Selected Presenter Slides

COMORBITIES ASSOCIATED WITH LENNOX-GASTAUT

SYNDROME

NATIONAL LGS MEETINGCerritos CA May 3,4 2013

Michael G. Chez MDDirector Pediatric Neurology and Epilepsy, Sutter Neuroscience InstititueSacramento, CA

Professional Advisory Board LGS Foundation

No conflicts with today’s lecture

History

William G. Lennox 1884–1960 Henri Gastaut 1915-1995

Defined EEG and Clinical Abnormalities of this disease

LGS clinically described syndrome is actually spectrum of causes

• DEFINED BY CLINICAL FINDINGS

• HETEROGENOUS/ THEREFORE VARIOUS CAUSES

• NOT ONE CAUSE SO NOT ALL CASES RESPOND RESPOND THE SAME

LENNOX GASTAUT SYNDROME

Defining LGS

Incidence: estimate 2:100,000 0.002%

Approximately 5% of Children with epilepsy

20 % prior Infantile Spasms of West Syndrome

Clinical Definition

Age of onset typically after age 2

Can be normal before onset

May rarely start in adolscence or adult

Mortality rate ranges from 3% to 7%

Clinical Manifestations

Seizure Onset may be sudden and progress rapidly if not prior seizure history (i.e. prior infantile spasms)

Spectrum of CausesIdiopathic 30%Lesional 70%SyndromeGenetics

• INJURY TO BRAIN• GENETICS/ DRAVETS• OTHER GENETICS FOX,

CDLK, KCNQ2 VARIENT,TSC1,2

• ANGELMANN'S; AICARDI, TSC RETTS ETC

• De Novo Mutations CNV• INFECTION• IDIOPATHIC

LGS ETIOLOGY

LGS defined by clinical seizure type and EEG pattern

Irregular backgroundHigh amplitude slowSlow spike and waveElectrodecremental

response spike waveFast “buzz”type

discharges in sleep

LGS DEFINEDEEG FINDING

LGS EEG

COMPLICATED REFRACTIVEMULTIPLE MEDICATIONS

VARIABLE ETIOLOGYUNDERLYING BRAININJURYSIDE EFFECTSCOMPLLAINCEPHYSICAL INJURY/CONCUSSION

LGS CLINICAL COURSE

LGS COMORBITIES

LGS COMORBID CONCERNSMEDICAL ISSUESETIOLOGYISSUES CONCERN OUTCOMETREATMENT VARIABILITYSIDE EFFECTS TREATMENT

TREATMENT LGS

TREATMENT LGS

MEDICATIONSCOGNITIVE EFFECTSOLD VS. NEW MEDICATIONS

LGS SEIZURE and TREATMENT

LGS Seizure Patterns

Can Alter OutcomeEarly InterventionDrop Attacks/ Atonic Atypical Absence

WorsenEtilogyDoose vs. DravetHead Injuries/ Status EpilepsticusAtypical Absence

EEG Improvement ususally correlates with better seizure control and cognitive outcome

TREATMENT LGSEEG PATTERN CORRELATES WITH DEVELOPMENTAL ARREST EARLY IN COURSEIF EEG IMPROVES MAY SEE BETTER OUTCOME

EEG PATTERNSGeneralized attentionFocal Memory

AEDS IN LGSAEDS CAN CAUSE SIDE EFFECTSEEG PATTERNS CAN AFFECT ATTENTION (GENERALIZED SPIKE WAVE)EEG PATTERNS CAN AFFECT MEMORY (FOCAL)ATYPICAL ABSENCE/ STUPOR

Often PolytherapyOften mixture mechanismsAll AEDs inhibitory cortical excitation

AEDS IN LGSAEDS CAN CAUSE SIDE EFFECTSEEG PATTERNS CAN AFFECT ATTENTION (GENERALIZED SPIKE WAVE)EEG PATTERNS CAN AFFECT MEMORY (FOCAL)ATYPICAL ABSENCE/ STUPOR

AED Polytherapy the norm: > 3 AED typical in LGS

AED sedationMechanisms inhibit learningCombination Therapy SedatingBehavioral side effectsTopamax memory, cognitiveKeppra /Phenobarbitol irritabilityDepakote/ others: attention sedationBenzodiazepines muscle tone,oral motor,

sedation

If Cortex in LGS less excitable then local synaptic modeling less likely to adopt and learn new connectivity or learning may be inhibited

LGS Brain may be less excitable than normal brain

Cause vs underlying issue of disease state?

