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Current Strategies for the Management of Lennox-Gastaut Syndrome (LGS): Recommendations of the
LGS Working Group of Experts
Robert Gilbert, STL, CMPPVasanti Anand, PhD
PharmaWrite/MedValScientific Information Services
Princeton, NJ
• The LGS Working Group of Experts convened in Chicago (2012) to discuss several topics believed to be essential for improving the care and treatment of patients with LGS, especially children
• The articles in this supplement form a consensus providing recommendations for management of patients with LGS, including diagnosis, treatment, and interaction among all concerned professionals involved in their care
Current Strategies for the Management of Lennox-Gastaut Syndrome (LGS)
Funded by Eisai, Inc.
Blaise F. D. Bourgeois, MD
Emeritus Professor of Neurology, Harvard Medical School
Director, Division of Epilepsy & Clinical Neurophysiology
William G. Lennox Chair in Pediatric Epilepsy
Children's Hospital
Boston, MA
Laurie M. Douglass, MD
Director, Pediatric Epilepsy
Pediatric EEG Director, Pediatric Neurology Residency Program
Division of Pediatric Neurology
Boston Medical Center
Boston, MA
Patricia A. Gibson, MSSW, ACSW
Director, Epilepsy Information Service
Associate Director, Comprehensive Epilepsy Program
Wake Forest University
Winston-Salem, NC
Tracy A. Glauser, MD
Director, Comprehensive Epilepsy Center
Co-Director, Genetic Pharmacology Service
Professor, Department of Pediatrics, University of Cincinnati
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio
Eric H. W. Kossoff, MD
Associate Professor, Neurology and Pediatrics
Medical Director, Ketogenic Diet Center
Director, Pediatric Neurology Residency Program
Johns Hopkins Hospital
Baltimore, MD
Georgia D. Montouris, MD
Clinical Associate Professor of Neurology
Boston University School of Medicine
Director of Epilepsy Services
Comprehensive Epilepsy Care Program for Children and Adults
Boston Medical Center
Boston, MA
LGS Working Group Members:
Current Strategies for the Management of Lennox-Gastaut Syndrome (LGS)
John M. Pellock, MD (Chair)
Chairman , Division of Child Neurology
Professor of Neurology, Pediatrics, and
Pharmacy and Pharmaceutics
Virginia Commonwealth University School of Medicine
Children’s Pavilion
Richmond, VA
Jay Salpekar, MD
Director, Neuropsychiatry and Epilepsy Program
Kennedy Krieger Institute
Baltimore, MD+
Christina SanInocencio
President and Executive Director
Lennox-Gastaut Syndrome Foundation
New York, NY
Raman Sankar, MD, PhD
Professor and Chief, Rubin Brown Distinguished Chair
Division of Pediatric Neurology, 22-474 MDCC
David Geffen School of Medicine at UCLA
Los Angeles, CA
W. Donald Shields, MD
Chief, Clinical Trials in Pediatric Neurology
Director, Pediatric Epilepsy Program
Member, The Ketogenic Diet Program
Professor Emeritus, Pediatrics
Los Angeles, CA
James W. Wheless, MD (Chair)
Director, Neuroscience Institute and Le Bonheur Comprehensive Epilepsy Program
Le Bonheur Chair in Pediatric Neurology
Le Bonheur Childrens Hospital
Professor and Chief, Department of Pediatric Neurology
University of Tennessee Health Science Center
Memphis, TN
LGS Working Group Members (cont.):
Current Strategies for the Management of Lennox-Gastaut Syndrome (LGS)
A consensus approach to differential diagnosis
Authors: Blaise F.D. Bourgeois, Laurie M. Douglass, and Raman Sankar
Current Strategies for the Management of Lennox-Gastaut Syndrome (LGS)
Epilepsia, 55(Suppl. 4):4–9, 2014
A Consensus Approach to Differential Diagnosis
The classic diagnostic criteria for LGS:
Adapted from Arzimanoglou A, Resnick T. Epileptic Disord 2011;13(Suppl. 1):S3–S13.
1st clinical feature
Foundation for diagnosis
NCSE lasts days to weeks in half of the patients with LGS
• Paroxysmal fast rhythms (10-20 Hz) during sleep (non-rapid eye movement) are considered key to differential diagnosis of LGS (Image courtesy of Dr. Blaise Bourgeois)
A Consensus Approach to Differential Diagnosis
A Consensus Approach to Differential Diagnosis
• Tendency to often misdiagnose LGS whenever there are multiple seizure types or drop attacks
• Drop attacks and other characteristics of LGS are also seen in other epilepsy types [eg., focal epilepsies with secondary bilateral synchrony, myoclonic–astatic epilepsy (Doose syndrome), Dravet syndrome, West syndrome, and atypical benign partial epilepsy of childhood]
• Accurate diagnosis involves careful evaluation of clinical and EEG abnormalities (including comprehensive neonatal screen)
• Diagnostic criteria include: multiple seizure types; EEG with generalized SSW during the waking state and bursts of generalized paroxysmal fast activity often seen during sleep; and cognitive and behavioral impairment
• Comprehensive physical examination and additional investigations are important in identifying underlying etiology
• Differential diagnosis is challenging but important for determining prognosis
Conclusions:
A Consensus Approach to Differential Diagnosis
The efficacy and tolerability of pharmacological options in LGS
Authors: Georgia D. Montouris, James Wheless, and Tracy Glauser
Current Strategies for the Management of Lennox-Gastaut Syndrome (LGS)
Epilepsia, 55(Suppl. 4):10–20, 2014
The Efficacy and Tolerability of Pharmacological Options in LGS
Mean reduction in total seizure frequency on anticonvulsants versus placebo:
Adapted from Vanstraten AF, Ng YT. Pediatr Neurol 2012;47:153–161.
The Efficacy and Tolerability of Pharmacological Options in LGS
Adapted from Vanstraten AF, Ng YT. Pediatr Neurol 2012;47:153–161.
