04 saturday post lunch track 2 10-25-14

Current Strategies for the Management of Lennox-
Gastaut Syndrome (LGS): Recommendations of the
LGS Working Group of Experts
Robert Gilbert, STL, CMPP
Vasanti Anand, PhD
PharmaWrite/MedVal
Scientific Information Services
Princeton, NJ

Current Strategies for the Management
of Lennox-Gastaut Syndrome (LGS)
• 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
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:

LGS Working Group Members (cont.):
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

A consensus approach to differential diagnosis
Authors: Blaise F.D. Bourgeois, Laurie M. Douglass, and Raman Sankar
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

Diagnosis
• 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)

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]

Conclusions:
• 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
Diagnosis

The efficacy and tolerability of pharmacological options in LGS
Authors: Georgia D. Montouris, James Wheless, and Tracy Glauser

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.

Mean reduction in drop attack frequency on
anticonvulsant versus placebo:

Percent of patients with >50% reduction in drop attacks
on anticonvulsant versus placebo:

A tabulated summary of key clinical trial data for FDA-approved
and commonly used medications (valproate, clonazepam, and
zonisamide) is also provided:

Conclusions:
• 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- and
long-term efficacy of the different treatment options

Surgical options for patients with Lennox-Gastaut syndrome
Authors: Laurie M. Douglass and Jay Salpekar

Surgical Options for Patients With LGS
Surgical evaluation criteria for patients with LGS who do not respond adequately
to pharmacotherapies

Surgical approach to the evaluation of LGS (Figure created by Dr. Douglass):
a= If patient has atonic seizures,
consider corpus callostomy over VNS

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 the
epilepsies. New York: Raven Press, 1993:609–621.

Engel class outcomes of resective surgery in children with LGS

Conclusions:
• 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 resective
surgery

Nonpharmacologic care for patients with Lennox-Gastaut syndrome:
Ketogenic diets and vagus nerve stimulation
Authors: Eric H. W. Kossoff and W. Donald Shields

Nonpharmacologic care for patients with
Lennox-Gastaut syndrome: Ketogenic diets and
vagus nerve stimulation
Composition of the 4 major ketogenic diets (KD):
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
Adapted from Kossoff EH, Hartman AL. Curr Opin Neurol 2012;25:173–178.

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.

Summary of recent studies reporting the effectiveness
of VNS in patients with LGS:

Conclusions:
• 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

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)
- Health care providers should have these resources
on hand and recommend them to patients with
LGS and their families
- Resources include: Advocacy support groups, education,
and national support

Resources for caregivers and families of
patients with Lennox-Gastaut syndrome
Gibson P. Epilepsia, 55(Suppl. 4):34–36, 2014

Other Publications
Lennox-Gastaut syndrome: impact on the caregivers and families of patients
Author: Patricia A. Gibson.
- Pilot survey designed to explore the impact of
epilepsy on caregiver’s QoL (based on Ms. Gibson’s
clinical experience)
- Physical, social, emotional, and financial impact
on the entire family
- Resource for health care professionals
Journal of Multidisciplinary Healthcare 2014:7;441–448

Other Publications
The impact of Lennox-Gastaut Syndrome on Families (Epilepsy and Seizure
Series Part 4)
Author: Patricia A. Gibson.
EP Magazine. 2014;48-51
• Informational resource for parents and
caregivers of patients with LGS

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 Hospital
Baylor College of Medicine

Three Stories and Two Proposals
• The Everolimus Trials for TSC
• Other Epilepsy Encephalopathy Genes –
Mouse, Fish and Cell-Based Models of Dravet
Syndrome
• 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
PTEN
mTOR
P P
S6
GFR
IR
PDK1
TSC
1
TSC
2
Akt
P
Rapamycin
6SK
4E-BP1
eIF4E
eIF4E
eIF4G
P
48S
P
mRNA Translation
Cell Growth
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

The NS-Pten Knock-out Mouse
The PI3K/mTOR pathway is activated knockout neurons
PTEN pS6 PTEN/pS6
PTEN and phospho-S6 (pS6) double immunofluorescence of cortical layer Ljungberg, Sunnen et al., Dis Models Mech 2: 389-398,
2009
PI3K
mTOR
S6
PTEN
growth
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
Ground
EEG
Sunnen, Anderson et al.

