– 6 with persistance of IS >2yr

– 6 with recurrence of spasms after IS remission

– 4 with new onset spasms > 2 years (range 2-20)

» TSC2 mutations > TSC1 mutations

» 6/19 seizure free with medications– 4 with vigabatrin, 1 with vigabatrin and LGIT, 1 with felbamate

» 5/19 spasm free after epilepsy surgery

Heish et al, Epil Res 2013

Tuberous Sclerosis ComplexEpilepsy overview

• “Natural history” of epilepsy in TSC at Herscot Center» Effect of genotype:

– Infantile spasms more common with TSC2 mutation *But central TSC2 mutations lower risk of IS (van Eeghen et al, Epil Res

2012)

– TSC1 = TSC2 = NMI for % with epilepsy, intractability

– NMI more likely to achieve remission


Treatment of epilepsy in TSCin 2016 and beyond

• Anticonvulsant medications remain first line therapy» Partial onset seizures, so most medications could work

– Anecdotal experience on efficacy, particularly of new drugs

– No controlled comparison trials

» Vigabatrin drug of choice for infantile spasms in TSC– But: possible retinopathy

– And: possible MRI signal change in deep gray nuclei

• But what when medications don’t work?» Dietary therapy

» Vagus nerve stimulation

» Epilepsy surgery

• And what about mTOR inhibitors? cannabidiol?

Dietary therapy of epilepsy:does dietary treatment “work” in TSC?

• Classic ketogenic diet (Kossoff et al, Epilepsia 2005)

• Low glycemic index treatment:» MGHfC retrospective study of 15 TSC patients started on LGIT

– Average age 8.5 yrs (1.8-20.9 years)

– Average age of seizure onset 8.2 mo

– 14/15 with medically refractory epilepsy at time of diet initiation

– Duration on diet 0.7-55 mo, average 16 mo

» 10/15 had >50% reduction in seizure frequency on LGIT– 1/15 became seizure free

– 2/15 with >90% reduction

– 7/15 with 50-90% reduction

– 5/15 <50% improved

Larson et al, Epil Res 2011

Dietary therapy of epilepsy:TSC case history

• 23 mo old boy with TSC» Seizure onset at 6 mo with IS, 8.5 mo partial seizures

» Refractory to 3 ACDs, scheduled for invasive monitoring and resective surgery

» On OXC and ZNG, having 3-4 seizures per day

• Seizure free after 20 days on LGIT» Tapered off of ACD by 11 months on diet

» Tapered off of LGIT after 16 months and normal EEG

• Seizure free now over 4 years off diet» Normal/precious development, on no medications


• Vagus nerve stimulation» Limited experience, but likely effective although not

a cure

» At least 50% will experience > 50% reduction in seizures

» Also possible improvements in quality of life and adaptive behaviors

– Parain et al 2001, Major et al 2008, Elliot et al 2009, Zamponi et al 2010


• Epilepsy surgery» Increasing experience, “comfort” and success

… and a possible “cure”

» But “who, what, when, where and why”?

» What is the ideal way of identifying the “hot” tuber?– EEG? MEG?

– Alpha methyl tryptophan PET?

– Coregistration of MRI, PET and MEG?

– SPECT?

» And what about the other tubers?– But, seizure control can be long term

Tuberous Sclerosis Complex:What we need to know

• Why seizures?

• Are tubers epileptogenic, or irritating to neighboring neurons?

• Are all tubers created equal? Are some more epileptogenic than others?

• Is epileptogenicity related to diffuse and/or more subtle cortical or subcortical abnormalities?

• Are particular individuals with TSC at risk for seizures?

8 year old girl with TSC: tuber burden, and cystic changes on MRI

TSC: what are cyst-like tubers,and do they matter?

• Retrospective study of 173 TSC patients with MRI

• 46% had at least one cyst-like tuber

» TSC2 > TSC1 (p=0.002)

» More common in patients <18 yr (p=0.00006)

» No association with gender

Chu-Shore et al, Neurology, 2009

TSC: what are cyst-like tubers,and do they matter?

• Cyst-like tubers somehow related to epilepsy» More common in those with infantile spasms (p=0.00005)» More common in those with epilepsy (p=0.0038)» More common in those with refractory epilepsy (p=0.0007)

• But is this a primary or secondary effect?

• And what is relationship to tuber type?

• And what about subgroup of very young children with diffuse rapid cystic progression of multiple tubers?


TSC CNS involvement: Multifocal cyst-like tubers What do calcified tubers mean?

Calcified tubers:What are they, and what do they mean?

• 18 year old girl, TSC1 splice site mutation» h/o infantile spasms

» h/o refractory epilepsy, “constant” seizures

» MRI with multiple cortical tubers including L frontal tuber which became calcified around 4 yr of age

• Epilepsy surgery 12/09 due to refractory seizures» Resection of L frontal calcified tuber

» Pathology of tuber

Gallagher A et al. Neurology 2011;76:1602-1604

Gallagher A et al. Neurology 2011;76:1602-1604

TSC: Epilepsy, Cognition and Behavior

• And, it is not just the seizures!

• Presence of refractory epilepsy and infantile spasms in TSC is significantly associated with:» Cognitive impairment

» Autism spectrum disorders

» Psychiatric disorders, including self injurious behaviors

» Sleep disorders

• Therefore, crucial to control epilepsy!Van Eeghen et al, Epil Behav 2010,

Numis et al, Neurology 2010, Chu-Shore eal, Epilepsia 2009Winterkorn et al, Neurology 2007, Muzykewicz et al Epil Behav 2007,

Kopp et al Epil Behav 2007, Staley et al Epil Behav 2008 ,

Cognitive profiles in TSC

• 107 of 208 patients seen had neuropsychological testing at MGH» Demographics of “study group” similar to overall clinic group,

except that study group had younger age, IS more common

• IQ/DQ scores approximated a bimodal distribution with means of 93 (± 16) and 44 (± 25)

» Roughly 50:50 split between two modes

0

2

4

6

8

10

12

14

16

<10 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99 100-109

110-119

>=120

DQ/IQ

Patients

Observed

Expected (high)

Expected (low)

Winterkorn et al, Neurology 2006

Cognitive profiles in TSCSignificant variables in outcome

• Higher IQ/DQ: » Older age at seizure onset

– Of patients with seizure onset >2.5 years (n=18), none with IQ/DQ<70

» Familial TSC– Although also higher TSC1, lower frequency of IS and refractory

seizures

• Lower IQ/DQ: » Current seizure activity

» Refractory seizures and mixed seizure types

» TSC2 mutation

Autism in TSC

• Herscot Center retrospective study; single neuropsychologist evaluation

• 41/103 (40%) with ASD

• Those with ASD:» Significantly more likely to have TSC2 mutation

» Significantly more likely to have h/o IS, refractory epilepsy

» Significantly lower IQ (51 vs 81)

» Not more likely to be male

» Not significant difference in TSC related brain involvement

Numis et al, Neurology 2011

TSC and Autism spectrum disorders:Relationship to anatomic features

• No significant difference between regional distribution of largest sized tuber or of overall tuber burden» Trend for TSC/ASD patients to have their largest tuber

burden (but not largest sized tuber) in L temporal lobe

• No difference between cerebellar tubers, calcified tubers, radial glial bands or subependymal nodules

• Significantly higher incidence of cyst like tubers

Autism in TSC:Does the genetic mutation matter?

• Mutational analysis:» Fewer TSC1 mutations in TSC/ASD group

than TSC without ASD

» TSC2 mutations common!– Present in 90% of TSC/ASD patients vs 59% w/o ASD

» no significant difference regarding mutation type, or truncating vs non-truncating

» ? Relationship to ASD and mutation in hamartin interaction domain of TSC2 (found in 28% of TSC/ASD patients compared to 5% without ASD)

Autism in TSC:Relationship to epilepsy

• Seizure history of patients with TSC/ASD:» Epilepsy more common

» Prior infantile spasms more common

» Earlier age of seizure onset

» Greater seizure frequency

» Higher incidence of refractory epilepsy

• EEG with greater epileptiform features in those with ASD, particularly left temporal lobe

Herscot Center for TSC:TSC Associated Neuropsychiatric Disorders

• 66% have at least one psychiatric symptom» 37% have greater than one symptom» Most common: mood disorders, anxiety, ADHD, aggressive,

disruptive behaviors

• Adults with TSC at much greater risk of psychiatric disorders than general population (SCL-90)» Main difficulties: interpersonal sensitivity, social alienation,

depression, cognitive performance

• Self injurious behavior in 10%» Highly associated with TSC2 mutation, history of IS, sz,

cognitive impairment and autism

Muzykewicz et al, Epilepsy Behav. 2007Pulsifer et al, Epilepsy Behav, 2007Staley et al, Epilepsy Behav, 2008

And what can genotype tell us?

• TSC2 mutations usually more severe phenotype

• But maybe more?» ? Relationship to Autism spectrum disorders and mutations in

hamartin interaction domain of TSC2 Numis et al, Neurology 2011

» Cognitive phenotype– Protein truncating mutations in TSC2 associated with lower IQ– Missense and small in-frame deletions in TSC2 associated with

higher IQ Location of missense mutation might also matter

» Mutations near HID or GAP domain more impairedvan Eeghen et al, EJHG 2011

The Neurology of TSC:Epilepsy, Cognition, and Behavior

• Tubers

• Seizures

• Interictal discharges

• Genotype

• Role of haploinsufficiency?