Mean reduction in drop attack frequency on anticonvulsant versus placebo:
The Efficacy and Tolerability of Pharmacological Options in LGS
Adapted from Vanstraten AF, Ng YT. Pediatr Neurol 2012;47:153–161.
Percent of patients with >50% reduction in drop attackson anticonvulsant versus placebo:
The Efficacy and Tolerability of Pharmacological Options in LGS
A tabulated summary of key clinical trial data for FDA-approved and commonly used medications (valproate, clonazepam, and zonisamide) is also provided:
The Efficacy and Tolerability of Pharmacological Options in LGS
• LGS is one of the most challenging epilepsies to manage• This publication summarizes data relating to the efficacy and
tolerability of available treatments • No one drug is more efficacious than the other in controlling the
seizures; more research needed to compare available therapies (although most recent publications have found clobazam to be more efficacious compared with other anticonvulsants)
• Future clinical trials would help determine both the short- andlong-term efficacy of the different treatment options
Conclusions:
Surgical options for patients with Lennox-Gastaut syndrome
Authors: Laurie M. Douglass and Jay Salpekar
Current Strategies for the Management of Lennox-Gastaut Syndrome (LGS)
Epilepsia, 55(Suppl. 4):21–28, 2014
Surgical Options for Patients With LGS
Surgical evaluation criteria for patients with LGS who do not respond adequately to pharmacotherapies
Surgical Options for Patients With LGS
Surgical approach to the evaluation of LGS (Figure created by Dr. Douglass):
a= If patient has atonic seizures, consider corpus callostomy over VNS
Surgical Options for Patients With LGS
Surgical evaluation criteria for patients with LGS
Adapted from Engel J Jr, Van Ness PC, Rasmussen TB, et al. In Engel J Jr (Ed); Surgical treatment of theepilepsies. New York: Raven Press, 1993:609–621.
Surgical Options for Patients With LGS
Engel class outcomes of resective surgery in children with LGS
Surgical Options for Patients With LGS
• Successful seizure reduction and modest intellectual improvement can be achieved in select patients with LGS with focal lesions (dominance of EEG discharges from one hemisphere)
• Patients ineligible for focal resection can achieve seizure control with palliative procedures such as corpus callosotomy and VNS
• Radiosurgical callosotomy (newer technique) may help reduce complications of corpus callostomy
• Transient side-effects associated with callosotomy and resectivesurgery
Conclusions:
Nonpharmacologic care for patients with Lennox-Gastaut syndrome: Ketogenic diets and vagus nerve stimulation
Authors: Eric H. W. Kossoff and W. Donald Shields
Current Strategies for the Management of Lennox-Gastaut Syndrome (LGS)
Epilepsia, 55(Suppl. 4):29–33, 2014
Nonpharmacologic care for patients with Lennox-Gastaut syndrome: Ketogenic diets and
vagus nerve stimulation
Composition of the 4 major ketogenic diets (KD):
Adapted from Kossoff EH, Hartman AL. Curr Opin Neurol 2012;25:173–178.
The classic KD has 4 g of fat for each gram of carbohydrate plus protein combined and is described as a 4:1 ketogenic ratio
Outcome data for children with LGS treated with KD:
Adapted from Lemmon ME, Terao NN, Ng YT, et al. Dev Med Child Neurol 2012;54:464–468.
Nonpharmacologic care for patients with Lennox-Gastaut syndrome: Ketogenic diets and
vagus nerve stimulation
Summary of recent studies reporting the effectivenessof VNS in patients with LGS:
Nonpharmacologic care for patients with Lennox-Gastaut syndrome: Ketogenic diets and
vagus nerve stimulation
• Both KD and VNS are efficacious non-pharmacological treatment options for children with LGS
• >50% seizure reduction observed with both treatment options; >90% reduction in seizures observed in some patients; seizure freedom is rare
• Use of non-pharmacological treatments may reduce the side effects and other burdens associated with high anticonvulsant use of many patients with LGS and thus improve alertness
Conclusions:
Nonpharmacologic care for patients with Lennox-Gastaut syndrome: Ketogenic diets and
vagus nerve stimulation
Current Strategies for the Management of Lennox-Gastaut Syndrome (LGS)
Epilepsia, 55(Suppl. 4):34–36, 2014
- Health care providers should have these resources on hand and recommend them to patients withLGS and their families
- Resources include: Advocacy support groups, education, and national support
Appendix: Resources for caregivers and families of patients with Lennox-Gastaut syndrome . Author: Patricia A. Gibson (Director of Epilepsy Information
Service at Wake Forest University School of Medicine)
Resources for caregivers and families of patients with Lennox-Gastaut syndrome
Gibson P. Epilepsia, 55(Suppl. 4):34–36, 2014
Lennox-Gastaut syndrome: impact on the caregivers and families of patients
Author: Patricia A. Gibson.
Other Publications
Journal of Multidisciplinary Healthcare 2014:7;441–448
- Pilot survey designed to explore the impact ofepilepsy on caregiver’s QoL (based on Ms. Gibson’sclinical experience)
- Physical, social, emotional, and financial impacton the entire family
- Resource for health care professionals
The impact of Lennox-Gastaut Syndrome on Families (Epilepsy and Seizure Series Part 4)
Author: Patricia A. Gibson.
EP Magazine. 2014;48-51
Other Publications
• Informational resource for parents and caregivers of patients with LGS
www.lgshope.com
www.lgshope.com: Resources Registry
www.lgshope.com: Helpful Resources
www.lgshope.com: LGS Hope Newsletter
www.lgshope.com (LGS Hope Newsletter)
www.lgshope.com: Interviews With Experts
Lennox-Gastaut Syndrome: Making a Case for Animal Models
John W. Swann Ph.D.The Cain Foundation Laboratories
The Jan and Dan Duncan Neurological Research Institute
Texas Children’s HospitalBaylor College of Medicine
Three Stories and Two Proposals
• The Everolimus Trials for TSC
• Other Epilepsy Encephalopathy Genes –Mouse, Fish and Cell-Based Models of DravetSyndrome
• Infantile Spasms – establishing criterion for model development and meeting them.