LGS less synaptic potentiationLess ability to learn or inhibitdefective inhibition/excitation

Synaptic stability is new area of neuroscience

Many genes associated with comorbid psychiatric conditions exhibit less synaptic excitation/ inhibition

Protein scaffolding abnormal Shank Genes and Rett’s Fragile X etc

COMORBID LEARNING ISSUES IN LGS

Attention DeficitMay see with AED and frequent

generalized seizuresAbsence/ atypical absence>40% children with epilepsy may have

ADD/ ADHD

Atypical Absence

Prolonged staring

Slow spike and wave or polyspike –wave

1-3 hz FrequencyMay be refractive

to typical medications for absence seizures

Sometimes worse benzodiazepines

LANGUAGE COMORBIDITY

EARLY ONSET EPILEPSY

Focal Epilepsy Language Regions

Sleep Dysruption

Oral Motor Delay

Etiology

Prior IS Genetics Brain Injury

Auditory Processing Issues

Memory

BEHAVIORAL ISSUES LGS

Delayed speechDelayed impulsesFrontal Lobe Pseudobulbar AffectSleep IssuesAggressionSelf-Injury

Autism Features80% will have autism spectrum featuresWorse with poor seizure control

PSYCHIATRIC COMORBIDITY LGS

Depression 30-40% epilepsy

Bipolar/ Psychosis 15-25% Epilepsy

Cognitive Decline/ Cognitive Disability (IQ<70)

CASE EXAMPLE LGS GENETIC denovo mutation 7q21 deletionThis is a case of 3.5 yr old boy with history of autism behavior and atypical absence seizures who begins drop attacks while starting valproic acid therapy

Patient found genetic defect on microarray 7q21-

Patient negative for channelopathy screen

Parents negative for mutation

Patient had diagnosis autism pre-treatment and LGS on EEG and seizures clinically12 weeks after normal EEG no longer autistic no in regular 1st grade mild ADHD

JP 7q21.3 copy deletion post-depakote/pre-felbatol/clobazam

JP post felbatol and depakote 4 weeks 7q21.3

JP Chromosome 7q21.3 deletionpost-felbatol and clobazam July 2011 at 8 weeks

SCN1A defect Dravet EEG change high dose clobazam 1mg/kg

LGS Pre-Valium/Post-Valium

2p11- case

Variability in LGS ComorbityTREAT THE PATIENT

EEG TREATMENT CRITICAL

COMORBID MEDICATION ISSUES NEED TO BE CONSIDERED

AED choices should use rational polytherapy: complimentary mechanisms

Patient comorbid ADHD mood or anxiety, sleep, or other disorders need to be managed per individual

Early aggressive EEG treatment/ seizure control probably most effective effort to llimit cognitive outcome especially in idiopathic cases, but also some genetic subtypes

LGS Summary

Treatment should be aggressive due to refractory nature of seizures

Treatment should include pharmacological, dietary, immune, and surgical options

Treatment of comorbid neuropsychological aspects may improve quality of life

Thorough Genetic evaluation needed all cases without clear brain injury like HIE or stroke /infection

Neuromodulation

Eric BJ Segal, MDPediatric Epileptologist

Northeast Regional Epilepsy GroupHackensack, New Jersey

Goal of treatment of epilepsy

Eliminate seizures without a significant impact on behavior or cognition.

Initial therapy – medications More than 50% of patients become

seizure-free with initial therapy Less than 20% will become

seizure-free with further medications.

When to consider non-medication therapies?

When medications do not prevent seizures or side effects are intolerable.

Non-pharmacolgic therapies

Epilepsy surgery Diet therapy Neuromodulation

What is neuromodulation? Seizures are caused by synchronized

firing of an inappropriate network of neurons.

Electrical current can be used to suppress neuronal firing or interfere with synchronized firing of a population of neurons.

Electrical stimulation of the central nervous system in order to prevent seizures.