• Cognition

• Behavioral / psychological issues

• Autism

What are the relationships between

10/16/16

1

Intellectualdisability, behaviorandepilepsy intuberoussclerosis

Professor Paolo CuratoloDirector, Pediatric Neurology and Child Psychiatry UnitTor Vergata University of Rome, [email protected]

Tuberous Sclerosis Complex

• Oneofthe “mTORopathies”• Epilepsyin72-85%– Onsetbefore1yearofagein67%ofcases– Neonatalonsetin5.7%ofepilepticpatients– Infantilespasmsin38%– Drugresistantseizuresin2/3ofcases

• Intellectual disability in50%• ASDin40-50%

Chu-Shoreetal,Epilepsia2010;Kotulskaetal,EJPN2014;Curatoloetal,LancetNeurol2015

1 5

1. Bombardieri R et al. Eur J Ped Neurol. 2010;14:146-149.2. Cusmai R et al. Epilepsy Behav 2011;22:735-739.3. Jóźwiak S et al. Eur J Ped Neurol. 2011;15:424-431.

Treatment initiation and Intellectual Disability

• Some clinical studies suggest a correlation between early drugtreatment, early seizurecontrol andbetter cognitive outcome 1-3

Curatolo P et al, EJPN 2015

Dysregulated mTORSignaling IsConnected toNeuropathology andNeurological Phenotypes inTSC

• Dysplastic neurons• Giant cells• Abnormally shaped

astrocytes

• Cortical tubers• Epilepsy• SENs

• Disruption in dendritic spines

• Intellectual disability

• Autism

• Loss of 6-layered cortical structure

• Abnormal dendritic arborization

• Abnormal cortical lamination

• Cortical tubers• SEGAs• Epilepsy

Abnormal neuronal morphology

Increased growthand proliferation

Reduced autophagy and apoptosis

Abnormal migration and or ientation

Ion channels/neurotransmitter

receptorsSynaptic plasticity

Dysregulated mTOR Signaling in Brain

• ê GABAergic inhibition

• é Glutamatergic excitation

Napolioni etal. Brain &Dev 2009; Curatolo et al,JCN 2010; Aronica et al,2012; Curatolo et al.Pediatr Neurol 2015

• Cortical tubers• Epilepsy• Autism• Neurocognitive

impairment• Social dysfunction

• Cortical tubers• Epilepsy• Neurocognitive impairment• White matter abnormalities

mTO Ri / ot her???

TSC2TSC gene mut at i on

mTO R act i vat i on

Di srupt i on i n dendri t i c spi nes

Abnormal synapt ogenesi s

Abnormal connect i vi t y

Abnormal neurot ransmi ssi on

Sei zures

I nt el l ect ual di sabi l i t y,

aut i sm

Bi rt h

6 mont hs

12 mont hsmTO Ri

mTO Ri

VG B

EXI ST- 3

Tri al s ongoi ng

Precl i ni cal dat a

A Critical Time Window May Exist in Using Targeted Therapy to Prevent Seizures and Developmental Delay

mTOR, mammal ian target o f rap amycin ; mTOR i ; mTOR inh ib i to r;TSC , tuberou ssclero sis comp lex; VGB ,vigabatrin .

Adap ted with p ermission fromCu rato lo P etal . Eu r JP a ed ia tr Neu ro l . 2 0 1 6 ;2 0 :2 03 -2 11 .

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Current Treatment Options for Epilepsy in TSC

Darcy A. Krueger, MD PhDDirector, Tuberous Sclerosis Clinic

Cincinnati Children’s Hospital Medical CenterCincinnati, Ohio, USA

Disclosure

Novartis Pharmaceuticals

Upsher‐Smith Laboratories

Learning Objectives

• Review currently available treatments for epilepsy in TSC

• Present building clinical evidence for treating epilepsy in TSC with mTOR inhibitors

CNS manifestations of TSC: Epilepsy

NoEpilepsy

Epilepsy(Infantile Spams)

Epilepsy(No Infantile Spasms)

Mullen Scales of Early Learning6 Months 12 Months 18 Months 24 Months

Epilepsy

No EpilepsyChu‐ShoreCJ et al. Epilepsia. 2010;51:1236‐1241.Jóźwiak S et al. J Child Neurol. 2000;15:652‐659.Capal JK et al., TACERN Study Group

Anticonvulsants for treatment of epilepsy in TSC

AED NEffective

YesEffective

No% Refractory Reference

Topiramate 14 9 5 36% Franz 2000

Lamotrigine 57 45 12 21% Franz 2001

Levetiracetam 29 14 15 52%Franz 2001Collins 2006

Oxcarbazepine 16 11 5 31% Franz 2001

Clobazam 29 20 9 31% Jennesson 2013

Lacosamide 46 22 24 52% Geffrey 2015

TOTAL 191 121 70 37%

Vigabatrin for infantile spasms in TSC

Hancock Responders Nonresponders

TSC (N=77) 73 (95%) 4 (5%)Non‐TSC (N=313) 169 (54%) 144 (46%)Total (N=390) 242 (62%) 148 (38%)

Camposano Responders Nonresponders

TSC (N=42) 31 (74%) 11 (26%)Non‐TSC (N=26) 7 (27%) 19 (73%)Total (N=68) 38 (56%) 30 (44%)

Hancock E, Osborne JP. 1999. J Child Neurol 14:71‐4Camposano et al. 2008. Epilepsia 49:1186‐91

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Fallah A et a. (2015) Neurosurgery 77(4):517‐24

N=74

HR = 2.9095%CI = 1.17 – 7.18P = 0.022

Epilepsy surgery for TSC refractory epilepsy Other non‐pharmacologic treatments for epilepsy in TSC

• Ketogenic diet– 7/15 (47%) responders @ 6 months (Larsa 2012)– 11/12 (92%) responders @ 0.2‐5 years (Kossoff 2005)

• Vagus‐nerve stimulation– 8/11 (72%) responders @ 12 months (Zamponi 2010)

– 10/19 (53%) responders @ 0.7‐9.6 years (Elliott 2009)– 10/16 (63%) responders @ 0.5‐8.6 years (Major 2008)

2012 International TSC Consensus Group Recommendations for the Diagnosis and Treatment of TSC

www.tsalliance.org/consensus

2012 International TSC Consensus Recommendations:

Epilepsy

• In newly diagnosed patients– Detailed seizure history/parent education

– Routine EEG at baseline to assess for subclinical seizures

– Prolonged (24h) EEG in patients with TAND features or spells of uncertain etiology

• In patients already diagnosed with definite or possible TSC– Routine or prolonged (24h) EEG as clinically needed

– Vigabatrin as first line agent for treatment of infantile spasms; ACTH as second-line therapy.

– Treatment for other types of seizure follow that of other epilepsies

– Epilepsy surgery referral appropriate at recommended early, especially when TAND features are present

Brain: Cortical dysplasias (e.g. tubers), subepenymal nodules, SEGA

Lung: LAM Kidney: Angiomyolipomas, cysts

Eye: Retinal hamartomas

Heart: Rhabdomyoma

Skin: Hypopigmentedmacules, facial

angiofibromas, plaques, fibromas, Shagreen patch

Clinical Manifestations of TSC Throughout the Body Major TSC clinical trials targeting mTOR in TSC

2002 2010 20142006

Everolim

us

Open‐label

Blinded/Placebo

SEGA

AML/LAM*

Neurocognition

Epilepsy

Sirolim

us

*FDA Indication in TSC

Angiofibromas

SEGA*

AML*/LAM

Neurocognition

Epilepsy

Angiofibromas

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Mechanisms of Epileptogenesis in TSC

Energy/Nutrient Deprivation

LKB1

TSC1TSC2

S6K

PI3K

STRADᵅ AMPK

Rheb

mTORC1

Akt PTEN

4E‐BP1

Ribosomal S6 eIF4E

Insulin/Nutrient Stimulation/IGF

Abnormal cell development

Cortical dysplasia

EpilepsyFocal deficits

Cognitive impairment

Neuronal excitability

Synapse/membrane remodeling

mTOR Pathway in TSC Seizures1‐5

IGF, insulin-like growth factor.

1. Ryther RCC, Wong M. Curr Neurol Neurosci Rep. 2012;12:410-418. 2. Curatolo P. Pediatr Neurol. 2015;52:281-289. 3. Wong M, Roper SN. J Neurosci Methods. 2016;260:73-82. 4. Saxena A, Sampson JR. Semin Neurol. 2015;35:269-276. 5. de VriesPJ. Am Soc Exp Neurotherapeutics 2010; 7L275-282.

mTORC1 inhibitors to treat SEGA

aDefinitive diagnosis per modified Gomez criteria or a positive genetic test.bUpon completion of the core phase, patients can continue to receive everolimus if evidence of therapeutic benefit.