• LGS Genes and Model Development
• Infantile Spasms Models – evolution to LGS
Cytomegalic Neurons of Human Cortical
Dysplasia
Ljungberg, D’Arcangelo et al.
Human Cytomegalic Neurons have an Overabundance of pS6
Ljungberg et al. Ann Neurol. 2006
PI3K-mTOR Signaling Pathway
S6
GFR
IR
PDK1
TSC
1
TSC
2
Akt
P
Rapamycin
6SK
PP
4E-BP1
eIF4E
eIF4EeIF4G
P
48S
P
mRNA Translation
Cell Growth
PTEN
mTOR
PI3K
Signaling Pathways are like Molecular Freeways
Rapamycin
mRNA Translation
Cell Growth
TSCs and Pten Slow the Speed of Molecules
Rapamycin
mRNA Translation
Cell Growth
TSCs and Pten Slow the Speed of Molecules
Rapamycin
mRNA Translation
Cell Growth
TSCs and Pten Slow the Speed of Molecules
Rapamycin
mRNA Translation
Cell Growth
The NS-Pten Knock-out Mouse
The PI3K/mTOR pathway is activated in cortical PTEN
knockout neurons
PTEN and phospho-S6 (pS6) double immunofluorescence of cortical layer V in an adult conditional
knockout brain shows many PTEN depleted cells with elevated levels of pS6 (arrows). Western blots of
cortical homogenates from adult wild type and knockout littermates show increased levels of pS6 and
phospho-Akt, both downstream targets of mTOR.
Adult cortex
PTEN pS6 PTEN/pS6
The PI3K/mTOR pathway is activated in cortical PTEN
knockout neurons
PTEN and phospho-S6 (pS6) double immunofluorescence of cortical layer V in an adult conditional
knockout brain shows many PTEN depleted cells with elevated levels of pS6 (arrows). Western blots of
cortical homogenates from adult wild type and knockout littermates show increased levels of pS6 and
phospho-Akt, both downstream targets of mTOR.
Adult cortex
PTEN pS6 PTEN/pS6
Adult cortexAdult cortex
PTEN pS6 PTEN/pS6
Ljungberg, Sunnen et al., Dis Models Mech 2: 389-398, 2009
PI3K
S6
PTEN
growth
mTOR
Neuronal Hypertrophy
Pten KO in granule neurons:
Dentate Gyrus
Cerebellum
Pten KO also in some cells in
Neocortex
NS-Pten KO mice have epileptiform activity and seizures
EEG
Ground
EEG
Ground
Sunnen, Anderson et al.
Can Rapamycin take the place of Pten or TSC ?
3 4 5 6 7 8 9
Electrode
Implant
EEG Recording
Rapamycin
or Vehicle
Sacrifice
Age (in weeks)3 4 5 6 7 8 9
Electrode
Implant
EEG Recording
Rapamycin
or Vehicle
Sacrifice
Age (in weeks)
PI3K
S6
PTEN
growth
Rapamycin
mTOR
Ljungberg, Sunnen et al., Dis Models Mech 2: 389-398, 2009
0
25
50
75
100
Vehicle
Rapamycin
6 wks 9 wks4 wks
*****
Ep
ilep
tifo
rm A
cti
vit
y (
% t
ime)
Rapamycin Suppresses Seizures in NS-Pten Knock-out Mouse
Ljungberg, Sunnen et al., Dis Models Mech 2: 389-398, 2009
Rapamycin Suppresses Seizures in TSC-2
Knock Out Mice
Zeng et al. Ann Neurol 63: 444-453, 2008
TSC1 TSC2
Growth
Rapamycin
The Clinical Uses of m-TOR Inhibitors
• Therapy for a variety of cancers
• Immunosuppressant therapy following organ transplant
• Thousands of patients –including children -have been successfully treated with these drugs
Houston Chronicle Nov 25, 2009
mTor Inhibitors and Tuberous Sclerosis Complex
(TSC)
• Alterations in TSC1 or TSC2 Genesresult in TSC
• Incidence: 1/6000 individuals
• 80% have epilepsy – most severe
• Tubers (benign tumors) are responsible
• SEGAs - Subependymal Giant Cell Astrocytomas
Everolimus treatment of refractory epilepsy in tuberous sclerosis complex
Annals of NeurologyVolume 74, Issue 5, pages 679-687, 10 SEP 2013 DOI: 10.1002/ana.23960http://onlinelibrary.wiley.com/doi/10.1002/ana.23960/full#ana23960-fig-0002
Conclusion
• Study of relevant animal models can lead to the development of clinical trials and hopefully the development of new treatments for childhood epilepsy.
Other Genetic Models of EOEE: DravetSyndrome
• Nearly 80% of Dravet syndrome cases are caused by de novo mutations in the SCN1A gene.
• Thus, Dravet syndrome is a relatively homogeneous genetic disorder.
• SCN1A encodes the α subunit of the voltage gated sodium channel Nav1.1.
• Seizures begin during the first year of life as febrile seizures.
• Commonly children become intellectually disabled.
Dravet Syndrome Mouse Model
Yu et al. Nature Neurosc. 2006
Dravet Syndrome Zebrafish Model
Baraban et al. Nature Comm. 2013
IPS Cells from Dravet Patients
Liu et al. Annals Neurol. 2013
Genes for Lennox Gastaut Syndrome
Epi4K Consortium, Nature 2013
Of the 4 cases with GABRB3 mutations, 3 had LGS.
Lennox‐Gastaut syndrome: A consensus approach to differential diagnosis.
Criterion for an animal model?
