1. 3rd International KLS Conference 2018
KLS Foundation
3rd International KLS Conference 2018

2. Welcome and introduction
Welcome and Personal introduction
Stephen Maier, CPA

3. Welcome
Welcome to the KLS Foundations 2018 Conference. Its been 3 years since our last conference at the Emory Center in Atlanta and 7 years since our first conference that we held here in SF. The conferences have been a great success, both in bringing together KLS patients and families to connect live and share experiences. They have also brought the leading KLS researchers together to collaborate and share findings, theories and ideas about the future direction of research. For those not able to join us live we are planning to live stream and record the conference as we did for the last 2 conferences. We will post links to the videos of the various presentations on our website for future reference.

4. Agenda

5. If you have not already please put cell phones on silent or vibrate
Restrooms
Breaks
Lunch will be provided today (on your own for dinner)
Questions for researcher panels should be written down and placed in the basket prior to the panel discussions
Appetizers with KLSF Board
KLSer social at the pool
Logistics

6. Our Mission
Mission
The KLS Foundation provides information and support to those diagnosed with KLS and their families. The Foundation exchanges information with patients and the medical community to help in the diagnosis and care of those affected by KLS, and supports research programs. Our goals are to raise awareness, support scientific research, to find effective treatment and ultimately find a cure for Kleine-Levin Syndrome.

7. KLS Board of Directors Dani Farber Neal Farber, PhD
Gaylene Grossman, RN,
BSN, CNOR
Varda Farber
Jenny Grossman
Lori Haller Schiller
Caron Krieger
Lucinda Maier
The KLS board. There are no paid positions in the KLS Foundation – everything that is done is done by volunteers, primarily the by the BOD members. The average age of the BOD has now moved above 50 and while that experience is valuable, the time and energy and value of new ideas is critical to the continued success of the KLSF.
Richard B. Maier,
CPA
Stephen Maier,
CPA
Donna White
Alanna Wong

8. Future of the Foundation
So where does the KLSF go from here.
The most visible piece – the “face” of the Foundation is the Website and FB page – this is how the majority of the community connects with us.
However, there is alot of behind the scenes effort Fundraising, interacting with Media sources, providing patient support, the administration and finance functions of the foundation. At this point almost all of this effort is put in by the BOD members. If the KLSF is going to expand its impact or even maintain we will have to increase the level of support from the KLS community. The “next generation” of the KLS community will need to be engaged to support the efforts of the Foundation. Having Alana join the board has provided what I hope is the start of this. I would encourage everyone step to help – you will be surprised what we will be able to accomplish.

9. KLS Community
The Foundation has also been able to continue to expand awareness and connect more and more patients and their families. In addition, there are currently a number of sites or Facebook groups that have been started by KLS patients or their families along with the KLSF site and FB page and KLS group. All of these resources have helped people to connect, share stories and experiences. The way we engage the KLS community has changed over the years from limited live meetings and phone calls, to the initial website and s, to more dynamic and frankly challenging Facebook pages and real time chats.
All of this has led to increasing engagement with the KLS community globally.
This also brings challenges – managing contact information, how to keep it current, who and how to share information with researchers and/or other organizations or new patients looking to make connects. Creating and maintaining list of doctors that have seen KLS patients – how to determine if they are ones we should send other patients to, how to share information with both new patients – who are getting a base of knowledge and existing contacts who are more interested in new updates.
Many large Companies in the valley here have spent millions of dollars trying to do this successfully and some of the largest have still failed miserably.
Finding the time to connect live with patients, respond to messages and questions, interact with the research community, media sources….and then keeping up with the times in terms of tools and ways to communicate.
This is where Alanna has been invaluable to the Foundation and one of our focus areas is expanding the engagement of the KLS community and our BOD.

10. KLS Events
Courts for Life Tennis & Tennis on Campus UCR Tournament Benefiting the KLS Foundation Research Fund
KLS makes its first Times Square debut!
Annual Run for Ryan
Yoga in the park fundraiser
First Annual Coop-A-Thon Event Raises Over $100,000 for KLS Research!
SLEEP 2017 conference – KLSF sponsored dinner
Photo of KLSF dinner attendees (from left): Rosa Peraita-Adrados, M.D., Ph.D. (Madrid, Spain),
Logan Schneider, M.D. (Stanford University Sleep Center), Kiran Maski, M.D. (Boston Children's
Hospital), David Rye M.D. Ph.D. (Emory University, Atlanta, GA) and Catherine Rye, Neal Farber,
Ph.D. (KLS Foundation), Emmanuel Mignot M.D. Ph.D (Stanford University), Charles Czeisler
Ph.D. M.D. (B&W Hospital, Harvard Medical School), Tom Scammel M.D. (BIDMC, Harvard
Medical School), Hanna Ollila, Ph.D. (Stanford University), Xu Liyue M.D. (Beijing, China), Yan
Han M.D. (Beijing, China). Not pictured: Yves Dauvilliers M.D. (Montpellier, France).