NCT00411619

N=28

• ≥3 years of age with TSCa

• Serial SEGA growth (≥2 MRI scans)

• No signs of cerebral herniation or critical hydrocephalus

Extension phaseb

(n=27)

6-month core phase

Everolimus 3 mg/m2/day,

titrated to target trough 5−15 ng/mL

(n=28)

Primary analysis(data cut-off

December 9, 2009)

≥2-year analysis(data cut-off

December 31, 2010)

Study completion (LPLV) January 28, 2014

End of core phaseJune 18, 2009

≥4-year analysis(data cut-off

December 12, 2012)

EVEROLIMUS FOR SEGA: PHASE I/II

Everolimus Reduces Seizures in TSC Patients Treated for SEGA

Krueger et al. New Engl J Med. 2010

• Patients with daily seizures,by caregiver observation:– Baseline: 7/26 (27%) – Month 6: 2/25 (8%)– Month 12: 1/25 (4%)

• Change in seizure frequency at 6 months by video EEG:

• Decreased in 9/16 (56%) • No change in 6/16 (38%)• Increased in 1/16 (6%)

6.30

2.75

0

2

4

6

8

10

No. of Events

Everolimus Reduces Seizures in TSC Patients Treated for SEGA

Krueger et al. New Engl J Med. 2010

mTORC1 inhibitors to treat SEGA

Franz et al. Lancet. 2013

EVEROLIMUS FOR SEGA: PHASE III (EXIST‐1)Key eligibility requirements:

• At least one SEGA lesion ≥ 1 cm in longest diameter

• At least one of the following:• Serial radiologic evidence of

SEGA growth• New SEGA lesion measuring

≥ 1cm• New or worsening

hydrocephalus

• Patients enrolled irrespective of age

Progression (n=6)

Placebo (n=39)

Everolimus (n=78)

Initial dose 4.5 mg/m2/day and adjusted to target trough level of 5‐15 ng/mL as tolerated

Randomization

(2:1)

Everolimus for Epilepsy in TSCEXIST-1 SEGA Trial Results

Everolimus Placebo

Baseline Week 24 Baseline Week 24

All patients n = 78 n = 39

Seizures/24 hours: median (range) 0.0(0 – 42.6)

0.0(0 – 31.6)

0.0(0 – 78.9)

0.0(0 – 91.5)

Change from baseline: median (95% CI) 0.0(0.0, 0.0)

0.0(0.0, 0.0)

p = 0.2004

Patients with ≥ 1 seizure at baseline n = 24 n = 11

Seizures/24 hours: median (range) 5.9(1.0 – 42.6)

3.99(0 – 31.6)

11.0(1.0 – 78.9)

6.8(1.0 – 91.5)

Change from baseline: median (95% CI) ‐2.9(‐4.0, ‐1.0)

‐4.1(‐10.9, +5.8)

p = 0.2988

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Krueger et al. Annals Neurol 2013; Krueger et al. Neurology 2016

EVEROLIMUS EFFECT ON SEIZURES: Phase I/II

mTORC1 inhibitors to treat Epilepsy in TSC

Baseline Titration Maintenance Extension1,2

4 weeks 4 weeks 8 weeks 0 – 48 months

Physical exam23-hr video EEG

Seizure diaryQuality of life

Nisonger CBRFSafety LabsAED levelsBiomarkers

Physical examSeizure diarySafety Labs

Everolimus level AED levelsBiomarkers

Physical exam23-hr video EEG

Seizure diaryQuality of life

Nisonger CBRFSafety Labs


Physical examSeizure diaryQuality of life








Everolimus level AED levels

Initial dose = 5 mg/m2/dayInitial dose = 5 mg/m2/dayAdjust dose if needed for

target trough level 5-10 ng/mlAdjust dose if needed for

target trough level 5-10 ng/ml

1Extension phase participation optional for qualifying subjects (responders and near-responders). 2Adjustment of concurrent AED regimen permitted in extension phase only.

Initiated Treatment(n=20)

Completed Main Study (n=20)

Entered Extension Phase (n=18)

Extension Phase – 1YR(n=17)




12 (60%)

4 (20%)

≥ 50% Seizure Reduction

25‐49% Seizure Reduction

13 (76%)

1 (6%)



12 (75%)

2 (13%)



12 (80%)

2 (13%)



13 (93%)

0 (0%)



Lost efficacy (month 10)



Withdrew (month 40)

Krueger et al. Annals Neurol 2013; Krueger et al. Neurology 2016



Krueger et al. Ann Neurol, 2013Krueger et al. Neurology 2016

Individual Response (n=20)

‐100%

‐50%

0%

50%

100%

p = 0.006

0

20

40

60

80

100

120

Week 1-4 Week 5-8 Week 9-12 Week 13-16Baseline Titration Maintenance

p<0.05

p<0.05

Grouped Response (n=20)

Percent C

hange in

Seizures

Total Seizures



Krueger et al. Ann Neurol, 2013Krueger et al. Neurology 2016

Ave

rag

e S

eizu

res

per

Mo

nth

Months Treatment in Extension Phase

0 12 24 36 48-20

0

20

40

60 p<0.001



French JA et al. Lancet, 2016

• Patients aged 1‐65 years with definitive diagnosis of TSC

• Minimum16 treatment‐resistant seizures in 8‐week baseline

• 1‐3 AEDs at stable dose for ≥4 weeks prior to baseline phase

• Patients aged 1‐65 years with definitive diagnosis of TSC

• Minimum16 treatment‐resistant seizures in 8‐week baseline

• 1‐3 AEDs at stable dose for ≥4 weeks prior to baseline phase

AEDs + Placebo (n=119)

AEDs + Placebo (n=119)

AEDs + Everolimus 3‐7 ng/mL (n=117)




Seizure Count (diaries)Seizure Count (diaries)

Stable dose of AEDsStable dose of AEDs

6‐week Titration Perioda

(3 pre‐dose blood samples collected biweekly to determine everolimus

Cmin)

12‐week Maintenance Period

18‐week Core Phaseb18‐week Core Phaseb8‐week Baseline Phase8‐week Baseline Phase

AEDs, anti‐epileptic drugs; TSC, tuberous sclerosis complex. aDose was titrated via Interactive Response Technology (IRT) in a blinded fashion until each patient reached his/her target Cmin range. bEverolimus Cmin levels were measured at weeks 1, 3, 5, 10, 14, and 18 of the core phase. Additional pharmacokinetic blood samples were collected 2 weeks after any change in the dose of study medication, or change in use of concomitant CYP3A4/PgP inhibitors or inducers. After completion of the core phase, patients entered into the extension phase and received everolimus.

Randomization

Randomization

EVEROLIMUS EFFECT ON SEIZURES: Phase III (EXIST‐3)

mTORC1 inhibitors to treat Epilepsy in TSCEVEROLIMUS EFFECT ON SEIZURES: Phase III (EXIST‐3)



Error bars denote 95% confidence intervals.

50% responder ratePercentage reduction from baseline in seizure frequency

15.1

28.2

40

0

10

20

30

40

50

60

Response rate, %

P < 0.001

P = 0.008

Placebo

EverolimusLow

exposure(3‐7

ng/mL)

Everolimus High

exposure (9‐15 ng/mL)

14.9

29.3

39.6

0

10

20

30

40

50

60

Red

uction in

seizure frequen

cy, %

P = 0.003

P < 0.001

Placebo

EverolimusLow

exposure(3‐7

ng/mL)

EverolimusHigh

exposure(9‐15 ng/mL)

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14.9

20.6

35.6

39.7

47.7

0

10

20

30

40

50

60

70

Med

ian

% r

educ

tion

from

bas

elin

ein

sei

zure

freq

uenc

y

Placebo <3 3-7 >7-<9 9-15

Time-normalized everolimus Cmin, ng/mL



• aReactivation, aggravation, or exacerbation of any pre-existing infection was reported in 1 patient in the placebo group; 1 patient in the everolimus high-exposure group reported noninfectious pneumonitis.

AE (all grades), %Placebo (n = 119)

Everolimus low exposure(n = 117)

Everolimus high exposure

(n = 130)

Stomatitis 3.4 28.2 30.8

Diarrhea 5.0 17.1 21.5

Mouth ulceration 4.2 23.9 21.5

Nasopharyngitis 16.0 13.7 16.2

Upper respiratory tract infectiona 12.6 12.8 15.4

Aphthous ulcer 1.7 4.3 14.6

Pyrexia 5.0 19.7 13.8

Cough 3.4 11.1 10.0

Vomiting 9.2 12.0 10.0

Rash 2.5 6.0 10.0





Hematologic and biochemical AEs (regardless of suspected relationship to study medication) in ≥20% of patients

AE (all grades), %Placebo (n = 119)

Everolimus low exposure(n = 117)

Everolimus high exposure

(n = 130)

Hypercholesterolemia 58.0 85.5 85.4

Hypercalcemia 67.2 60.7 55.4

Hypertriglyceridemia 21.8 42.7 38.5

Neutropenia 22.7 24.8 36.9

Hypermagnesemia 41.2 43.6 33.8

Low hemoglobin 21.0 26.5 30.0

Hypocalcemia 23.5 22.2 30.0

Hypernatremia 24.4 23.9 24.6 Increased creatinine 25.2 20.5 24.6

Leukopenia 17.6 13.7 24.6

Elevated ALT 5.9 17.1 22.3

Lymphocytosis 16.0 31.6 17.7

Elevated alkaline phosphatase 28.6 23.9 16.2

Conclusions

• Epilepsy has high prevalence and high morbidity in TSC

• Epilepsy is often highly refractive to conventional anticonvulsants in TSC (except vigabatrin for IS)

• Consensus guidelines provide framework for evaluation and management of each organ potentially involved in TSC

• mTORC1 inhibition with everolimus has shown beneficial effects for treatment of refractory epilepsy in TSCmTORC1=mammalian target of rapamycin complex 1; TSC = tuberous sclerosis complex

Conclusions: Impact on Clinical Care

• Epilepsy has high prevalence and high morbidity in TSC• Epilepsy is often highly refractive to conventional anticonvulsants in TSC (except vigabatrin for IS)

• Consensus guidelines provide framework for evaluation and management of each organ potentially involved in TSC

• mTORC1 inhibition with everolimus has shown beneficial effects for treatment of refractory epilepsy in TSC

#AES2016

11/28/2016

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EEG tracking of epileptogenesis in TSC patients

Lieven LagaePaediatric Neurology

University of Leuven, Belgium

Disclosures L. Lagae

Speakers honoraria, advisory boards and consultancy :Shire, Zogenix, Livanova, UCB, Novartis

