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, 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:

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.):

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

• 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)

• 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:

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 attackson 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:

• 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

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 theepilepsies. New York: Raven Press, 1993:609–621.

Engel class outcomes of resective surgery in children 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

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.

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

• 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:

- 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

Rapamycin

4E-BP1

eIF4EeIF4G

mRNA Translation

Cell Growth

Signaling Pathways are like Molecular Freeways

Rapamycin

mRNA Translation

Cell Growth

TSCs and Pten Slow the Speed of Molecules

Rapamycin

mRNA Translation

Cell Growth

Rapamycin

mRNA Translation

Cell Growth

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

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

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)

growth

Rapamycin

Vehicle

Rapamycin

6 wks 9 wks4 wks

Rapamycin Suppresses Seizures in NS-Pten Knock-out Mouse

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

• 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 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

GABRB3 Knockout Mice are Learning Impaired

DeLorey T M et al. J. Neurosci. 1998;18:8505-8514

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

• 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

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

Epileptic

encephalopa

-thies

Single

disease

Professional

society

Provides

Grant funding

Epilepsy

Foundation

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?

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

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%)

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

What is this?Features Asymmetric spasms

due to…

seizure onset

Mild delays Often abnormal- 70%

West syndrome is ≈

Predominant seizure

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?

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

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

EEG- Ictal

What is this?Features Alpers/POLG1 LGS

seizure onset

Normal Often abnormal- 70%

West syndrome is ≈ 1/3,

Predominant seizure

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

Age at presentation: 1 month-25 years

Progression over 3 months to 12 years

Valproic acid toxicity!

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

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

Goals of Strategic Research Plan Revised LGS Foundation Research Program

Proposed Timeline

Measurable Outcomes

Table of Contents

Background

Cochrane Review

IOM Report

Disparities

Goals of Strategic Research Plan

Proposed Timeline

Measurable Outcomes

BACKGROUND:

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

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 LGSF Strategic Research Committee (SRC)

Cochrane Review

IOM Report

Disparities

Barriers to LGS Research, Diagnosis and Quality of Life

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

and Quality of LifeLack of

Optimal

Treatment

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 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

and Quality of LifeDifficulty in

making

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 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)

Cochrane Review

IOM Report

Disparities

Barriers to LGS Research, Diagnosis and Quality of Life

Communications Strategy

Proposed Timeline

Measurable Outcomes

Better

Research

Educate &

Engage

Families

Expand

Cohort of

Researchers

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

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

Better Research:

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

Better Research:

Suggested / Targeted Grant Areas

Finding the

Genotyping /

Phenotyping

Patient

Centered

Research

Treatments

Epidemiolog

Quality of

Better

Researc

And open to other targeted grant areas

Better Research:

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

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

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

Cochrane Review

IOM Report

Disparities

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

stQuarter

Jan. 1 – Launch research Plan!Journal Decision Choose lay reviewersOpen new research cycle

Quarter Small LGS professional conference Discussion re: rare epilepsy conference Systematic review of LGS treatments/Cochrane

QuarterDecember 1 - Announce 2016 Research

Opportunities

Table of Contents

Background

Cochrane Review

IOM Report

Disparities

Proposed Timeline

Measurable Outcomes

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

How is performance measured? What tool or data

collection method will be used to collect performance

information from what source, how often?

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