Types of neuromodulation modalities

Vagal Nerve Stimulation Deep Brain Stimulation Trigeminal Nerve Stimulation* Responsive Neurostimlation Transmagnetic Stimulation*

Vagal nerve stimulation (VNS)

Generator delivers intermittent electrical stimulus to wire coiled around left vagus nerve in neck

Vagal nerve then transmits signal to the brainstem and then to areas involved in epileptogensis.*

VNS practicalities

Battery is replaceable/removable. Programmed by non-invasive

paddle. Additional stimulation

administered through magnet

VNS efficacy (for LGS) At 6 months – 27-64% reduction. 50% seizure reduction rate at 6 months–

50% 50% seizure reduction rate at 12

months – 65% Drop seizures decreased by 88%.

References: Arzimangolu 2009, Kotagal 2011, Rosenfeld 2009.

VNS Complications

Infection rate: 3% (1% require explant)

Most common side effects: hoarseness/voice alteration (37%), throat pain (11%), cough (7%).*

Additional considerations

Generator can be removed, wire generally not.

MRI compatible only if MRI has a send/receive coil.

VNS vs. corpus callosotomy: which is better for seizures? Only 2 studies comparing both procedures –

small number of patients. VNS is less invasive, lower risk procedure.

VNS efficacy can be improved over time. Can take up to 6-12 months to see full effect.

Callosotomy has higher risk of complications (but relatively low vs. other surgeries). Immediate improvement (does not continue to improve over time). Better for tonic/atonic seizures compared to generalized tonic-clonic seizures.

Deep brain stimulation

Successfully used in movement disorders.

Similar structures stimulated in movement disorders are thought to be helpful in epilepsy.

How is it done?

Deep Brain Stimulation

Chronic electrical stimulation applied directly into deep nuclei in the brain.

Why are these nuclei chosen?

Generalized seizures are likely generated by deep structures of the brain.

Utilize relay stations that communicate with the cortex.

Utilize inhibitory neurons in the brain.

Anterior Nucleus of Thalamus Many animal

epilepsy models involve the Circuit of Papez.

Interruption of this circuit prevents seizures.

The anterior portion of the thalamus is part of this circuit.

Stimulation of anterior nucleus of thalamus

SANTE (double-blinded, placebo-controlled) –110 patients with partial seizures. 3 months: 40.4% median

decrease vs. 13.5%. 2 years (unblinded): 56%

median reduction with 54% have a >50% seizure reduction.

5 years later, >50% seizure reduction rate 69% and median seizure reduction rate also 69%.

Stimulation of anterior nucleus of thalamus

Side effects: 18.2% paresthesias, 10.9% implant site

pain, 9.1% site infections,8.2% lead

replacement.

CentroMedian (CM) nucleus thalamic stimulation

CM is part of the reticulthalamocortical system that is related to the modulation of the sleep-wake cycle and general alertness.

Neurons from brainstem communicates with the thalamus and then sends signals throughout cerebral cortex.

High frequency stimulation demonstrates EEG desynchronization in animal studies.

Centromedian stimulation efficacy

Open label trial with 13 LGS patients (Velasco 2005) demonstrated overall seizure reduction 80%.

30% decrease in generalized tonic clonic seizures compared to 8% in double blind study (7 patients, Fischer 1992).

Cerebellar stimulation Cerebellum uses inhibitory

neurons to affect other parts of the brain including the hippocampus.

Hypothesis: inhibition of hippocampus and cortex can suppress seizures. Therefore use electical stimulation to activate cerebellum to inhibit seizure pathways.

CAVEAT: stimulation of cerebellum can suppress cerebellar fibers.

Cerebellar stimulation Velasco (2005) –

Double-blinded, Randomized-controlled study. 5 patients with motor seizures placed stimulator in superomedial cerebellar cortex.

Cerebellar stimulation

Generalized tonic-clonic seizures decrease by 24% (mean)

Tonic seizure (54%) Drop attacks (35%).

Cerbellar stimulation

Side effects: Electrode migration (3-

required repeat surgery) Infection (1) Ataxia (1).

Subthalamic nucleus Stimulation

Used in movement disorders.

9 patients implanted, up to 80% seizure reduction.