Learning objectives

• Understand the contribution of EEG parameters in epileptogenesis• Explain how TSC is a perfect human model for studyingepileptogenesis

• Decribe the benefits of standardisation of EEG epileptic abnormalities

Neuroscientist 2005

In (some) animal models:

‐ spikes occur before onset of clinical seizures

‐more spikes : more seizures

Staley et al, Neurosc Lett, 2011 Reid AY et al, Epilepsia 2016

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West syndrome : focal spikes and fast activitybefore onset of spasms

Epilepsy in Tuberous Sclerosis Complex

Chu‐Shore et al, Epilepsia 2010, Curatolo et al, 2015

TSC : High frequency of epilepsyand early onset

• Prospective study in TSC < 7 months, seizure free and on no AED• Regular video EEG

• > 12 months : 68 % epilepsy (epileptic spasms, focal seizures)• first EEG abnormalities : 4,2 months, • Onset epilepsy after EEG abnormalities : delay 1,9 months

Pediatric Neurology 2016 Pediatric Neurology 2016

European Journal of Paediatric Neurology, 2011

Long‐term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy –Tuberous sclerOsis comPlex

11/28/2016

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Scoring system

1. Background : normal or abnormal during W and / or S

BGN background normal both in sleep and wake normal backgroundBGA background abnormal in sleep and during wake BGAw background abnormal only in wakeBGAs background abnormal only during sleep

(consider focal slowing, no spindles, no or too low frequency dominant rhythm, hypsarrhythmia,…)

Scoring system: 2. interictal epileptic activity (IED):

Distribution

0 no epileptic abnormality during wake and sleep

A 1 brain area with epileptic activity in one hemisphere (exception O1 and O2 together considered as 1 brain area)

B >1 brain areas in one hemisphere with epileptic activity (non adjacent electrodes show interictal epileptic activity, or adjacent electrodes with IED but with clear temporal off‐set )

C Multifocal : 2 or more areas not in the same hemisphere

D Generalized (or typical hypsarrhythmia)

Scoring system: 2.interictal epileptic activity (IED):

Severity

0 no epileptic abnormality

I very rare IED , < 1% of time

II epileptic activity for 1‐10 % of the time

III epileptic activity 10 ‐ 50 % of the time

IV epileptic activity > 50% of the time

V Hypsarrhythmia

Scoring system: 3. seizures

Seizures

NS No seizures (NS)

S Clinical seizure with concordant EEG changes

CS Clinical seizures only (video) , no EEG correlate

SS subclinical (electrographic) seizures, no video correlate

EPISTOP randomisation criteria

Eligible for randomization

(treatment or no treatment):

minimum

A.III or B or C or D

(sub)clinical seizures : always treatment

“Standard of care group” analysis (67 pt)

Randomisation Y ‐ Treatment N: 15 ptRandomisation Y ‐ Treatment N no seizures: 6 ptRandomisation Y ‐ Treatment N seizures: 9 pt

Randomisation Y – Treatment Y because of seizures: 11 pt

Randomisation candidates: 4 pt

Observation patients: 37 pt

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67 TSC children ‘standard of care group’

38/67 male patients60/67 born a termAge enrollment:

median age 33 days (range: 0‐121) Follow‐up:

median 432 days (range: 16 ‐839 )

EEG(corrected for multiple EEGs per time period)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0‐2m 3‐5m 6‐8m 9‐11m 12‐14m 15‐17m 18‐20m 21‐23m 24m

Standard of care, N = 67

0 A B C D

First seizure (N) 16 12 6 1 2 1 1 0 0

39/67 seizures58%

Standard of care group

39/67 seizuresMedian age onset 100 days, range 1‐622 days

14/39 subclinical seizures (SS)Median age onset 21 days, range 1‐398 days

7/14 with SS developed clinical seizuresmedian age first clinical seizure 70 days, range 47‐131 days. median time SS untill clinical seizure: 56 days, range 22‐130 days.

10/17/2016

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TSC: understanding and modifying epileptogenesis

Imaging biomarkers for TSC related epilepsy

Jurriaan M Peters, MD, PhD

Assistant Professor of Neurology

Division of Epilepsy and Clinical Neurophysiology

Boston Children’s Hospital & Harvard Medical School

Learning Objectives

• Understand clinical application of key imaging modalities for localization of epilepsy in TSC

• Understand utility of imaging markers for predictionof epilepsy in TSC

• Be up‐to‐date on potential of imaging markers of epileptogenesis in TSC

Reflects abnormalities of migration, proliferation and differentiation

Tubers

Subependymal nodules

Subependymal giant cell astrocytomas

Radial migration lines and transmantle cortical dysplasias

(Cyst‐like tubers)

TSC: Structural MRI

Peters et al. Future Neurol. 2013

TSC: Structural MRI ‐ localization

Jahodova et. al. Eur J Radiol 2014

Kannan et al. Brain 2016

TSC lesion characteristics: Tuber, calcification, cystic degenerationFCD lesion characteristics: Cortical thickness, perilesional cortical gyration, gray/white matter junction blurring, transmantle change“Tuber centre”: epileptogenesis and inter‐tuber propagation

TSC: Diffusion MRI ‐ localization

Chandra et al., Epilepsia 2006

Jansen et al., Arch Neurol 2003

TSC: Diffusion MRI ‐ localization (ct’d)

Yogi et al., Neurology 2015

545 tubers, 33 epileptogenicROItuber+perituber sens 81%, spec 44%

Positive predictive value 8%

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TSC: Structural MRI ‐ prediction

Chu‐Shore et al. Neurology 2009

24 mos 4 y 10 mos

Lesion burden ‐ count‐ volume‐ tuber‐brain proportion

van Eeghen et al. Neuroradiology 2013

Goodman et al. J Child Neurol 1997Chou et al. Eur J Ped Neuro 2008Jansen et al. Neurology 2008

TSC: Structural MRI – prediction (ct’d)

Gallager et al. J Neurol 2010

Type A Type B Type C

T2

FLAIR

T1 =

ADC =

TSC: Diffusion MRI ‐ prediction

Cingulum, left cerebral peduncle, superior cerebellar peduncles, posterior limbs internal capsule, external capsule, inferior frontooccipital fasciculus, temporal trunk

Peters et al. Acad Radiol 2012Moavero et al. Epilepsy Behav 2016

TSC: Diffusion MRI ‐ prediction

Peters et al., in preparation

TSC: Diffusion MRI ‐ epileptogenicity

Peters et al., Neurology 2015

For each voxel calculate slope of FA change over time

Next express fitted slope (or intercept) as color, including negative evolution

Superimpose masked image on T1 image

TSC: Diffusion MRI ‐ epileptogenicity

Peters et al., in preparation

1 mo 12 mo 18 mo 24 mo

FA

age

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TSC: Diffusion MRI – what does diffusion measure?

T1-weighted T2-weighted

Peters et al., in preparationPeters et al., in preparation

7T

7T

H&E 7T

TSC: Diffusion MRI – what does diffusion measure?

Impact on Clinical Care and Practice

• Clinical utility structural MRI for epilepsy localization• Corroborated by neurophysiology (EEG, MEG)

• Diffusion imaging of white matter functions as biomarker for disease burden• Non‐specific (epilepsy, autism, cognition)• Role in identification of epileptogenic tuber• Improves when combined with other modalities (PET)

• Longitudinal diffusion changes may characterize changes associated with epileptogenesis

#AES2016

11/28/2016

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Molecular Biomarkers in the Epileptogenesis of TSC

Pediatric State of the Art Symposium2016 American Epilepsy Society Meeting

December 5, 2016

Michael Wong, MD, PhDDepartment of Neurology, Pediatrics, and Anatomy & Neurobiology

Washington University School of MedicineSaint Louis, MO

Disclosure

Grant Support from National Institutes of Health, Department of Defense.

Site PI for Novartis-sponsored clinical trial on everolimus/Affinitor for epilepsy in tuberous sclerosis.

Site PI for GW Pharmaceuticals clinical trial on cannabidiol for epilepsy in tuberous sclerosis.

Learning Objectives

• To understand the general clinical utility of molecular biomarkers for prediction, monitoring, and prognostication of epilepsy in TSC.

• To understand the role and potential utility as biomarkers of the mTOR pathway and other downstream cellular and molecular mechanisms in epileptogenesis in TSC.