Epilepsiapages 4-9, 3 OCT 2014 DOI: 10.1111/epi.12567http://onlinelibrary.wiley.com/doi/10.1111/epi.12567/full#epi12567-fig-0001
Infantile Spasms
• Severe syndrome of infancy - average onset age – 6 months
• Incidence: approximately 1 in every 3225 live births
• Long term outcome – usually poor – intractable epilepsy and learning impaired
• Over 200 disparate conditions associated with this seizure disorder ranging from:– CNS infections,
– Developmental brain abnormalities – cortical dysplasia
– Hypoxic-ischemic encephalopathy to
– Single gene mutations like TSC1 and 2 and ARX
• Spasms consist of brief bilateral jerking contractions of muscles of the extremities, neck and/or trunk – can be violent or subtle and most often cluster
• Therapies – ACTH and Vigabatrin
TABLE 3. Criteria for an ideal animal model of infantile spasms
1. Unprovoked spasms or myoclonic seizures early in postnatal development
2. EEG correlates of seizure events (ictal decremental response)
3. Abnormal interictal EEG ("hypsarrhythmia") reflecting generalized epileptic
encephalopathy
4. Response to clinical relevant treatment (e.g., ACTH and/or vigabatrin)
5. Behavioral/cognitive sequelae
Stafstrom Carl E., Moshé, Solomon L., Swann, John W., Nehlig, Astrid, Jacobs, Margaret P. & Schwartzkroin, Philip A.Models of Pediatric Epilepsies: Strategies and Opportunities.Epilepsia 47 (8), 1407-1414, 2006.
Infantile Spasms: Human & Rodent
General Timeline
Hypsarrhythmia
Hypsarrhythmia in Rat Model
TABLE 3. Criteria for an ideal animal model of infantile spasms
1. Unprovoked spasms or myoclonic seizures early in postnatal development
2. EEG correlates of seizure events (ictal decremental response)
3. Abnormal interictal EEG ("hypsarrhythmia") reflecting generalized epileptic
encephalopathy
4. Response to clinical relevant treatment (e.g., ACTH and/or vigabatrin)
5. Behavioral/cognitive sequelae
Stafstrom Carl E., Moshé, Solomon L., Swann, John W., Nehlig, Astrid, Jacobs, Margaret P. & Schwartzkroin, Philip A.Models of Pediatric Epilepsies: Strategies and Opportunities.Epilepsia 47 (8), 1407-1414, 2006.
Long Term Video EEG Recordings to Test Therapies
Vigabatrin Suppresses Spasms
Vigabatrin Suppresses Spasms
Vigabatrin Suppresses Spasms
Vigabatrin Suppresses Hypsarrhythmia
Conclusions
• It is possible to develop an animal model of infantile spasm
• And meet many of the rigorous criterion for an “ideal” model.
Lennox‐Gastaut syndrome: Criteria for an Ideal Animal Model?
Epilepsiapages 4-9, 3 OCT 2014 DOI: 10.1111/epi.12567http://onlinelibrary.wiley.com/doi/10.1111/epi.12567/full#epi12567-fig-0001
Lennox Gastaut Syndrome Genes
Epi4K Consortium, Nature 2013
Of the 4 cases with GABRB3 mutations, 3 had LGS.
GABRB3 Knockout Mice Have Multiple Seizure Types
DeLorey T M et al. J. Neurosci. 1998;18:8505-8514
©1998 by Society for Neuroscience
GABRB3 Knockout Mice are Learning Impaired
DeLorey T M et al. J. Neurosci. 1998;18:8505-8514
©1998 by Society for Neuroscience
Another Approach
• Twenty percent of children with infantile spasms will go on to have Lennox-Gastaut syndrome.
• Animals with epileptic spasms early in-life go on to have other types of seizures later in life.
• In the TTX model, prolonged focal seizures are common.
• It is possible that in one or more of these models a condition closely resembling Lennox Gastautsyndrome may be present.
• More work will be required to examine this possibility.
Conclusions
• There are good reasons to be optimistic that animal models of the epileptic encephalopathies can be developed and that these will lead to a better understanding of these syndromes and new therapies.
• Clinicians and basic scientists working together will speed discovery.
Acknowledgements
• Chong Lee Ph.D.• James Frost M.D.• Richard Hrachovy M.D.• John Le• Sunita Misra M.D. Ph.D.• Carlos Ballester-Rosado Ph.D.• Matt Weston Ph.D. • Masataka Nishimura M.D. Ph.D.• JR Casanova Ph.D.• Denae Nash Ph.D. • Trang Lam• Kevin Winoske
Supported by Grants from: NIH (NINDS) and the CURE Infantile Spasms Initiative
Katherine Nickels, MDChild and Adolescent Neurology and Epilepsy, Mayo ClinicOctober 25, 2014
Disclosures
• I have nothing to disclose.
What is Epilepsy?• Epilepsy is a medical disorder characterized by
repetitive seizures.
• There are many conditions that can lead to epilepsy
• Can be associated with developmental delay
• “epileptic encephalopathy”
• These disorders are rare but:
• can be very difficult to treat
• account for a disproportionate amount of disability in the population
Early Life Epilepsy for PERC
• Early life epilepsies (ELE) occur in nearly
1/500 young children in the population and
affect ~4000-5000 children per year in the
US.
• They include some of the most devastating
forms/causes of epilepsy.
• Refractory epilepsy
• Developmental devastation
• Life-long disability
• Early mortality
Reasons for devastating developmental outcomes
• Underlying causes
• Treatment
• Impact of abnormal activity in the brain
• Impact of all of these during critical times in neurodevelopment
Over the past ~2 decades
• Major advances in
• Understanding specific diagnoses
• Syndromic & seizures
• Genetic causes
• Neuroimaging
• Treatments
• Drugs
• Diet
• Surgery
• Steroids, immune
Questions• Are we doing a better job of treating infantile
epilepsies?
• How can we improve the processes and
outcomes further?
Lack of Evidence for Most Circumstances
• Use of Genetic testing
• Selection of medication
• Use of diet
• Use of surgery
Mission
• Create a national network of pediatric epilepsy centers
• Facilitate pivotal trials to improve the care and outcomes of children with epilepsy
• Provide research opportunities and experiences for junior investigators and develop research capacity for the future
Pediatric Epilepsy Research Consortium
• Multicenter collaboration of US-based pediatric epilepsy centers.
