05 sunday morning 10-26-14

RESEARCH UPDATES

OVERVIEW

STRATEGIC RESEARCH PLAN

REN

FUNDRAISING

PART ONE:

LGSF Strategic Research Plan

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

Disparities

The SRC identified additional disparities and

needs for a strategic research plan in Lennox-

Gastaut Syndrome. These include:

Diagnosis:

1. Phenotypic variability within LGS

2. Diagnosis is inconsistently applied, making it

challenging for researchers to study this

population

3. Shortage of pediatric neurologists in the U.S.

and worldwide

BACKGROUND

Motivation for the Strategic Research Plan

Disparities

The SRC identified additional disparities and needs for

a strategic research plan in Lennox-Gastaut

Syndrome. These include:

Patient engagement:

1. The disease itself is a great burden to families making it

difficult for families to participate in studies.

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

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 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 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)

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:

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

Better

Researc

h

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

Better

Researc

h

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

h

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

Better

Researc

h

FAMILY-SPONSORED NAMED RESEARCH GRANTSAmount TBD / unique to each family; minimum grant = $10,000

Goals of the Strategic Research Plan

Educate &

Engage

Families

Engage Families

Get families more involved in

research

Family conference

Patient registry / database Encourage families to

fundraise

Named research grants

Educate

&

Engage

Families

Goals of the Strategic Research Plan

Expand

Cohort

Part Two: REN

The Rare Epilepsy Network

Funded by PCORI, the REN arose out of Vision 20-20 and is a

collaboration between the Epilepsy Foundation, Columbia

University, New York University, RTI International and 10 rare

epilepsy organizations listed below:

Aaron’s Ohtahara

Aicardi Syndrome Foundation

Dravet Syndrome Foundation

Dup15q Alliance

Hope for Hypothalamic Hamartomas

International Fondation for CDKL5 Research

Lennox-Gastaut Syndrome Foundation

PCDH19 Alliance

Phelan-McDermid Syndrome Foundation

Tuberous Sclerosis Alliance

Create a Registry of 1500 well-characterized patients with rare epilepsy including anatomic features, co-morbidities, genotypes, treatment histories, seizure history and seizure characteristics

Data will be used to understand the syndrome natural histories and improve diagnoses, treatment and quality of life

FU surveys will be implemented annually for longitudinal data

Clinicians may refer eligible patients to website for enrollment

Patient population and data will be used to enable future research including observational studies and clinical trials.

Investigators interested in applying to use the data or resource may visit the study website

http://REN.rti.org

Goals and Objectives

REN (continued)

REN: Sample Questions

2 | Affected Person’s Information & Demographics

3 | Caregiver’s Information & Demographics Affected Person’s

History and Current Status

4 | Seizure History and Characteristics

5 | Affected Person’s Development, Other Conditions, &

Symptoms

6 | Seizure Treatments & Medications

7 | Surgery

8 | Genetic Testing, EEGs, MRIs, Video EEGs

9 | First Seizure & Diagnosis of Epilepsy / Seizure Disorder &

Syndrome

10 | Seizure History

11 | Birth & Maternal Symptoms

12 | Caregiver’s Quality of Life

Get Involved in Research!

Named Research Grants

Raise $10,000 or more and the LGSF will create a

research grant in your child’s name

Fundraise

Many ways to do so!!!

Download a packet or get ideas from LGSF

Great way to raise awareness

Campaigns

Awareness campaigns

Birthday, Holiday, Wedding

Social Media

Thank You!

Dietary Therapies for Epilepsy

Elizabeth A. Thiele, MD, PhD

Director, Center for Dietary Therapy

Director, MGH Pediatric Epilepsy Program

Professor of Neurology, Harvard Medical School

• Classic Ketogenic Diet» History, formulation, and experience

» Ketogenic diet 2014

• Variations on a theme:» Modified Atkins Diet

» Low Glycemic Index Treatment

• Dietary therapy of epilepsy:

» Who, what, where, when, and why?

» And what is experience in other disorders?

Dietary Therapy of Epilepsy

• Fasting as a treatment for epilepsy was described in the Bible

and in texts from the Middle Ages

» Hippocrates, “Sacred Disease”, wrote that modification of diet

required to treat epilepsy

– Based on belief that epileptic patient’s body was “polluted” and

modification of diet allows “purification”

» Erasistratus 3rd century BC - “one inclining to epilepsy should be

made to fast without mercy and be put on short rations”

– Based on belief of a connection between epilepsy, the bowels and

digestive organs

» St. Mark; 9:29 (The Bible, King James version)

An epileptic child was brought to Jesus, who said to disciples,

“This kind can come forth by nothing but by prayer and fasting”

Dietary therapy of epilepsy

• In 1921, Dr. Rawle Geylin reported to the AMA the

successful treatment of epilepsy by fasting, by

osteopath Dr. Hugh Conklin.

• Conklin believed epilepsy was caused by intoxication

from the Peyer’s patches of the intestine, so he

developed program to “put intestines at rest”.