Biomarkers

Applications of Biomarkers in Disease

• Diagnose patients with a disease

• Identify patients at risk for a disease

• Indicate severity, extent, or progression of a disease (e.g. staging)

• Indicate disease prognosis

• Predict or monitor response to therapy (efficacy or toxicity/side effects)

Definition of Biomarker*: A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention

* NIH Biomarkers Definitions Working Group 2001

Walker et al. Epilepsia 2016

Hamartin

Tuberin

mTOR (mTORC1)

Protein synthesis

TSC1/TSC2 genes

Cell growth/proliferationMetabolism

Synaptic plasticity

Normal

S6K/S64E-BP1/eIF4E

Other pathways

Hamartin

Tuberin

mTOR (mTORC1)

Protein synthesis

TSC1/TSC2 genes


Synaptic plasticity

Normal

S6K/S64E-BP1/eIF4E

Other pathways

TSC

Cell Growth/ProliferationTumorigenesis

11/28/2016

2

Hamartin

Tuberin

mTOR (mTORC1)

Protein synthesis

TSC1/TSC2 genes


Synaptic plasticity

Normal

S6K/S64E-BP1/eIF4E

Other pathways

TSC

Cell Growth/ProliferationTumorigenesis

Before Rapamycin After Rapamycin

Franz et al. 2006

Rapamycin“Rapa Nui”

Hamartin

Tuberin

mTOR (mTORC1)

Protein synthesis

TSC1/TSC2


Synaptic plasticity

Normal

S6K/S64E-BP1/eIF4E

Other pathways

TSC

Tumorigenesis Epileptogenesis

Rapamycin

mTOR Inhibitors and Epilepsy inAnimal Models of TSC

Adapted from Ryther and Wong 2012

Epilepsy in Tsc1GFAPCKO mice

Erbayat-Altayet al. Epilepsia 2007

Hamartin

Tuberin

mTOR (mTORC1)

TSC1/TSC2

Normal

S6K/S64E-BP1/eIF4E

Other pathways

Tsc1GFAPCKO Mice

Epileptogenesis

Tsc1 inactivation in GFAP-positive cells

Rapamycin

Early rapamycin treatment prevents development of epilepsy and prolongs survival of Tsc1GFAPCKO mice

Zeng et al. Ann Neurol. 2008

11/28/2016

3

Late rapamycin treatment decreases seizure frequency and prolongs survival of already symptomatic Tsc1GFAPCKO mice

Zeng et al. Ann Neurol. 2008

Vigabatrin may have antiepileptogenic properties in Tsc1GFAPCKO mice by inhibiting mTOR

Zhang et al. PLoS One 2013

Dose-dependence and duration of rapamycin inhibition of mTOR activity and epilepsy

Rensing et al. Epilepsia 2015

mTOR Activity as a Biomarker in Human TSC

Baybis et al. Ann Neurol 2004

Tuber Control

P-S6K

P-S6

Hamartin

Tuberin

mTOR (mTORC1)

Protein synthesis

TSC1/TSC2


Synaptic plasticity

Normal

S6K/S64E-BP1/eIF4E

Other pathways

TSC

Tumorigenesis Epileptogenesis

Epileptogenesis in TSC

Abnormal Circuitstubers/perituberal cortex,synaptic reorganization,disruption of inhibitory circuits

+

Abnormal Cells giant cells, cell growth/proliferation,neuronal death, neurogenesis, astrogliosis

Abnormal Moleculesion channels, neurotransmitters, inflammatory molecules

Epileptogenesis/Seizures

?

11/28/2016

4

Hamartin

Tuberin

mTOR (mTORC1)

TSC1/TSC2

Normal

S6K/S64E-BP1/eIF4E

Other pathways

TSC

Abnormal CircuitsTuber formationSynaptic ReorganizationLoss of Inhibitory Circuits

Abnormal CellsCell Growth/ProliferationNeuronal Death/ApoptosisNeurogenesisAstrogliosis

Abnormal MoleculesIon ChannelsNeurotransmitter Receptors Structural/synaptic ProteinsInflammatory Molecules

Epileptogenicmechanisms

The TSC genes and mTOR regulate numerous downstream genes/proteins

Translational/mRNA profiling with Tsc2 knock-down

Proteomics of epilepsy geneswith mTOR inhibition

Nie et al. J Neurosci 2015Niere et al. Mol Cell Proteomics 2016

Hamartin

Tuberin

mTOR (mTORC1)

TSC1/TSC2

Normal

S6K/S64E-BP1/eIF4E

Other pathways

TSC





G

G

G

G

G

G

G

GG

G

GG

Presynaptic Neuron Postsynaptic Neuron

G

G G

GG

Astrocyte

GLT-1/GLAST

AMPAReceptors

EPSP

Tsc1 HamartinTuberin

mTOR

S6K/S6, eIF4E

Rheb

Protein synthesis

?

G

G

G

G

G

AMPA/NMDAReceptors

EPSP

Excitotoxic Cell Death

Seizure

Glutamate transporter expression and function is decreased in astrocytes from Tsc1GFAPCKO mice

Wong et al. Ann Neurol. 2003

Glutamate transporter current

Control Tsc1 CKO

Cur

rent

den

sity

(pA

/pF

)

0.0

0.5

1.0

1.5

2.0

*

Extracellular Glutamate Levels

Pharmacological induction of Glt1 decreases neuronal death and epilepsy in Tsc1GFAPCKO mice

Zeng et al. Neurobiol Dis. 2010

11/28/2016

5

Hamartin

Tuberin

mTOR (mTORC1)

TSC1/TSC2

Normal

S6K/S64E-BP1/eIF4E

Other pathways

TSC





Inflammatory markers are increased in Tsc1GFAPCKO mice

Zhang et al. Neurobiol Dis 2015

IL-1β localizes to astrocytes in Tsc1GFAPCKO mice and is inhibited by anti-inflammatory epicatechins (ECG)


Anti-inflammatory epicatechins (ECG) decrease seizures and prolong survival in Tsc1GFAPCKO mice


Abnormal Glt1 and Inflammatory Markers in Tuber Tissue

Boer et al. Brain Pathol 2010

Hamartin

Tuberin

mTOR (mTORC1)

TSC1/TSC2

Normal

S6K/S64E-BP1/eIF4E

Other pathways

TSC





11/28/2016

6

Summary

• mTOR activity is critical for epileptogenesis in TSC mouse models, is elevated prior to onset of epilepsy, and also correlates with response to treatment, indicating it may be an appropriate biomarker for predicting epilepsy in TSC and following response to treatment.

• Other molecules, downstream from mTOR, such as glutamate transporters and inflammatory chemokines, may be more specifically correlated with epileptogenesis in TSC mouse models and could also serve as potential biomarkers or additional therapeutic targets for epilepsy in TSC.

• Additional clinical studies are needed to verify the validity of these biomarkers in TSC patients and to develop clinically-feasible assays (e.g. serum, CSF, molecular imaging).

Wong LabLinghui ZengBo ZhangNick RensingBrennan BeelerElizabeth GriffinDongjun GuoLirong Han

Support

National Institutes of HealthDepartment of DefenseTuberous Sclerosis Alliance Citizens United for Research on

Epilepsy (CURE)

David Gutmann – Wash UPeter Crino – Univ. of Penn.David Kwiatkowski – Harvard

Collaborators

Acknowledgements

Impact on Clinical Care and Practice

• Although currently at the research stage, molecular biomarkers have the potential to identify TSC patients at risk for epilepsy, predict prognosis, and follow response to treatment

• The mTOR pathway and downstream cellular and molecular mechanisms may be useful as biomarkers of epileptogenesis and novel therapeutic targets for epilepsy in TSC.

#AES2016

19.09.2016

1

Targeting Early and Preemptive Treatment of Epilepsy in TSC

Sergiusz Jóźwiak, MD, PhD Pediatric Neurology

Medical University of Warsaw

Disclosures for Dr. Jóźwiak

Dr. Jóźwiak has received speaking and advisory board honoraria from Novartis, Eisai and UCB

Dr. Jóźwiak has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the presentation

0

20

40

60

80

100

120

1 2 3 4 5 6 7 8 9 10 11 12 13 years

Numberof

pa4ents EpilepsyonsetinTSC:agedistribu4on

Jóźwiak S, et al. Biology of seizure susceptibility in developing brain. Montrouge, France: John Libbey, EuroText Ltd.;2008:221-31

In 57,9% the first seizures appear in the first six months of life, in 75% in the first year of age. Only 6,4% had first seizures at the age of 5 or more

Neonatal presentation of epilepsy in TSC

•  21/421 (5%) of TSC patients developed seizures in the first month of life.

•  11 (52%) displayed large FCD on brain MRI

•  Early epilepsy was associated with high risk of drug-resistance of seizures and poor neurodevelopmental outcome

Kotulska et al.. Eur J Paediatr Neurol. 2014 Nov;18(6):714-21

Impact of early onset of epilepsy on intellectual disability

AgeatOnsetofEpilepsy

ProfoundID

SevereID

ModerateID

MildID

LessThan

Normal

Average

Total

<6mo 13 21 19 13 12 3 81

(57.9%)

6–12mo 2 7 6 5 3 1 24

(17.1%)

1–2yrs 1 1 2 2 4 4 14

(10.0%)

2–5yrs - 1 1 3 3 4 12

(8.6%)

>5yrs - - - 2 2 5 9

(6.4%)

Total 16

(11.4%) 30

(21.4%) 28

(20.0%) 25

(17.9%) 24

(17.1%) 17

(12.2%) 140

82%

ID, intellectual disability. Jóźwiak S, et al. Biology of seizure susceptibility in developing brain. Montrouge, France: John Libbey, EuroText Ltd.;2008:221-31.