• Inspired by and modeled after
• Pediatric Oncology Group (POG)
• Pediatric Heart Transplant Consortium
• Brain tumor consortium
• Canadian Pediatric Epilepsy Network (CPEN)
History of PERC• First meeting 2011 at our annual
professional meeting• 13 centers were initially involved• We now have:
• By-laws• Steering committee• Annual meeting • Conference call every 2 months• 37 centers actively involved
Map
Goals• Collaboration leads to:
• Improved research
• There are already several studies that have developed through our organization
• Standardized care for children with epilepsy
• We are developing standardized treatment for infantile spasms
• Dravet project using consensus to develop diagnosis and treatment standards
• We do not have means to fund research
Goals Vision• Develop an enduring, national infrastructure
• Pivotal randomized clinical trials
• Practice-changing research
• Rapidly address important treatment and management questions for children with epilepsy and their families.
• Rapidly lead to improvements in care and outcomes
• Create research experiences and opportunities for junior investigators and develop clinical research capacity for the future
PERCWhy now?• Individually rare disorders
• Recent advances in diagnostic capabilities and treatments provide hope that the negative impact of these disorders could be reduced
• Rapidly advancing understanding of contribution of genetics on etiology and possible treatment/outcome
• Requires large networks of centers and investigators working together
Ongoing Projects
• Prospective Infantile Spasms Database
• RIKEE
• Early onset epilepsy consortium
• Prevent West Syndrome
• Dravet Modified Delphi Consensus Project
• Ohtahara group
• Rare disease group
Infantile Spasms Database• A prospective database that identifies
children with infantile spasms• Early identification and proper treatment lead
to better outcomes• Increasing awareness of genetic etiologies (up
to 50% with previously “unknown” cause!)• Due to recent escalation in price of
medication there has been resurgence in the debate over the proper treatment for these children
• There is no definite standard of care• Will be evolving into a treatment trial
RIKEE“Rational Intervention for KCNQ2 Epileptic Encephalopathy”
• Identify neonates presenting with a rare genetic disorder (KCNQ2)
• Offer rapid genetic testing
• Allow a new novel seizure medication to be used early
• Modify the devastating developmental course of the epilepsy
Early Onset Epilepsy Consortium• Prospective data collection to learn more
about epilepsy in children age birth to 3 years (critical developmental period)
• Define current clinical diagnostic and treatment practices
• Lay the foundation for future randomized clinical trials.
Prevent West Syndrome• Involves six centers in the consortium.
• West Syndrome is a severe epileptic encephalopathy which is characterized by frequent seizures (infantile spasms) and an EEG pattern termed hypsarrhythmia
• The study tracks children with brain injury at birth for early recognition of this EEG pattern, prior to the start of seizures
• Subsequent milestones will target treatment in this population
Normal EEG
Hypsarhythmia
Rare disease group• No standard of care
• Multiple etiologies for the same clinical syndrome
• Potential diseases/causes to target:
• Myoclonic Atonic Epilepsy
• Lennox Gastaut Syndrome
• Epilepsy with myoclonic absences
• Malignant migrating focal epilepsy
• Will be forming working groups for these conditions soon!
As of September 21, 2014
• 38 US centers have joined the consortium
• 21 actively participating in one or both ongoing studies.
• National Infantile Spasms Consortium
• Early Onset Epilepsy Consortium
584 patients enrolled so far!!!!
Comparison of Existing Programs to PERC
Collaborative
research
Pediatric
epilepsy
only
Epileptic
encephalopa
-thies
Single
disease
Professional
society
Provides
Grant funding
PERC
X X X
Epilepsy
Foundation
X
CURE +/- X
PERF X X
DRAVET SYNDROME
FOUNDATIONX X X
AES X X
CNS X X
Pediatric Epilepsy Research Consortium
PERCCentralized
Infrastructure
Randomized Trials
KetogenicDiet
Surgery
Steroids
InfantileSpasms
DravetSyndrome
GENETICS
EEGMRI
SEMIOLOGY
Development,CognitionBehavior
Early LifeEpilepsies
Health ServicesCare Models
PERC and LGS?
• Currently NO LGS patients enrolled in PERC… for now. Why?
• Early onset epilepsy consortium:
“Prospective data collection to learn more about epilepsy in children age birth to 3 years (critical developmental period)”
• LGS is really hard to diagnose that early! Why?• Should we be able to diagnose earlier?
• Are there markers?
• Will this result in better therapies and outcome?
Epile
psi
a. 1
98
9
ILAE 1989• Ages 1-8 yrs• Seizures are difficult to control:
• Tonic-axial, atonic and absence • Myoclonic, GTCS and focal seizures are
frequent• High seizure frequency; frequent SE
• EEG:• Generalized slow spike-waves (<3 Hz)• Frequent multifocal abnormalities• Bursts of 10 Hz fast rhythms in sleep
• Intellectual disability usual:• 60% occurs in children with previous
encephalopathy, 40% is primary
Problems with defining/diagnosing Lennox-GastautLennox-Gastaut syndrome is often loosely used to
describe any severe epilepsy syndrome of
childhood with epileptic falls and SSW on EEG
Other syndromes present at a similar age, with
similar seizures and EEG patterns
The “typical” seizure types are not always
present at onset, or may be subtle and not
recognized
At onset, children may be in the range of normal
Case 1: LM
• 4 months: 1 hour right sided seizure with
fever after vaccinations, imaging and EEG
normal
• 6 months: 90 minute left sided seizure with
febrile illness
• 8 months-13 months: recurrent prolonged
episodes of status epilepticus occurring
twice per month, usually with illness
• Developmental plateau
What is this?Features Dravet Syndrome LGS
Neurologic status pre-
seizure onset
Normal Often abnormal- 70%
West syndrome is ≈ 1/3
Predominant seizure
type
Recurrent febrile status
epilepticus, then status
epilepticus and other
seizures without fever
Nocturnal tonic
Drops due to atonic or
tonic seizures
Myoclonus not
predominant type
Febrile seizures Yes Usually not
Family history 25-70% with family
history of epilepsy or FS
Usually negative (<10%)
EEG Normal, then
generalized SW, +/-
photic sensitivity
SSW (<2 Hz), frontally
predominant,
paroxysmal fast
Other features? Plateau of skills,
temperature sensitivity
Dravet Syndrome
Dr. Charlotte Dravet 1978: Severe Myoclonic
Epilepsy of Infancy (SMEI)
Majority due to SCN1A mutation, variable
expressivity
Seizures exacerbated by sodium channel
antagonists!
