The document discusses a strategic research plan for Lennox-Gastaut Syndrome (LGS). It outlines the goals of improving quality of life for individuals with LGS, educating families about research, and expanding the cohort of researchers studying LGS. It identifies barriers like difficulties in diagnosis and engaging families in research. The plan proposes strategies like supporting genetic studies, collecting more patient data through the Rare Epilepsy Network registry, and improving family outreach. The overall aim is to facilitate better research, engage more families, and expand the community working on LGS.

2. RESEARCH UPDATES

3. OVERVIEW
STRATEGIC RESEARCH PLAN
REN
FUNDRAISING

4. 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

5. 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

6. 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.

7. 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

8. Barriers to LGS Research, Diagnosis
and Quality of Life
Lack of
Optimal
Treatment
s
Strategy
 Identification of genes involved in LGS
 Support Epi4K or other genetic studies of LGS
 Target Identification
 Fund or support targeted RFAs for projects that elucidate
pathways involved in LGS
 Drug Screens
 Continue to fund or support high-throughput drug
screening projects
 Collect resources for iPSCs from LGS patients for drug
screens on human neurons

9. Barriers to LGS Research, Diagnosis
and Quality of Life
Lack of
Data from
Patients
with LGS
Strategy
 Create collection of LGS data
from patients
 Participate in REN
 Update data fields for LGSF
member registration
Metric
 Target:
 Enroll 250 LGS families in REN in
first twelve months
 Enroll another 150 in next twelve
months

10. Barriers to LGS Research, Diagnosis
and Quality of Life
Difficult for
families to
participate in
clinical
research
Strategy
 Improve awareness of research opportunities and
ease burden of participating in research
 Continue to fund travel grants for families
 Create opportunities for families to participate in research
at LGS conference
Metric
 Target: enroll 25% of probands, siblings, and
parents at the family conference in onsite bio-sample
collection (future goal)

11. Goals of Strategic Research Plan
Better
Research
Educate &
Engage
Families
Expand
Cohort of
Researchers

12. Goals of Strategic Research Plan
Better
Research

13. Better Research:
Revised LGSF Research Program
LGS Foundation Advocates for Better Research
Through:
 LGSF Research Program
 Participation in Rare Epilepsies Registry
Better
Researc
h
 Need for ICD-10 code or EMR’s / common data
elements that capture EEG pattern for studying LGS
patients

14. 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

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

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

17. Goals of the Strategic Research Plan
Educate &
Engage
Families

18. Engage Families
 Get families more involved in
research
 Family conference
 Patient registry / database
Encourage families to
fundraise
 Named research grants
Educate
&
Engage
Families

19. Goals of the Strategic Research Plan
Expand
Cohort

20. Part Two: REN

21. 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

22. Goals and Objectives
 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

23. REN (continued)

24. REN (continued)

25. 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

27. 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

29. Thank You!

31. 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

32. Dietary Therapy of Epilepsy
• 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?

33. 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”

34. The Ketogenic Diet: History
• 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

35. 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.

36. 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%

37. 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.

38. 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”

39. The Ketogenic Diet: History
• 1997: Charlie,
“…First Do No Harm”

40. 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?

41. Ketogenic Diet vs American Diet
American Diet
Carbs
Protein
Fats
Ketogenic Diet
Carbs Protein
Fats

42. 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

43. 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

44. Ketogenic Diet efficacy in
children with intractable epilepsy
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
1971 12 --- 50% 50%
et al. -- MCT
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%

46. 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.

47. 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

48. Variations on the theme:
Modified Atkins Diet

49. 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

50. Atkins for Seizures
• 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

51. KGD ≈ LGIT ≈

52. Glycemic Index (GI)
The two hour blood sugar response of
a high-GI food versus a low-GI food
Reference food (Glucose, GI=100)
Blood glucose
Test food with equal wt carbohydrate
Blood glucose
GI=40
Time Time

53. 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

54. American Diet
Carbs Protein
Carbs 4%
Protein 6%
Fat 90%
Carbs 50-60%
Protein 10-20%
Fat 30-40%
Carbs
Protein
Fats
Ketogenic Diet
Fats

55. American Diet
Carbs Protein
Protein
Low GI Carbs
Fat
LGIT
Protein
LGI Carbs 10%
Protein 20-30%
Fat 60-70 %
Carbs 4%
Protein 6%
Fat 90%
Carbs 50-60%
Protein 10-20%
Fat 30-40%
Carbs
Fats
Ketogenic Diet
Fats

56. 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

58. 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%)

59. 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

60. 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

61. 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

62. 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?

63. Dietary therapy of epilepsy
Who, 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?

64. Dietary therapy of epiliepsy
Who, 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

65. 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