Factors influencing mental outcome of infants with TSC

Epileptic EEG Seizures Drug-resistant

Intellectual disability

Epilepsy

Cortical tubers

19.09.2016

2

Prenatal diagnosis of TSC

Incidence of Epilepsy and Intellectual Disability in Children With Pre- or Perinatal

Diagnosis of TSC

Standard Care Group N = 31

Patients with epilepsy n = 22 (71%)

Patients without epilepsy n = 9 (29%)

Intellectual disability n = 15 (48%)

Normal IQ n = 7 (23%)

Intellectual disability n = 0


Jozwiak S, et al. EJPN, 2011, 15, 424-431

In TSC �Preventative” Antiepileptic Treatment Markedly Reduced Risk of Epilepsy and Intellectual

Disability

Preventative Group N = 14

Epileptiform EEG N = 10 (71%)

Normal EEG N = 4 (29%)

Patients with epilepsy

n = 6 (42%)

Patients without epilepsy

n = 4 (29%)

Patients with epilepsy

n = 0

Patients without epilepsy

n = 4 (29%)

Intellectual disability n = 2 (14%)






Jozwiak S, et al.EJPN, 2011, 15, 424-431

Evolution of epileptogenesis in infants with TSC

Normal EEG

Spikes

Multifocal spike and wave complexes (subtle focal seizures)

generalized activity/ hypsarhythmia (infantile spasms)

Domanska et al. EJPN, 2014, 18: 458-468

Evolution of epileptogenesis in infants with TSC

DSCF0290.MOV

Comparison of electroencephalographic findings

Standard group (n=31)

Preventative group (n=14)

Patients with medication (epilepsy or epileptiform discharges on EEG)

22 (71%) 10 (71%)

Normal EEG at age of 24 months

11/31 12/14 p=0.005

Patients receiving AEDs whose EEG turned to normal

2/22 8/10 p=0.0018

19.09.2016

3

Comparison of seizure severity and mental outcome

Standard group N=31

Preventative group N=14

Number of patients with epilepsy

22/31 (71%) 6/14 (42.9%) p=0.072

Patients with drug-resistant epilepsy

13/31 (41.9%) 1/14 (7.1%) p=0.039

Seizure free at 24 months

2/22 with epilepsy 5/6 with epi p=0.0003

Mean IQ score at 24 months

68,7 92.3 p<0.05

Patients with normal IQ

16/31 (52%) 12/14 (86%) p=0.031

Patients with moderate, severe or profound MR

10/31 (32.4%) 0 p=0.036

Proposal full title: Long-term, prospective study evaluating clinical and molecular biomarkers of epileptogenesis in a genetic model of epilepsy – tuberous sclerosis complex Type of funding scheme: Collaborative Project - Large-scale integrating project 16 partners from Europe, US and Australia

www.EPISTOP.eu

AIMS of the Project:

1.  To prove that early treatment of subclinical seizures significantly reduces drug-resistancy and neurodevelopmental delay in children

2.  Prospective analysis of clinical and molecular biomarkers (genes and proteins expression) in the course of epileptogenesis

HEALTH.2013.2.2.1-4

9

The local physician performing and interpreting the vEEG will be blinded to the clinical data, and his/her reports will be sent to the central coordinator. The treating neurologist will be told when his/her patient is diagnosed with epilepsy or not and if epilepsy is diagnosed the neurologist will immediately implement vigabatrin. He/she will be blinded to the vEEG findings. It means that if the child is not diagnosed as epileptic, the treating neurologist will not know whether it is because vEEG was normal or the patient has been randomized to group B. Similarly, if the patient is diagnosed with epilepsy, the treating neurologist will not know whether the drug is given because any clinical seizures were noticed on vEEG, or the patient has been randomized to group A (Fig.1.5).

Treating�neurologist� EEG��record�

ElectroencephalographerREPORT

Central�randomizer�

Feedback:epilepsy/no�epilepsy

Fig.1.4. Flowchart of the clinical study.

Fig.1.5.��Scheme�of�study�blinding:�the�treating�neurologist�will�not�know�the�results�of�EEG�recordings.�They�will�be��reported�by�electroencephalographer�blinded�to�the�clinical�data�of�the�patient�to�the�central��randomizer.�The�treating�neurologist�will�receive�only�the��diagnosis:�epilepsy�or�no�epilepsy�(meaning:�treat�or�not�treat,�respectively).��

HEALTH.2013.2.2.1-4

16

- Integrated analyses of these data sets to search for correlations between analytes and epileptogenesis onset and progression (BWH)

This comprehensive approach has never been applied to any clinical epilepsy model and is likely

to provide a rich collection of genes, proteins, immunological markers, and miRNAs involved in epileptogenesis in humans. Importantly, there are no published data on genomics, epigenetics, miRNA, proteomics, and metabolomics during epileptogenesis in the immature brain, neither in animals, nor in humans. EPISTOP will be the first study of the molecular mechanisms of epileptogenesis in immature brain.

Expression (RNA) profiling. Changes in the expression of several hundred genes in the brain during epileptogenesis have been reported in animal models (Lukasiuk, 2006). Genes with significant changes in expression include those involved in synaptic transmission, ion transport, immune function, cell proliferation, and apoptosis. However, comparisons among genes identified in this manner in different studies have shown little consistency, with only 46 (about 7%) showing altered expression in more than one study (Lukasiuk, 2012). The reasons for this inconsistency may include the use of different animals, different triggers of epileptogenesis, different time points for sampling, analysis of different brain regions, and methodological issues, including different array platforms and analysis algorithms. In humans, studies examining gene expression have been performed on epileptogenic brain tissue obtained from surgery for drug-resistant epilepsy (Becker, 2003, Bando, 2011), and thus provide little or no insight as to gene expression changes during early epileptogenesis. Only a few studies (Okamoto, 2010, Gorter, 2006, Becker, 2003) reported the changes in the transcriptome in the latent phase of epileptogenesis in animal models. During EPISTOP project we will be able to perform comprehensive transcriptome profiling at serial time points before and after onset of clinical seizures, to enable identification of those changes in gene expression that correlate with progressive epileptogenesis. As this is a human study, the only

Fig.1.5. Relationships between approaches and methods used to identify the molecular biomarkers of epileptogenesis and potential target for new drugs in WP3 and WP5.

What molecular biologists are expected to do in EPISTOP?

www.EPISTOP.eu

Newest European recommendations in epilepsy in TSC (Rome 2012)

Curatolo et al. Eur. J.Paediatr. Neurol. 2012, 16(6): 582-589.

- EEG Follow-up every 4 weeks in the first 6 months and every 6-8 weeks thereafter till 24th month of life.

- treatment should be initiated, in infants and children within 24 months of life if ictal discharges occur, with or without clinical manifestations.

- vigabatrin is the first-line therapy for infantile spasms with TSC

- vigabatrin should be used for focal seizures before the age of 1 year

19.09.2016

4

In conclusion, this study is the first multicenter pro-spective study to evaluate serial EEGs as a biomarker forsubsequent epilepsy in the infant population with TSC. Ourstudy demonstrates the feasibility and importance of closeEEG surveillance in infants with TSC, with high PPV ofepileptiform discharges for predicting those who subse-quently develop epilepsy. This interim analysis highlightsthe value of early diagnosis of infants with TSC and thevalue of serial EEG beginning at the time of diagnosis.Importantly, our study suggests there is a critical window oftime between emergence of epileptiform discharges andclinical seizure onset, which provides a unique opportunityto investigate potentially disease-modifying antiepileptogenictreatment strategies in this population.

Study Funding: Supported by the National Institute of Neurological Diseases andStroke of the National Institutes of Health (U01-NS082320, P20-NS080199) and theTuberous Sclerosis Alliance. JYW also supported by the NIH (R01-NS082649), theDepartment of Defense (W81XWH-11-1-0365) Congressionally Directed MedicalResearch Program, and the Today’s and Tomorrow’s Children Fund from MattelChildren’s Hospital at the University of California, Los Angeles. MS was supported bythe Senior Investigator award from Boston Children’s Translational Research Pro-gram. This study also utilized clinical research facilities and resources supported bythe National Center for Advancing Translational Sciences (NCATS) of the NationalInstitutes of Health Grant (8UL1TR000077 and UL1RR033176).

References

1. Sparagana SP, Roach ES. Tuberous sclerosis complex. Curr OpinNeurol. 2000;13:115-119.

2. Kwiatkowski DJ. Rhebbing up mTOR: new insights on TSC1 andTSC2, and the pathogenesis of tuberous sclerosis. Cancer Biol Ther.2003;2:471-476.

3. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex.N Engl J Med. 2006;355:1345-1356.

4. Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. Thenatural history of epilepsy in tuberous sclerosis complex. Epilepsia.2010;51:1236-1241.

5. Webb DW, Fryer AE, Osborne JP. On the incidence of fits and mentalretardation in tuberous sclerosis. J Med Genet. 1991;28:395-397.

6. Sparagana SP, Delgado MR, Batchelor LL, Roach ES. Seizureremission and antiepileptic drug discontinuation in children withtuberous sclerosis complex. Arch Neurol. 2003;60:1286-1289.

7. Curatolo P. Mechanistic target of rapamycin (mTOR) in tuberoussclerosis complex-associated epilepsy. Pediatr Neurol. 2015;52:281-289.

8. Aboian MS, Wong-Kisiel LC, Rank M, Wetjen NM, Wirrell EC,Witte RJ. SISCOM in children with tuberous sclerosis complex-related epilepsy. Pediatr Neurol. 2011;45:83-88.

9. Datta AN, Hahn CD, Sahin M. Clinical presentation and diagnosis oftuberous sclerosis complex in infancy. J Child Neurol. 2008;23:268-273.

10. Jozwiak S, Kotulska K, Domanska-Pakiela D, et al. Antiepileptictreatment before the onset of seizures reduces epilepsy severity andrisk of mental retardation in infants with tuberous sclerosis com-plex. Eur J Paediatr Neurol. 2011;15:424-431.

11. Bombardieri R, Pinci M, Moavero R, Cerminara C, Curatolo P. Earlycontrol of seizures improves long-term outcome in children withtuberous sclerosis complex. Eur J Paediatr Neurol. 2010;14:146-149.

12. Jozwiak S, Goodman M, Lamm SH. Poor mental development inpatients with tuberous sclerosis complex: clinical risk factors. ArchNeurol. 1998;55:379-384.

13. Northrup H, Krueger D, International Tuberous SclerosisComplex Consensus Group. Tuberous sclerosis complex diagnosticcriteria update: recommendations of the 2012 InternationalTuberous Sclerosis Complex Consensus Conference. Pediatr Neurol.2013;49:243-254.

14. Jozwiak S, Schwartz RA, Janniger CK, Bielicka-Cymerman J. Useful-ness of diagnostic criteria of tuberous sclerosis complex in pediatricpatients. J Child Neurol. 2000;15:652-659.