Clobazam and stiripentol most helpful
Mortality is high for adults and children
and often seizure- related (15%)
Dra
vet.
Ep
ilep
sia.
20
11
What do we learn from this?• History of febrile status epilepticus nearly
excludes diagnosis of LGS
• Seizures can be worsened by some
medications (phenytoin, carbamazepine,
oxcarbazepine)
• Syndrome specific medications exist
• Seizure-related mortality is high in Dravet
syndrome and families should receive
proper counseling
Case 2: RD
• 2 ½ year old with new spells of arm
extension and abduction with truncal
flexion occurring in clusters and
developmental regression
EEG- interictal
Video
What is this?Features Asymmetric spasms
due to…
LGS
Neurologic status pre-
seizure onset
Mild delays Often abnormal- 70%
West syndrome is ≈
1/3
Predominant seizure
type
Asymmetric spasms
Focal seizures
Nocturnal tonic
Drops due to atonic or
tonic seizures
Myoclonus not
predominant type
Febrile seizures None Usually not
Family history None Usually negative
(<10%)
EEG Generalized SSW (<2
Hz), hypsarrhythmia
SSW (<2 Hz), frontally
predominant, fast
Other features?
MRI
RD- SISCOM
What do we learn?
•Focal lesions can cause
“generalized” epilepsy
•Long term outcome following
resection is excellent and
should be pursued early
•Good outcome even if surgery
done later in childhood
Gu
pta
, et
al.
Ped
iatr
ic N
euro
logy
. 2
00
7
Case 3: VS
• 8 month old, previously healthy
• With URI, developed refractory
myoclonic status epilepticus
• Initial investigations normal, later
transaminitis (AST/ALT)
• Development plateaued and
regressed, progressively hypotonic,
decreased visual fixation, recurrent
status epilepticus
Video
EEG- Ictal
What is this?Features Alpers/POLG1 LGS
Neurologic status pre-
seizure onset
Normal Often abnormal- 70%
West syndrome is ≈ 1/3,
Predominant seizure
type
Drug resistant
myoclonic status
epilepticus, recurrent
status epilepticus, EPC
Nocturnal tonic
Drops due to atonic or
tonic seizures
Myoclonus not
predominant type
Febrile seizures No Usually not
Family history Autosomal recessive Usually negative (<10%)
EEG High amplitude slowing
and generalized SW
SSW (<2 Hz), frontally
predominant,
paroxysmal fast
Other features? Episodic regression,
often with illness, liver
failure, VPA toxicity
Alpers hepatopathic
poliodystrophy Autosomal recessive, deficiency in mtDNA
polymerase gamma activity
Normal at birth, then:
Intractable epilepsy
Hepatic failure with micronodular cirrhosis
Episodic neurologic deterioration
Death
Age at presentation: 1 month-25 years
Progression over 3 months to 12 years
Valproic acid toxicity!
Nav
iau
xan
d N
guye
n.
An
nal
s o
f N
euro
logy
. 2
00
4
What do we learn from this?
• Metabolic/genetic epilepsies can
present in adulthood
• Any patient with progressive course
must be evaluated for underlying
metabolic pathology
• Valproic acid, commonly used for
LGS, can exacerbate mitochondrial
disease and liver failure
Summary• Early onset epilepsies can lead to refractory epilepsy,
lifelong disability, and early mortality
• Collaboration is necessary to improve research, standardize care, and rapidly improve treatment
• PERC is a consortium of 37 centers with prospective databases of children with early onset epilepsy and infantile spasms
• LGS is very difficult to diagnose early due to
• Variable age at onset
• Variable presentation
• Variable etiology
• Variable course
Where do we go from here?
• Ensure proper diagnosis of LGS patients by:• Know electroclinical syndrome classifications!
• LGS clues:
• Difficult to control seizures, often both generalized and focal
• Drop attacks
• Nocturnal tonic seizures
• Intellectual disability
• EEG
Where do we go from here?
• Ensure proper diagnosis of LGS patients by• Recognizing the LGS mimickers
• LGS mimicker clues
• Prominent febrile seizures at onset
• Temperature sensitivity
• Family history of similarly affected individuals
• Persistent asymmetry to EEG and seizures
• Rapidly progressive course
• Other organ involvement
Where do we go from here?
• Use the multicenter model (PERC) to study rare diseases, such as LGS to determine
• Recommended evaluations for determining underlying (and potentially treatable etiologies)
• Most effective treatment options
• Best care practices
2014 STRATEGIC RESEARCH PLAN
Table of Contents
Background
LGSF Strategic Research Committee (SRC)
Motivation for the Strategic Research Plan
Cochrane Review
IOM Report
Disparities
Barriers to LGS Research, Diagnosis and Quality of
Life
Goals of Strategic Research Plan Revised LGS Foundation Research Program
Proposed Timeline
Measurable Outcomes
Table of Contents
Background
LGSF Strategic Research Committee (SRC)
Motivation for the Strategic Research Plan
Cochrane Review
IOM Report
Disparities
Barriers to LGS Research, Diagnosis and Quality of
Life
Goals of Strategic Research Plan
Proposed Timeline
Measurable Outcomes
BACKGROUND:
LGSF Strategic Research Committee (SRC)
Who we are:
A group of stakeholders and research professionals
Dedicated to:
Furthering research in Lennox-Gastaut Syndrome
Increasing opportunities & identifying gaps in LGS
research
Reducing barriers to research
With the overall goal of:
Improving quality of life for individuals with LGS
Educating families to facilitate engagement in research
Expanding the cohort of investigators in LGS
BACKGROUND
Motivation for the Strategic Research Plan
Cochrane Review
According to the Cochrane review, the optimum treatment for Lennox-Gastaut syndrome has yet to be established.