Can Rapamycin take the place of Pten or TSC ?
Electrode
Implant
EEG Recording
Rapamycin
or Vehicle
Sacrifice
3 4 5 6 7 8 9
Age (in weeks)
PI3K
mTOR
S6
PTEN
Rapamycin
growth
Ljungberg, Sunnen et al., Dis Models Mech 2: 389-398,
2009

Rapamycin Suppresses Seizures in NS-Pten
100
75
50
25
0
Vehicle
Rapamycin
***
**
4 wks 6 wks 9 wks
Epileptiform Activity (% time)
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 Genes
result 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 Neurology
Volume 74, Issue 5, pages 679-687, 10 SEP 2013 DOI: 10.1002/ana.23960
http://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: Dravet
Syndrome
• 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
Of the 4 cases with GABRB3 mutations, 3 had LGS.
Epi4K Consortium, Nature 2013

Lennox‐Gastaut syndrome: A consensus approach to
differential diagnosis.
Criterion for an animal model?
Epilepsia
pages 4-9, 3 OCT 2014 DOI: 10.1111/epi.12567
http://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

Long Term Video EEG Recordings to Test
Therapies

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?
Epilepsia
pages 4-9, 3 OCT 2014 DOI: 10.1111/epi.12567
http://onlinelibrary.wiley.com/doi/10.1111/epi.12567/full#epi12567-fig-0001

Lennox Gastaut Syndrome Genes
Of the 4 cases with GABRB3 mutations, 3 had LGS.
Epi4K Consortium, Nature 2013

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 Gastaut
syndrome 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, MD
Child and Adolescent Neurology and Epilepsy, Mayo Clinic
October 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

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

PERC
Why 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
FOUNDATION
X X X
AES X X
CNS X X

Pediatric Epilepsy Research Consortium
PERC
Centralized
Infrastructure
Randomized
Trials
Ketogenic
Diet
Surgery
Steroids
Infantile
Spasms
Dravet
Syndrome
GENETICS
SEMIOLOGY
MRI EEG
Development,
Cognition
Behavior
Early Life
Epilepsies
Health Services
Care 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?

Epilepsia. 1989
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-Gastaut
Lennox-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%)
Dravet. Epilepsia. 2011

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

What is this?
Features Asymmetric spasms
due to…
LGS
onset
Mild delays Often abnormal- 70%
West syndrome is ≈
1/3
Predominant seizure
type
Asymmetric spasms
Focal seizures
Nocturnal tonic
tonic seizures
Myoclonus not
predominant type
Febrile seizures None Usually not
Family history None Usually negative
(<10%)
EEG Generalized SSW (<2
Hz), hypsarrhythmia
predominant, fast
Other features?

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
Gupta, et al. Pediatric Neurology.
2007

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

What is this?
Features Alpers/POLG1 LGS
onset
Normal Often abnormal- 70%
West syndrome is ≈ 1/3,
Predominant seizure
type
Drug resistant
myoclonic status
epilepticus, recurrent
status epilepticus, EPC
Nocturnal tonic
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
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!
Naviaux and Nguyen. Annals of
Neurology. 2004

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

• 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

• 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

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
 Cochrane Review
 IOM Report
 Disparities
Life

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
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
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
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
Disparities
 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
Disparities
 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
 Cochrane Review
 IOM Report
 Disparities
Life
 Revised LGS Foundation Research Program
 Communications Strategy

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

and Quality of Life
Lack 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

and Quality of Life
Lack 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

and Quality of Life
Difficulty 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

and Quality of Life
Difficult 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)

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
Better
Researc
 One-year research grants up to $20,000 (including
no more than 10% in indirect costs)
h
 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 Research:
LGS Foundation’s Revised Research Program
Better
Researc
 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
h

Better Research:
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:
LGS Foundation Revised Grant Types
SEED GRANTS
One-year research grants up to $30,000 (including no more than 10% in indirect costs)
POST-DOCTORAL RESEARCH GRANTS
Two-year research grants up to $50,000
COLLABORATIVE GRANTS
Amount TBD each year
FAMILY-SPONSORED NAMED RESEARCH GRANTS
Amount TBD / unique to each family; minimum grant = $10,000
Better
Researc
h

Better Research:
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
Educate
Engage
Families
 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 Families
 Provide better education to families on the
importance of research in LGS
Educate
&
Engage
Families
 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

Goals of the Strategic Research Plan
Expand
Cohort

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
LGS Published Research
Expand
Cohort
 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

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
2015
1
st
Quarter
Jan. 1 – Launch research Plan!
Journal Decision
Choose lay reviewers
Open new research cycle
nd
/ 3
2
rd
Quarter
Small LGS professional conference
Discussion re: rare epilepsy conference
Systematic review of LGS treatments/Cochrane
th
4
Quarter
December 1 - Announce 2016 Research
Opportunities

Table of Contents
 Background
 Cochrane Review
 IOM Report
 Disparities
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?

04 saturday post lunch track 2 10-25-14

04 saturday post lunch track 2 10-25-14

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to 04 saturday post lunch track 2 10-25-14

Similar to 04 saturday post lunch track 2 10-25-14 (20)

More from LGS Foundation

More from LGS Foundation (17)

Recently uploaded

Recently uploaded (20)

04 saturday post lunch track 2 10-25-14