• He would fast patients, with water only, for as long as

tolerated, up to 25 days

• “cure” rates of 90% in juvenile patients, 50% in adults

The Ketogenic Diet: History

• 1924: The “Ketogenic Diet” was designed to mimic

starvation.

» First described at the Mayo Clinic, with 1 g of protein per

kilogram of body weight in children, 10-15 g of carbohydrate

per day, and the remainder of calories as fat. Subsequent

reports from Harvard, Univ. of Rochester.


• 1927: Talbot at MGH, Harvard described the

protocol still used for calculating and initiating diet:

» 36-48 hours of fasting to hasten production of ketosis

» gradually increasing amounts of dietary fats introduced

over several days during hospitalization

» Maintenance on diet:

– Specific meal plans requiring weighing of all foods

– Caloric restriction to 75%

– Fluid restriction to 80%


• Because bromides and phenobarbital were the only

medications available at the time, there was a flurry of

clinical and research activities on the Ketogenic Diet.

• The diet was widely used during the 1930’s, but it fell

out of vogue when diphenylhydantoin was introduced

in 1938. Compared with DPH treatment, the diet was

viewed as difficult, rigid, and expensive.


• Changing focus of epilepsy treatment:

• Talbot’s Treatment of Epilepsy 1930

» One small chapter on medication

» Half of book focused on the ketogenic diet

• Lennox’s Epilepsy and Related Disorders 1960

» Single paragraph on ketogenic diet

» “for most patients, young and old, drug therapy is the kingpin

of treatment”


• 1997: Charlie,

“…First Do No Harm”


http://en.wikipedia.org/wiki/File:...first_do_no_harm.jpg

http://en.wikipedia.org/wiki/File:...first_do_no_harm.jpg

The Ketogenic Diet: Resurgence of popularity

• Ketogenic diet in popular culture

» 1997: First do no harm (Charlie Foundation)

• Ketogenic diet in medical literature:

Medline citations (ketogenic diet and epilepsy):

» 1965-1995 56 in 31 years

» 1996-2014 980 in 18 years

• Ketogenic diet in the kitchen: The Atkins diet?

Ketogenic Diet vs American Diet

American Diet

CarbsFats

Protein

Ketogenic Diet

Fats

ProteinCarbs

Ketogenic Diet: Formulation

• Calories - based on age, ideal body weight, and current intake.

• Protein - RDA or above.

• Vitamins and minerals – RDI

Ketogenic ratio

Ratio (by grams) Fat : (Protein + Carbohydrate)

i.e. 4:1 ratio implies

4 grams of fat to 1 gram combined of protein and carbohydrate.

• Ratio is limited by protein requirement

Ketogenic Diet - Food Groups

• Cream

• Fat

• Fruit or Vegetable

• Protein

No bread, pasta or grains

No sugar

No starchy fruit or vegetable

• Vigilant exclusion/monitoring of extra carbohydrates

e.g. in medications, non-nutritive sweetener formulations, toothpastes

Seizure Control

Author Year # Pts >90% 90-50% <50%

Peterman 1925 37 60% 35% 5%

Helmholz 1927 91 31% 23% 46%

Wilkins 1937 30 24% 21% 50%

Livingston 1954 300 43% 34% 22%

Huttenlocher et al. -- MCT

1971 12 --- 50% 50%

Trauner - MCT 1985 17 29% 29% 42%

Sills et al. - MCT 1986 50 24% 20% 56%

Kinsman et al. 1992 58 29% 38% 33%

Freeman et al. 1998 125 34% 26% 40%

Katyal et al. 2000 42 38% 33% 29%

overall 762 37% 30% 33%

Ketogenic Diet efficacy in children with intractable epilepsy

The Ketogenic Diet: Side effects

• Elevated serum lipids

• Constipation, possibly related to fluid restriction and

decrease in bulk of food intake

• Deficiencies in water soluble vitamins and calcium

• Renal stones (5-8%)

• Growth inhibition (linear growth usually continues

normally; as should weight gain)

• Acidosis and excess ketosis during illness.

Ketogenic Diet: 2014

• Fasting probably not required» Advantages to initiating without fast:

– Shorter hospitalization

– Better tolerated with less acidosis, hypoglycemia

– Less stressful for child and parents

• Inpatient vs outpatient initiation» Inpatient recommended

• Ketogenic diet team crucial!!» Knowledgeable dietician

» Pediatric neurologist

» Epilepsy nurse specialist

Variations on the theme: Modified Atkins Diet

Atkins for Seizures

• Case series of 6 patients (4 over age 18 yr)

Kossoff et al, Neurology 2003

• Prospective open label study of 20 patients 16/20

completed 6 mo study

» Mean age: 6.5 yr

» Mean seizure per week: 163

» Mean ACD trials: 6.5

Kossoff et al, Epilepsia 2006

• JHMI Modified Atkins protocol:

» Outpatient initiation

» No initial fast

» No caloric, fluid restriction

» No weighing of foods; no specific meal plans

» CHO limited to 10 gm/day for first month; increase to 20 gm

after1-3 mo (any CHO)