15. Devlin LA, Shepherd CH, Crawford H, Morrison PJ. Tuberoussclerosis complex: clinical features, diagnosis, and prevalencewithin Northern Ireland. Dev Med Child Neurol. 2006;48:495-499.

16. Doma!nska-Pakie1a D, Kaczorowska M, Jurkiewicz E, Kotulska K,Dunin-Wasowicz D, Jó!zwiak S. EEG abnormalities precedingthe epilepsy onset in tuberous sclerosis complex patients - aprospective study in 5 patients. Eur J Paediatr Neurol. 2014;18:456-468.

17. Muzykewicz DA, Costello DJ, Halpern EF, Thiele EA. Infantile spasmsin tuberous sclerosis complex: prognostic utility of EEG. Epilepsia.2009;50:290-296.

18. Krueger D, Northrup H, on behalf of the International TuberousSclerosis Complex Consensus Group. Tuberous sclerosis complexsurveillance and management: recommendations of the 2012International Tuberous Sclerosis Complex Consensus Conference.Pediatr Neurol. 2013;49:255-265.

19. Curatolo P, Jó!zwiak S, Nabbout R, TSC Consensus Meeting for SEGAand Epilepsy Management. Management of epilepsy associatedwith tuberous sclerosis complex (TSC): clinical recommendations.Eur J Paediatr Neurol. 2012;16:582-586.

J.Y. Wu et al. / Pediatric Neurology 54 (2016) 29e3434

Original Article

Clinical Electroencephalographic Biomarker for ImpendingEpilepsy in Asymptomatic Tuberous Sclerosis Complex Infants

Joyce Y. Wu MDa, Jurriaan M. Peters MD, PhDb, Monisha Goyal MD c,Darcy Krueger MD, PhDd, Mustafa Sahin MD, PhDb, Hope Northrup MDe,Kit Sing Au MDe, Gary Cutter PhD c, E. Martina Bebin MD, MPA c,*

aDivision of Pediatric Neurology, Mattel Children’s Hospital at UCLA, Los Angeles, CaliforniabDepartment of Neurology, Boston Children’s Hospital, Boston, MassachusettscDepartment of Neurology, University of Alabama Birmingham, Birmingham, AlabamadCincinnati Children’s Hospital, Cincinnati, OhioeUniversity of Texas Houston, Houston, Texas

abstract

BACKGROUND:We assessed the clinical utility of routine electroencephalography (EEG) in the prediction of epilepsyonset in asymptomatic infants with tuberous sclerosis complex. METHODS: This multicenter prospective observa-tional study recruited infants younger than 7 months, seizure-free and on no antiepileptic drugs at enrollment,who all underwent serial physical examinations and video EEGs throughout the study. Parental education onseizure recognition was completed at the time of initial enrollment. Once seizure onset occurred, standard of carewas applied, and subjects were followed up until 24 months. RESULTS: Forty patients were enrolled, 28 older than12 months with completed EEG evaluation at the time of this interim analysis. Of those, 19 (67.8%) developedseizures. Epileptic spasms occurred in 10 (52.6%), focal seizures in five (26.3%), generalized tonic-clonic seizure inone (5.3%), and a combination of epileptic spasms and focal seizures in three (15.7%). Fourteen infants (73.6%) hadthe first emergence of epileptiform abnormalities on EEG at an average age 4.2 months, preceding seizure onset bya median of 1.9 months. Hypsarrhythmia or modified hypsarrhythmia was not found in any infant before onset ofepileptic spasms. All children with epileptiform discharges subsequently developed epilepsy (100% positivepredictive value), and the negative predictive value for not developing epilepsy after a normal EEG was 64%.CONCLUSIONS: Serial routine EEGs in infants with tuberous sclerosis complex is a feasible strategy to identify in-dividuals at high risk for epilepsy. The most frequent clinical presentation was epileptic spasms followed by focalseizures, and then a combination of both seizure types.

Keywords: epileptic spasms, EEG, video EEG use in epilepsy, partial seizuresPediatr Neurol 2016; 54: 29-34

! 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Tuberous sclerosis complex (TSC) is an autosomaldominant disease that affects approximately one in 6000people, represents one of the most common genetic causes

of epilepsy,1-3 and is caused by TSC1 or TSC2 mutation. Theneurological manifestations in TSC are common and inchildren represent the most disabling problems of the dis-ease, including epilepsy, intellectual disabilities, psychiatricproblems, and autism. Epilepsy is particularly prevalent,affecting about 80% of individuals with TSC4-6 with over 60%having seizures that are severe and refractory.4,7,8 Almosthalf of infants with TSC develop epileptic spasms, which isassociated with poor neurological prognosis.4

Increasingly TSC is diagnosed at a young age before theonset of epilepsy from non-neurological findings, such as

Article History:Received July 24, 2015; Accepted in final form September 6, 2015* Communications should be addressed to: Dr. Bebin; Department of

Neurology; CIRC 312; 1530 3rd Ave S; Birmingham, AL 35294-3280.E-mail address: [email protected]

Contents lists available at ScienceDirect

Pediatric Neurology

journal homepage: www.elsevier .com/locate/pnu

0887-8994/! 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).http://dx.doi.org/10.1016/j.pediatrneurol.2015.09.013

Pediatric Neurology 54 (2016) 29e34

J.Child Neurology 2011, Nov; 26(11): 1411-21.

Antiepileptogenic treatment !

Figure 2. Time course of epileptogenesis151

An initial insult, such as traumatic brain injury and/or status epilepticus, is followed by a latentperiod lasting weeks to months or even years before the onset of spontaneous seizures. Duringthis latent period, a cascade of molecular and cellular events occurs that alters the excitabilityof the neuronal network, ultimately resulting in spontaneous epileptiform activity. Thealterations that occur during the latent period might provide a good opportunity for biomarkerdevelopment and therapeutic intervention. The cascade of events that are presently suggestedby experimental evidence can be classified temporally following the initial insult. Earlychanges, including induction of immediate early genes and post-translational modification ofreceptor and ion-channel related proteins, occur within seconds to minutes. Within hours todays, there can be neuronal death, inflammation, and altered transcriptional regulation of genes,such as those encoding growth factors. A later phase, lasting weeks to months, includesmorphological alterations such as mossy fiber sprouting, gliosis, and neurogenesis.

Rakhade and Jensen Page 21

Nat Rev Neurol. Author manuscript; available in PMC 2010 February 16.

NIH

-PA

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Rakhade et al. 2010

Stages of epileptogenesis

Figure 2. Time course of epileptogenesis151

An initial insult, such as traumatic brain injury and/or status epilepticus, is followed by a latentperiod lasting weeks to months or even years before the onset of spontaneous seizures. Duringthis latent period, a cascade of molecular and cellular events occurs that alters the excitabilityof the neuronal network, ultimately resulting in spontaneous epileptiform activity. Thealterations that occur during the latent period might provide a good opportunity for biomarkerdevelopment and therapeutic intervention. The cascade of events that are presently suggestedby experimental evidence can be classified temporally following the initial insult. Earlychanges, including induction of immediate early genes and post-translational modification ofreceptor and ion-channel related proteins, occur within seconds to minutes. Within hours todays, there can be neuronal death, inflammation, and altered transcriptional regulation of genes,such as those encoding growth factors. A later phase, lasting weeks to months, includesmorphological alterations such as mossy fiber sprouting, gliosis, and neurogenesis.

Rakhade and Jensen Page 21

Nat Rev Neurol. Author manuscript; available in PMC 2010 February 16.

NIH

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IH-P

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Stages of epileptogenesis

Which of them are irreversible?

First trials of preventive treatment

Seizure, 2002, 11: 145-150.

doi:10.1053/seiz.2001.0629, available online at http://www.idealibrary.com onSeizure 2002; 11: 145–150

Prophylactic antiepileptic treatment in Sturge–Weberdisease

D. VILLE† , O. ENJOLRAS‡ , C. CHIRON† & O. DULAC†

†Department of Neuropaediatrics, Saint Vincent de Paul Hospital, Paris, France; ‡Department ofDermatology, Tarnier-Cochin Hospital, Paris, France

Purpose: In Sturge–Weber disease, motor and cognitive defects are supposed to result mostly from severe epilepsy. They might,therefore be partly prevented by prophylactic antiepileptic drug treatment. This condition constitutes a possible model for thestudy of prophylactic drug treatment in severe epilepsy. In the present study, we compared the outcome of patients treatedprospectively with phenobarbitone before the first seizure, with those referred following the first seizure, in order to identify theissues related to the evaluation of prophylactic treatment of severe epilepsy.Methods: Motor and cognitive outcome were compared in patients treated prophylactically with phenobarbitone (16 cases) andin those treated following the first seizures (21 cases).Results: Whereas the incidence of motor deficit was similar in both groups (44 vs. 52%), that of mental retardation was lowerin the group treated prophylactically (76.2 vs. 43.7%, P < 0.05). The major methodological issues encountered included thesmall number of patients identified at birth that could be included in the study, the need for randomization taking into accountthe size of the angioma, and the choice of the prophylactic medication, including the occurrence of epilepsy together with thecourse of motor and cognitive functions among the endpoints.Conclusion: Prophylactic anti-epileptic drug treatment is worth considering for Sturge–Weber disease, but a randomized prospec-tive study is necessary to determine this. It should be multicentric, take in account the size of the angioma, and decide what themost appropriate medication should be.

c� 2002 BEA Trading Ltd. Published by Elsevier Science Ltd. All rights reserved

Key words: Sturge–Weber disease; neonatal delay; hemiplegia; phenobarbital.