Side effects: mild facial twitching, numbness in extremities during adjustment.

Responsive neurostimulation Electrodes placed

over brain and record activity.

Brain is stimulated when seizure is detected.

Only tested for focal seizures.

Responsive neurostimulation

191 patients implanted, randomized. 12 weeks study period blinded.

37.9% decrease in seizure frequency vs. 17.3% (sham).

Near 50% have >50% seizure reduction by 2 years.

Side effects: headache, dysesthesia, increased seizures.

Comparing stimulation devices

Comparing side effects

Trigeminal stimulation

Trigmenial nerve = 5th cranial nerve.

Responsible for sensation of the face/head.

Sends back signals to the brainstem which then transmits signals to thalamus and cortex.

Trigeminal stimulation External and subcutaneous

devices. Phase 2 study - 2013

(DeGiorgio) – 12 hours/day, external device.

50 patients randomized control, 18 weeks.

Trigeminal stimulation efficacy

Seizure reduction rate mean 37.9%

>50% seizure reduction in 40.5% treatment group.

Side effects: skin irritation (14%), headache (4%), anxiety (4%)

Transcranial magnetic stimulation

Hand-held magnet is currently used to map the motor strip.

Non-surgical therapy.

Stimulation can feel like a static shock.

Studied for focal seizures.

Transcranial magnetic stimulation efficacy

Mixed results in controlled trials: Theodore (2002) – mild and short-

lived seizure reduction (n=24). Fregni (2006) – significant seizure

reduction and EEG improvement (n=21).

Cantello (2007) – significant EEG improvement; no change in seizures (n=43).

Why are TMS results inconsistent?

Low number of patients studied.

Anatomy of stimulation – suboptimal for mesial seizure-generators.

Coil construction (round vs. figure of 8).

Where do we stand now?

None of these devices make patients 100% seizure-free.

Only VNS is FDA-approved. Of the long-term studies, there continues

to be improvement in many patients. DBS is awaiting final decision by FDA. FDA

panel approved DBS by close vote (7-5). DBS is currently being used off-label and in

31 countries. RNS received unanimous approval by FDA

panel in 2/13 and is awaiting final approval.

Final thoughts…

Stimulation can be very effective, but not a cure.

These decisions require an epilepsy center team approach.

Questions? 201-343-6676, epilepsynj@epilepsygroup.com

Lennox-Gastaut Syndrome (LGS) Foundation Initiatives

Robert Gilbert, STL, CMPPPharmaWrite/MedVal Scientific Information Services

Princeton, NJ

Lennox-Gastaut Syndrome (LGS) Working Group Members

Blaise F. D. Bourgeois, MDProfessor of Neurology, Harvard Medical School Director, Division of Epilepsy & Clinical Neurophysiology William G. Lennox Chair in Pediatric Epilepsy Children's HospitalBoston, MA

Laurie M. Douglass, MDDirector, Pediatric Epilepsy Pediatric EEG Director, Pediatric Neurology Residency ProgramDivision of Pediatric Neurology Boston Medical Center South Boston, MA

Patricia A. Gibson, MSSW, ACSWDirector, Epilepsy Information ServiceAssociate Director, Comprehensive Epilepsy ProgramWake Forest UniversityWinston-Salem, NC

Tracy A. Glauser, MD Director, Comprehensive Epilepsy CenterCo-Director, Genetic Pharmacology ServiceProfessor, Department of Pediatrics, University of CincinnatiCincinnati Children's Hospital Medical CenterCincinnati, Ohio

Eric H. W. Kossoff, MDAssociate Professor, Neurology and PediatricsMedical Director, Ketogenic Diet Center Director, Pediatric Neurology Residency Program Johns Hopkins HospitalBaltimore, MD

Georgia D. Montouris, MDClinical Associate Professor of NeurologyBoston University School of MedicineDirector of Epilepsy ServicesComprehensive Epilepsy Care Program for Children and AdultsBoston Medical CenterBoston, MA

LGS Working Group Members (cont.)