» Multivitamin, calcium supplementation

» Weekly weights

» Labs (CBC, electrolytes, lipid profile) q 3 mo

» Urinary ketones measured semiweekly

Atkins for Seizures

KGD ≈ LGIT ≈

Glycemic Index (GI)

The two hour blood sugar response of

a high-GI food versus a low-GI food

Reference food (Glucose, GI=100)

Blo

od g

lucose

Blo

od g

lucose

Time Time

Test food with equal wt carbohydrate

GI=40

Glycemic Index (GI)

Examples of foods with various glycemic index:

Fruits Breads

HIGH Melons Bagels

MODERATE Apple Whole Grain Bread

LOW Grapefruit Whole Grain Bread 2.5 - 3 gms fiber

American Diet

ProteinCarbs

Carbs 4%

Protein 6%

Fat 90%

Carbs 50-60%

Protein 10-20%

Fat 30-40%

CarbsFats

Protein

Ketogenic Diet

Fats

American Diet

ProteinCarbs

Protein

Fat

Low GI Carbs

LGIT

LGI Carbs 10%

Protein 20-30%

Fat 60-70 %

Carbs 4%

Protein 6%

Fat 90%

Carbs 50-60%

Protein 10-20%

Fat 30-40%

CarbsFats

Protein

Ketogenic Diet

Fats

MGH- LGIT Program

20 patients initiated on LGIT:

- 9 after , 11 prior to a trial of the classic KGD

Ages: 5 - 34 years; M:F 7:13

average # of previous AED’s = 7

Seizure frequency: 100/day - one/6wks

Length of treatment: 2.5-124 w (avg 20 w)

10 had >90% seizure reduction 6 on LGIT prior to KGD had >90%

Pfeifer and Thiele, Neurology 2005

MGHfC retrospective study of LGIT:efficacy, safety and tolerability

• 76 children » 89% with history of refractory epilepsy (>3 prior ACD)

• Efficacy almost as good as prior study

• Efficacy correlated with lower blood glucose, not ketone levels

• Well tolerated—Lethargy in 3/76 only reported side effect

• No significant change in BMI or BMI z-scores

• Most common reason for discontinuation: restrictiveness (24%)

MGH: LGIT Protocol

• Calorie goals are based on current intake according to three day food records and food frequency questionnaires (to maintain adequate growth and development)

• Individualized goals for grams of protein, fat and carbohydrates are provided based on calorie needs.

• Carbohydrates are limited to 40-60 gms per day from low glycemic index sources (GI<50)

• Food is not weighed, but based on portion sizes

• Fluid is not restricted, rather encouraged

• Vitamins and minerals are supplemented to meet individualized needs

• Initiation as outpatient with follow up 1 month post diet initiation and then every 3 months for duration of treatment

Low glycemic index treatment

• Effective for partial onset and generalized seizures

• No dramatic change in b-hydroxybutyrate levels

• Better tolerated than KGD

» Less restrictive for child

» Easier to administer for family and clinic

» Initiation does not require hospitalization

LGIT in Lennox Gastaut Syndrome

• Prospective study to evaluated efficacy, tolerability of

LGIT in 20 individuals with LGS

• Inclusion criteria:

» clinical diagnosis of LGS

» EEG with slow spike and wave activity

» > 1 seizure per month

» “failed” >1 ACD

• 4 month trial

» EEG, Neuropsych at baseline, 4 month visits

Funded by LGS Foundation

Dietary therapy in epilepsy:where do we go from here?

• Classic KGD» ? Most effective treatment available for intractable epilepsy

» However, implementation and restrictions difficult for child and family

» Would initiation without fast, and liberalization of fluids make more “doable”?

• Current alternatives---modified Atkins and LGIT» Both very promising initial observations---need broader

experience.

» Multicenter trials comparing efficiacy and tolerability

• But why do these diets work?

Dietary therapy of epilepsyWho, what, when, where and why?:

• Proven efficacy in all seizure types» Evolving and important role in treatment of infantile spasms

• Proven efficacy with many etiologies» Genetic etiologies

– Myoclonic astatic epilepsy

– Dravet’s syndrome

» Structural/metabolic etiologies

– Glucose transporter deficiency (GLUT1)

– Tuberous sclerosis complex

– Angelman syndrome

• Proven efficacy in children—what about adults?

Dietary therapy of epiliepsyWho, what, where, when and why?:

• And why?

• Dietary therapy is the most effective treatment for

medically refractory epilepsy, and remains so even

with increasing availability of new anticonvulsant

medications

MGH Center for the Dietary Therapy of Epilepsy

• Elizabeth Thiele, MD PhD Director, Neurologist

• Heidi Pfeifer, RD LDN Dietitian

• Ron Thibert, DO MPH Neurologist

• Patricia Bruno, RN Nurse coordinator

• Amy Morgan PhD Neuropsychology

• Sarah Pollack Research assistant

• Alexandra Geffrey Research assistant

• Ayahnna Williams Clinical coordinator

• Funding: LGS Foundation, ASF, Herscot Center for TSC

05 sunday morning 10-26-14

Health & Medicine

Transcript of 05 sunday morning 10-26-14