INTRODUCTION

Although the mechanisms of intractability of epilepsyremain poorly understood, there is growing evidencethat it affects certain categories of patients from thevery beginning of the first seizure disorder1. Pre-vention of the first seizure by prophylactic treatmentcould be one means of avoiding an intractable course,for conditions in which a high risk of intractabilitycan be identified before the occurrence of the firstseizure. However, such an unusual concept is likelyto raise methodological difficulties that have not beenaddressed to date.Sturge–Weber disease (SW)2 is one of those rare

conditions in which a high risk of intractable anddevastating epilepsy can be predicted before theoccurrence of any seizure. Indeed, it combines afacial port-wine stain over the area of the first branchof the trigeminal nerve (V1) that can be identifiedfrom birth, and the ipsilateral leptomeninges that is

responsible for the severe epilepsy that affects 80%of the children3. Choroid angiomas may also beobserved. Epilepsy usually starts very early in life andoften comprises prolonged convulsions as the initialmanifestation, followed by frequent intractable anddisabling seizures4, 5.Mental retardation and motor deficits (that respec-

tively affect 60% and 50% of patients) follow the onsetof epilepsy4–6. Therefore, controlling epilepsy is amajor aspect of treatment. Ideally, treatment shouldprevent the first seizures since they are likely tobe devastating. In this perspective, Gilly et al., andSalman6, 7 proposed treating ‘before the onset of theseizures in the newborn with facial port wine stain’↵ associated pial angioma. They proposed to identifysuitable cases on the basis of ‘reduced cortical activityon EEG and/or abnormal cerebral scintography’.From 1978, we applied this concept of prophylactic

treatment prospectively in the Neuropaediatric De-partment of Saint Vincent de Paul Hospital, treating

1059–1311/02/$22.00/0 c� 2002 BEA Trading Ltd. Published by Elsevier Science Ltd. All rights reserved

Two groups: 16 children treated prophyllactically with PB 21 children treated historically after first seizure Results: Incidence of motor deficits was similar (44 vs 55%), but of mental retardation was lower (76% vs 43%; p<0.05)

19.09.2016

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March 2016

Should epileptiform discharges be treated?*†Iv!an S!anchez Fern!andez, †Tobias Loddenkemper, ‡Aristea S. Galanopoulou, and

‡§Solomon L. Mosh!e

Epilepsia, **(*):1–13, 2015doi: 10.1111/epi.13108

SUMMARY

To evaluate the impact of epileptiform discharges (EDs) that do not occur within seizure patterns – such as spikes,sharp waves or spike waves – on cognitive function and to discuss the circumstances under which treatment of EDsmight be considered. Methods used in this article is “Review of the literature”. EDsmay disrupt short-term cognition inhumans. Frequent EDs for a prolonged period can potentially impair long-term cognitive function in humans. However,there is conflicting evidence on the impact of EDs on long-term cognitive outcome because this relationship may beconfounded by multiple factors such as underlying etiology, seizures, and medication effects. Limitations of existingstudies include the lack of standardized ED quantification methods and of widely accepted automated spike quantifica-tion methods. Although there is no solid evidence for or against treatment of EDs, a non–evidence-based practicalapproach is suggested. EDs in otherwise asymptomatic individuals should not be treated because the risks of treatmentprobably outweigh its dubious benefits. A treatment trial for EDs may be considered when there is cognitive dysfunc-tion or regression or neurologic symptoms that are unexplained by the underlying etiology, comorbid conditions, orseizure severity. In patients with cognitive or neurologic dysfunction with epilepsy or EDs, treatmentmay bewarrantedto control the underlying epileptic syndrome. EDsmay cause cognitive or neurologic dysfunction in humans in the shortterm. There is conflicting evidence on the impact of EDs on long-term cognitive outcome. There is no evidence for oragainst treatment of asymptomatic ED.KEYWORDS: Antiepileptic drugs, Cognition, Epileptiform discharges, Memory, Sleep.

Approximately 1–5% of the population has epileptiformdischarges (EDs) on EEG.1,2 EDs are seen more commonlyin people with epilepsy than in controls, and include spikesor polyspikes, sharp waves, or spike and slow-wave com-plexes, occurring isolated or in brief runs, without obviousclinical correlates. EDs may acutely disrupt cognitive orneurologic functions in humans,3–5 and their duration anddistribution influences the type of dysfunction.5–8 However,the exact long-term impact of chronic EDs on neuronal cir-cuitry and on cognitive outcome has not been clarified. The

benefits and risks of treatments to suppress EDs are notclear.

The purpose of this article is to discuss the impact ofEDs on cognition, focusing on EDs that do not occurwithin recognizable seizure patterns or states, and toprovide recommendations on when treatment of EDsmight be considered. We will specifically refer to situa-tions in the ambulatory or nonacute settings, excludingstates with impaired consciousness. We focused thisreview on clinical data, as recent reviews discuss theanimal studies.9,10

Quantification of EDs andCognitive Function

Attempts to objectively quantify EDsMost methods for quantification of EDs have been

designed specifically for electrical status epilepticus insleep (ESES), an EEG pattern with almost continuousepileptiform activity during sleep.11,12

Spike–wave index (SWI) and spike–wave percentage (SWP)Spike–wave index (SWI) and spike–wave percentage

(SWP) provide measures of the percentage of the dura-

Accepted July 6, 2015.*Division of Epilepsy and Clinical Neurophysiology, Department of

Neurology, Boston Children’s Hospital and Harvard Medical School,Boston, Massachusetts, U.S.A.; †Department of Child Neurology,Hospital Sant Joan de D!eu, University of Barcelona, Spain; ‡Saul R.Korey Department of Neurology, Dominick P. Purpura Department ofNeuroscience, Laboratory of Developmental Medicine, Montefiore/Einstein Epilepsy Management Center, Montefiore Medical Center, AlbertEinstein College of Medicine, Bronx, New York, U.S.A.;and §Department of Pediatrics, Montefiore Medical Center, AlbertEinstein College of Medicine, Bronx, NewYork, U.S.A.

Address correspondence to Tobias Loddenkemper, Associate Professorof Neurology, Division of Epilepsy and Clinical Neurophysiology, HarvardMedical School, Fegan 9, Boston Children’s Hospital, 300 Longwood Ave-nue, Boston, MA 02115, U.S.A. E-mail: [email protected]

Wiley Periodicals, Inc.© 2015 International League Against Epilepsy

1

CRITICALREVIEWAND INVITEDCOMMENTARY

Patients with EDs, cognitive dysfunction/regression, andwell-controlled seizures

In a double-blind, placebo-controlled, single-crossoverstudy, 61 children (7–17 years) with well-controlled

seizures and behavioral and/or cognitive problems were ran-domized to lamotrigine or placebo.73 Well-controlled sei-zures were defined as no or infrequent focal or generalizedseizures. Behavior (assessed with the Conners ratings scales

Table 4. Several genetic defects that present with ASD, epilepsy, and ID in different combinations and degrees ofseverity

Author (year) Genetic defect Genetic productAssociation between ASD, epilepsy,

and intellectual disability

Lesca et al. (2012) and (2013)55,56 Mutations in theGRIN2A gene

NMDA glutamate receptoralpha-2 subunit

Approximately 20% of cases with atypical CECTS,Landau-Kleffner syndrome, and CSWS havemutations in GRIN2A. These patients presentwith epilepsy, ID, and autistic features indifferent combinations and degrees of severity

Novarino et al. (2012)58 Mutations in theBCKDK gene

Branched chain ketoaciddehydrogenase kinase

This mutation was detected in consanguineousfamilies presenting with ASD, epilepsy, and ID

Sahin et al. (2012)59 Mutations in TSC1 andTSC2 genes

Hamartin (TSC1) andTuberin (TSC2)

Patients with TSC have epilepsy (80-90%),ASD (50%), and ID (45%)

Mefford et al. (2012)57 Copy number changes indifferent chromosomeregions:1q21.115q11.215q13.315q2416p11.216p13.1117q12

Different genetic products Copy number changes in chromosomeregions are associated with ASD, epilepsy,and ID in different combinations and degrees ofseverity

ASD, autism spectrum disorder; CECTS, childhood epilepsy with centrotemporal spikes; CSWS, continuous spikes and waves during slow sleep; ID, intellectualdisability; TSC, tuberous sclerosis complex. GRIN2A, glutamate receptor, ionotropic, N-methyl D-aspartate 2A; BCKDK, branched chain ketoacid dehydrogenasekinase; NMDA,N-methyl-D-aspartate.

Figure 2.Suggested management of patients with EDs and different clinical conditions. When EDs appear in otherwise asymptomatic subjects,treatment is usually not recommended. In patients with cognitive dysfunction or regression and no ongoing seizures, there is insufficientevidence to recommend treatment, although treatment may be justified in individual cases when suspicion that cognitive dysfunctionrelates to EDs exists. When EDs occur in the setting of cognitive dysfunction or regression and ongoing seizures, treatment is warranted.Treatment in this case may address the entire syndrome. Therapies targeting the EDs may be considered if EDs are suspected to underliethe cognitive dysfunction and if risk is lower than benefit. Legend: B, benefits; EDs, epileptiform discharges; R, risks.Epilepsia ILAE

Epilepsia, **(*):1–13, 2015doi: 10.1111/epi.13108

10

I. S!anchez Fern!andez et al.

Take home messages

-  Prevention of epilepsy in TSC is possible

-  EEG is currently available biomarker of epileptogenesis in TSC

-  Other (better?) biomarkers are still investigated

Thank you to patients with TSC and

EPISTOP team

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