Lennox-Gastaut syndrome is a seizure disorder that is commonly associated with behavioral and mental health problems.
Many different treatments are currently used in the treatment of this disorder and many more have been tried in the past, often with little success.
Hancock EC, Cross HJ. Treatment of Lennox-Gastaut syndrome. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD003277. DOI: 10.1002/14651858.CD003277.pub2.
BACKGROUND
Motivation for the Strategic Research Plan
Cochrane Review:
The review of drug trials found no evidence to
suggest that any one drug was more effective than
another in the treatment of this disorder in terms of
controlling the different seizure types.
More research is needed to compare the
therapies currently available.
Hancock EC, Cross HJ. Treatment of Lennox-Gastaut syndrome. Cochrane Database of Systematic Reviews
2009, Issue 3. Art. No.: CD003277. DOI: 10.1002/14651858.CD003277.pub2.
BACKGROUND
Motivation for the Strategic Research Plan
Institute of Medicine Report on the Epilepsies:
The committee calls for improved data collection on epilepsy to inform health policy and to identify opportunities for reducing the burden of the disorder
Opportunities exist to prevent the consequences of epilepsy, including interventions to improve seizure control in people who have both epilepsy and depression, to reduce internalized feelings of discrimination, and to eliminate epilepsy-related causes of death, such as sudden unexpected death in epilepsy (SUDEP).
The committee highlights the need for additional research, which will contribute to new insights and approaches to the prevention of epilepsy
IOM Report From the report brief at: http://www.iom.edu/Reports/2012/Epilepsy-Across-the-Spectrum/Report-Brief.aspx
BACKGROUND
Motivation for the Strategic Research Plan
Disparities
The SRC identified additional disparities and needs for
a strategic research plan in Lennox-Gastaut
Syndrome. These include:
Diagnosis:
1. Phenotypic variability within LGS
2. Diagnosis is inconsistently applied, making it
challenging for researchers to study this population
3. Shortage of pediatric neurologists in the U.S. and
worldwide
BACKGROUND
Motivation for the Strategic Research Plan
Disparities
The SRC identified additional disparities and needs for
a strategic research plan in Lennox-Gastaut
Syndrome. These include:
Specific challenges to LGS research
1. Ill-defined cohort & lack of ICD-10 code makes LGS a
challenging patient population to study
2. Few well-described epidemiological studies in LGS
3. Dearth of high quality basic research on LGS
BACKGROUND
Motivation for the Strategic Research Plan
Disparities
The SRC identified additional disparities and needs for
a strategic research plan in Lennox-Gastaut
Syndrome. These include:
Patient engagement:
1. The disease itself is a great burden to families making it
difficult for families to participate in studies.
Table of Contents
Background LGSF Strategic Research Committee (SRC)
Motivation for the Strategic Research Plan
Cochrane Review
IOM Report
Disparities
Barriers to LGS Research, Diagnosis and Quality of Life
Goals of Strategic Research Plan Revised LGS Foundation Research Program
Communications Strategy
Proposed Timeline
Measurable Outcomes
Barriers to LGS Research, Diagnosis
and Quality of Life
Lack of
Optimal
Treatments
Lack of Data
from Patients
with LGS
Difficulty in
making LGS
Diagnosis
Difficult for
families to
participate in
clinical
research
Barriers to LGS Research, Diagnosis
and Quality of LifeLack of
Optimal
Treatment
s
Strategy
Identification of genes involved in LGS
Support Epi4K or other genetic studies of LGS
Target Identification
Fund or support targeted RFAs for projects that elucidate
pathways involved in LGS
Drug Screens
Continue to fund or support high-throughput drug
screening projects
Collect resources for iPSCs from LGS patients for drug
screens on human neurons
Barriers to LGS Research, Diagnosis
and Quality of LifeLack of
Data from
Patients
with LGS
Strategy
Create collection of LGS data from patients
Participate in REN
Update data fields for LGSF member registration
Metric
Target:
Enroll 250 LGS families in REN in first twelve months
Enroll another 150 in next twelve months
Barriers to LGS Research, Diagnosis
and Quality of LifeDifficulty in
making
LGS
Diagnosis
Strategy
Improve diagnosis of LGS through physician
awareness
Advocate for ICD-10 code for LGS
Advocate for inclusion of Slow Spike Wave Pattern in
Common Data Elements
Improve understanding of LGS phenotype
Promote phenotyping studies, including deep phenotyping
and genotype-phenotype studies
Barriers to LGS Research, Diagnosis
and Quality of LifeDifficult for
families to
participate in
clinical
research
Strategy
Improve awareness of research opportunities and
ease burden of participating in research
Continue to fund travel grants for families
Create opportunities for families to participate in research
at LGS conference
Metric
Target: enroll 25% of probands, siblings, and
parents at the family conference in onsite bio-sample
collection (future goal)
Table of Contents
Background LGSF Strategic Research Committee (SRC)
Motivation for the Strategic Research Plan
Cochrane Review
IOM Report
Disparities
Barriers to LGS Research, Diagnosis and Quality of Life
Goals of Strategic Research Plan Revised LGS Foundation Research Program
Communications Strategy
Proposed Timeline
Measurable Outcomes
Goals of Strategic Research Plan
Better
Research
Educate &
Engage
Families
Expand
Cohort of
Researchers
Goals of Strategic Research Plan
Better
Research
Better Research:
Revised LGSF Research Program
LGS Foundation Advocates for Better Research
Through:
Revised (stronger) LGSF Research Program
Participation in Rare Epilepsies Registry
Need for ICD-10 code or EMR’s / common data
elements that capture EEG pattern for studying LGS
patients
Further collaboration:
Rare Epilepsies Groups & Vision 20/20
Resources in Epilepsy Research
NINDS – hold a workshop on LGS ?