John M. Pellock, MDDivision Chairman, Vice Chairman, Department of Neurology Professor of Neurology, Pediatrics, and Pharmacy and PharmaceuticsVirginia Commonwealth University School of MedicineChildren’s PavilionRichmond, VA

Jay Salpekar, MDAssociate Professor of Psychiatry and PediatricsGeorge Washington University School of MedicineDirector, Outpatient Psychiatry ServicesChildren's National Medical CenterWashington, DC

Christina SanInocencio President and Executive Director Lennox-Gastaut Syndrome Foundation New York, NY

Raman Sankar, MD, PhDProfessor and Chief, Rubin Brown Distinguished ChairDivision of Pediatric Neurology, 22-474 MDCCDavid Geffen School of Medicine at UCLALos Angeles, CA

W. Donald Shields, MDChief, Clinical Trials in Pediatric Neurology Director, Pediatric Epilepsy Program Member, The Ketogenic Diet Program Professor Emeritus, PediatricsLos Angeles, CA

James W. Wheless, MDDirector, Neuroscience Institute and Le Bonheur Comprehensive Epilepsy ProgramLe Bonheur Chair in Pediatric Neurology Le Bonheur Childrens HospitalProfessor and Chief, Department of Pediatric NeurologyUniversity of Tennessee Health Science CenterMemphis, TN

LGS Resources Registry

• Resources for parents and caregivers to find solutions to challenges they will face in caring for a person with LGS

• Services identified by location • Available on LGS Foundation website and separate

portal

LGS Resources Registry (cont.)

LGS Resources Registry (cont.)

• LGS Support Groups• Specialized Epilepsy

Centers• Pediatric Neurologists

/Epileptologists• Adult Epileptologists• Neurosurgeons• Dieticians/Nutritionists• At-Home Nursing Care• Physical Therapy• Speech Therapy• Individualized Education

Plan (IEP)

• Adult Transitional Counseling Services (& Funding)

• Home Modifications• Vehicle Modifications• Seating and Mobility

Devices• Safety Devices • Respite or Support

Services (& Funding)• Residential or Daily

Rehabilitation Facilities (& Funding)

• Legal Advice

(& Funding)• Caregiver Skills• Job Training

Opportunities• Sheltered Workshops

/Supported Employment (& Funding)

• Summer/Day Camps for Children with Special Needs

LGS Resources Survey

• Information utilized to populate the LGS Resources Registry

• LGS Foundation members • Augmented with additional research • Survey to be initiated this month • Look for LGS Foundation email • http://www.lgshope.com/survey

LGS Resources Survey (cont.)

LGS Hope Monthly Newsletter

LGS Hope Monthly Newsletter (cont.)

• Introduction to recent research and literature • Updates on LGS Foundation activities • Interviews with caregivers and healthcare

professionals • Updates on new policies and regulations that impact

availability of LGS care • Available via email, website, or mailing

LGS Fact Sheet or FAQ

• Clinical overview of LGS • Diagnosis and prognosis • Transition into adulthood • Collaborative effort with medical societies and

patient advocacy organizations

LGS Physician Guide and Call Sheet

LGS Physician Guide • Increasing awareness among physicians of special needs

of LGS patients • Defining best practices in LGS diagnosis, treatment, and

management LGS Call Sheet • Standardized communication to be adopted by multiple

organizations • Answering calls from caregivers and healthcare providers

www.lgshope.com

www.lgshope.com (cont.)

SUPPORT SERVICES

Agenda:1.Transition into Adulthood and Person-Centered Planning

2.What’s Next? Resources for an Independent and Productive Life in the Community

3.Volunteering and Employment Possibilities

4. Q and A

What is Self-Determination?

• Every individual, regardless of ability, has the right to determine the course of their life. And it’s up to us; family, friends, providers to make sure the voices of our loved ones are heard.

• Four Basic Principles of Self-Determination:• Freedom: People must have the freedom to make basic life

choices. This includes balancing the risks and possible consequences.

• Authority: People must have control over their lives and meaningful options if they are to exercise freedom of choice

• Support: Supports must be available to help people connect with opportunities for increased personal and social inclusion.

• Responsibility: As people gain control over their lives, they will also be able to take on their obligations as citizens and give back to the community.

What Does this Mean?• Many well-intentioned parents will make choices for their adult sons and daughters, believing that as parents, they know what’s best.

