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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
Barriers to LGS Research, Diagnosis
and Quality of LifeLack of
Optimal
Treatment
s
Strategy
Identification of genes involved in LGS
Support Epi4K or other genetic studies of LGS
Target Identification
Fund or support targeted RFAs for projects that elucidate
pathways involved in LGS
Drug Screens
Continue to fund or support high-throughput drug
screening projects
Collect resources for iPSCs from LGS patients for drug
screens on human neurons
Barriers to LGS Research, Diagnosis
and Quality of LifeLack of
Data from
Patients
with LGS
Strategy
Create collection of LGS data from patients Participate in REN
Update data fields for LGSF member registration
Metric
Target: Enroll 250 LGS families in REN in
first twelve months
Enroll another 150 in next twelve months
Barriers to LGS Research, Diagnosis
and Quality of 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:
Revised LGSF Research Program
LGS Foundation’s Revised Research Program
Grants awarded to young and established
investigators, physician residents, and clinicians who
are interested in studying LGS
Our research grants are intended to
help researchers explore novel ideas and
answer questions related to the clinical aspects,
therapies and/or genetic causes of LGS
Better
Researc
h
Better Research:
Revised LGSF Research Program
LGS Foundation Revised Grant Types
SEED GRANTSOne-year research grants up to $30,000 (including no more than 10% in indirect costs)
COLLABORATIVE GRANTSAmount TBD each year
POST-DOCTORAL RESEARCH GRANTSTwo-year research grants up to $50,000
FAMILY-SPONSORED NAMED RESEARCH GRANTSAmount TBD / unique to each family; minimum grant = $10,000
Better
Researc
h
Better Research:
Revised LGSF Research Program
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 (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.
The Ketogenic Diet: History
• 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%
The Ketogenic Diet: History
• 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.
The Ketogenic Diet: History
• 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”
The Ketogenic Diet: History
• 1997: Charlie,
“…First Do No Harm”
The Ketogenic Diet: History
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