Other professional conferences
Better
Researc
h
Better Research:
LGSF Research Program
LGS Foundation’s Current Seed Grant Program
One-year research grants up to $20,000 (including
no more than 10% in indirect costs)
Awarded to young investigators, physician residents,
and clinicians who are interested in studying LGS
Our seed grants are intended to help researchers
explore novel ideas and answer questions related to
the clinical aspects, therapies and/or genetic causes
of LGS.
Better
Researc
h
Better Research:
Revised LGSF Research Program
LGS Foundation’s Revised Research Program
Grants awarded to young and established
investigators, physician residents, and clinicians who
are interested in studying LGS
Our research grants are intended to
help researchers explore novel ideas and
answer questions related to the clinical aspects,
therapies and/or genetic causes of LGS
Research grants include five targeted grant areas
Better
Researc
h
Better Research:
Revised LGSF Research Program
Suggested / Targeted Grant Areas
Finding the
Cause
Genotyping /
Phenotyping
OR
Patient
Centered
Research
New
Treatments
Epidemiolog
y
Quality of
Life
Better
Researc
h
And open to other targeted grant areas
Better Research:
Revised LGSF Research Program
LGS Foundation Revised Grant Types
SEED GRANTSOne-year research grants up to $30,000 (including no more than 10% in indirect costs)
COLLABORATIVE GRANTSAmount TBD each year
POST-DOCTORAL RESEARCH GRANTSTwo-year research grants up to $50,000
FAMILY-SPONSORED NAMED RESEARCH GRANTSAmount TBD / unique to each family; minimum grant = $10,000
Better
Researc
h
Better Research:
Revised LGSF Research Program
Revised Guidelines / Infrastructure
For grantees:
LGSF to develop a legally binding agreement
Measurable outcome statement needed
Ask for outcome / data back to foundation
PAB to help us interpret data and use as we see fit (effective and ineffective)
Standardize template to reduce the overhead of applying
Letter of inquiry – we will evaluate, not mandatory
Lay reviewers in addition to PAB / BOD
Next grant cycle will begin Jan 1 2015
No more than 10% in indirect costs
Better
Researc
h
Goals of the Strategic Research Plan
Educate &
Engage
Families
Engage Families
Get families more involved in research
Family conference is great platform
Patient registry / database (REN)
Encourage families to fundraise
Named research grants
Re-development of fundraising plan
End of year fundraising strategy
Fundraising packet re-developed
Funding graph on website / “where your money goes”
Improve communication with families about research
opportunities
Educate
&
Engage
Families
Engage Families
Communications plan
Communicate new findings with patient community in a lay
friendly way
Communication should bridge the gap between abstract
research and relevance to patient community’s daily
experience
Build enthusiasm about research and cultivate research
participants/donors
Cultivate advocates to further research
Disseminate LGS journal articles to constituents in an easy-to-
understand way
Families Should understand importance / relevance of research
as it relates to their circumstance and experiences.
Educate
&
Engage
Families
Educate Families
Provide better education to families on the
importance of research in LGS
Utilize clinical trial resources such as HERO website
(human epilepsy research opportunities) or Clinical Trial
Finder
Help families understand etiologies of LGS
More education on “worst-case” scenarios such as
SUDEP, status, seizure-related accidents
Educate
&
Engage
Families
Goals of the Strategic Research Plan
Expand
Cohort
Expand Cohort
Professional Development
Encouraging new investigators to get involved in LGS research
Rare epilepsies meeting possible; if not, further collaboration in professional organizations
Research Roundtable – maximize exposure at AES; lengthen meeting, invite new researchers
Participation in ERC (epilepsy resource center) during AES
Expanding professional session at LGSF conference
Electing a PAB chair to help facilitate and increase professional communication
Increase membership on PAB
Support investigators who are applying for larger funding above the LGSF’s program (CURE, NIH, NINDS).
Expand
Cohort
Expand Cohort
LGS Published Research
Promoting/supporting LGS research publications
White papers / position papers from LGSF
Self-publishing an LGS peer reviewed journal
PLOS ONE?
Further collaboration with LGS Hope / build upon
existing infrastructure
Expand
Cohort
Table of Contents
Background
LGSF Strategic Research Committee (SRC)
Motivation for the Strategic Research Plan
Cochrane Review
IOM Report
Disparities
Barriers to LGS Research, Diagnosis and Quality of
Life
Goals of Strategic Research Plan
Proposed Timeline
Measurable Outcomes
Proposed Timeline
2014• Database elements done!• Evaluating currently LGSF-funded projects• IDC Code – working on • Position paper - working on• Research liaison/coordinator – working on• Elect PAB chair• Update research page on w/s- done!• Announce prelim research plan at LGSF
meeting and research roundtable• Develop legally binding agreement / timeline
expectations• Measurable outcome statement – working on• Ask for outcome / data back to foundation
• Standardize template
• PAB expansion
20151
stQuarter
Jan. 1 – Launch research Plan!Journal Decision Choose lay reviewersOpen new research cycle
2nd
/ 3rd
Quarter Small LGS professional conference Discussion re: rare epilepsy conference Systematic review of LGS treatments/Cochrane
4th
QuarterDecember 1 - Announce 2016 Research
Opportunities
Table of Contents
Background
LGSF Strategic Research Committee (SRC)
Motivation for the Strategic Research Plan
Cochrane Review
IOM Report
Disparities
Goals of Strategic Research Plan
Proposed Timeline
Measurable Outcomes
Barriers to LGS Research, Diagnosis and Quality of
Life
Measurable Outcome Statement
What is the desired outcome of this research plan?
Who will benefit from this plan?
What will happen if the LGS Foundation does not
participate in research or follow through with this
plan?
How is performance measured? What tool or data
collection method will be used to collect performance
information from what source, how often?