• If we want to promote independence and encourage productive involvement in the community, it is our responsibility to ask our adult sons and daughters what they want from life. It is our responsibility to listen to their answers. And it is up to us to learn about the services available and maximize those community resources that support the life goals of the people we love.

• An individual’s Circle of Support come together to assist in helping that individual define his or her abilities, interests and dreams for the future.

• Focus on independence, possibilities, dreams, desires, meaningful experiences and quality of life.

• Emphasis is on:• Promoting Choice: How can we help people have

more control and choice in life?• Community Presence: How can we increase an

individual’s presence in the community, through an engaging and productive life?

• Supporting Contribution: How can we assist people to develop skills and competencies, How can we help them share their unique gifts with the world?

Person-Centered Planning

Video: Person-Centered Planning at AADD

TRANSITION – A

CHECKLIST

- What can you expect from the school?

- What can you not expect from the school?

- Things Change! Be flexible, and prepared to adapt as necessary!

Video: My Transition Story

What’s Next???Social Security

Independent LivingCommunity Involvement

Self-Advocacy

Healthy ChoicesTransportation

Legal IssuesEmployment

Using Your Budget – Creating Your Plan

Developmental Disabilities Assistance Act and Bill of Rights (2000)

• Federal Law creating funding for adults with developmental disabilities, promotes:

• Self-Determination• Independence

• Productivity• Integration and Inclusion

• Created:

• State Councils on Developmental Disabilities• Protection and Advocacy Systems for each state

• National Network of University Centers for Excellence in Developmental Disabilities

Federal Funding

State Funding

County Resources

Social Security Disability, Medicaid

State Health Care, State Funds (to match Federal Funds), and more…

Registration is at the county level, funds disbursed through county-run agencies, non-profit organizations and brokerages. You have a choice!

Services Current Future

Adaptive Aids

Transportation

Social/Recreational

Learning/Educational

Health/NutritionExercise

Employment/Volunteer

Other

Healthy Living• Opportunities to learn about nutrition

• Planning and cooking healthy meals

• Gym Memberships and Personal Trainers

• Community Classes

•Offered at non-profit organizations

•YMCA

•Community centers

•College campuses

Transportation

•Public Transportation – Learning to ride independently

•Public Transportation – Private Shuttle

•Driving with a Mentor•Family Involvement•Thinking outside of the Box!

Living Arrangements

• Residential Facilities (for adults with special healthcare needs)

• Community Care Facilities

• Developmental Centers

• Family Home Agency

• Independent Living

• Intermediate Care Facilities

• Supported Living Services

• Affordable Housing

Emergency Preparedness

•Brochure – Emergency Preparedness for People with Disabilities

•Let’s Get Prepared: Tools for Emergency Preparedness

Social Activities and Community Inclusion

• Large, national Non-Profit Organizations:- YMCA - Special Olympics

• Small, local Non-Profit Organizations that provide:- Art Programs - Athletic Training/Classes - Music Lessons- Outdoor Events/Camps - Social Events - Mentor

Programs

• State- and County-Funded Programs:- Day Habilitation

• Trip and Vacation Planning for adults with Disabilities

• Political Action and Self-Advocacy Groups

Mentorship and Skills Training

• Mentors can be funded with Plan dollars• Mentors can provide transportation• Mentors can provide companionship for activities in the community

• Mentors can provide guidance with regards to living skills

• Mentors can serve as coaches for volunteer work and paid employment

• Mentors may be knowledgeable about other activities in the community

• Non-Profit Organizations and local colleges often offer a variety of skills classes for adults with developmental disabilities.

Legal Issues• Disability Rights __________ (your state)• Non-profit legal groups found in most major cities

• Free Legal Advice for anybody with a disability:

• Accommodations• Discrimination• Policy Question• Access to Services• Social Security Offsets after attaining paid Employment

Volunteering and Employment• Video: Working for a Living – Andy Owens

• Volunteering in the Community

• Vocational Rehabilitation Services

• Vocational Assessments

• Job Coaches

• Natural Supports

• Video: Jennifer’s Story (time permitting)

Questions???

• “Pose your questions to people and you will get countless useless answers.”

― Dejan Stojanovic, The Sun Watches the Sun