11. KLS Research
Challenge: KLS is a rare, ‘orphan disease’ and 20 years ago no research was being conducted
No known cause – genetic, viral, immune, neuro, hormonal, environmental – some combination
No medical “test” to diagnos
Nature of illness (episodic, diminishes and/or stops over time)
Small patient population
Accurate diagnosis
Funding
The initial Foundation members – led primarily by Varda Farber held fundraisers and directly solicited family and friends to support the KLSFs efforts.
The Foundation has raised funds and provided nearly half a million dollars to various research efforts throughout the globe.
In 1999/2000 we connected with Dr Mignot and helped sponsor some of his initial research focused on collecting and summarizing past research. This led to additional work including collecting blood samples from patients and their families. We have subsequently provided seed funding for a number of research projects and where no research was being conducted 15 years ago there is now a number of studies being performed globally in the US, Europe and Asia. Including Isabelle Arnulf who is with us this weekend.
Unfortunately research in the real world does not work like what we see in movies and on tv – where is a matter of hours or days the heroes always seem to be able to find patient zero or the cause of the illness and rush a sample back to a lab, a few pictures of computers, and spinning machines and bingo a usually yellowish “cure” is produced. Research in the real world is much more trial and error and typically much more painstaking. This has periodically led to frustration by those who have participated in a project by donating blood and/or filling out a questionnaire. Participants would like to be kept up to date on the status of research – have they analyzed my sample, what have they found, etc. We have worked to balance the required confidentiality of the research process prior to results being published with the thirst for knowledge by the KLS community – especially those actively participating. This has been one of the biggest challenges we have faced. At the same time, the level of research that is now occurring related to KLS is also one of our greatest successes. I would encourage everyone to offer to participate in the research. Orphan diseases by their nature have small sample sizes to begin with and so every participant makes a difference. I would also tell you not to be discouraged if your sample is not used for a particular study – small sample sizes require certainty by the researcher so they tend to take the “typical” cases for some of the studies.

12. Kleine Levin Syndrome (“KLS”) Intro to Research
Neal Farber, PhD

13. Intro to research Outline
Why research?
How? - challenges
Where to start?
Who? – researchers, volunteers, all of us
How to make sense of publications
Issue of KLS diagnosis
Schedule of Research Sessions

14. KLS Research Introduction
Why research?
KLS is an unusual medical disorder:
Understanding the cause KLS will lead to better diagnosis & treatment for the benefit of patients and
lead to new insights in sleep, behavior & neurobiology
Challenge - KLS is a rare, ‘orphan disease’
15+ years ago, sparse research being conducted
Mostly medical ‘case reports’, little scientific value

15. Rare (“Orphan”) Diseases
U.S. Orphan Drug Act (1983): “any disease or condition that affects fewer than 200,000 people in the USA”
Estimated that 6%-10% of the world’s population will suffer from one of 7,000 known rare diseases, and almost 1 in 5 personally knows of an individual suffering from a rare disease. Finding a cure or better treatment for such patients is fundamental not only to their lives, but also to society as a whole.
… there is great potential to improve the work among all stakeholders: patient advocacy organizations, academic researchers, healthcare professionals, governmental authorities, drug developers, insurers, etc.
federal law that was written to encourage research into rare diseases and possible cures. or about 1 in 1,500 people

16. How - Building a Research Program
KLS Foundation mission … to support scientific research, to find effective treatment & ultimately a cure for KLS
Network leading KLS researchers:
2006 (Utah) – APSS Annual Sleep Conference - 1st KLS Symposium
2011 (California) – KLS Foundation Conference
2015 (S. Korea) - World Congress on Sleep Medicine KLS Symposium
2015 (Atlanta) – 2nd KLS Foundation Conference
2018 (California) – 3rd KLS Foundation Conference
Early fundraising
Engage labs, seed funding
Issue RFPs
Network investigators
Build resources
>$400,000 funded to date
worldwide

17. KLS Medical Research where to start?
August 12-14th 2011
KLS Medical Research where to start?
Some clinical observables:
All medical tests within normal ranges
Typically starts in adolescence; with the first episode following an illness, trauma or other stress event
Episodes are cyclical, lasting from a week to months
Frequency of episodes vary from monthly to years in between
There is no known test for KLS
There is no known cure or consistent treatment
Steve
We would like to spend the next session giving a brief overview of KLS, including having a discussion with a panel of KLS patients and parents who have been dealing with KLS for various periods. Not that you all don’t know what it is for you individually, but I am hoping it will be good hear that many of the symptoms and issues others are going through are similar to yours. The information provided will fall into what I call the 80/20 rule in that it will be consistent for many of you, but I know from my experience with the Foundation the last 10+ years that there are atypical symptoms and circumstances.
How many people here have KLS?
Keep your hand up if you have been formally diagnosed by a medical doctor. [not sure what that will get but will go from there]
The challenge is there is no test for KLS. It is made more difficult by the fact that when you are not in an episode there are typically no symptoms and in some cases even when in an episode it is not always apparent to someone who does not know you how different you are from your healthy state.
We often get calls from people that have found the website and think that they or their child could have KLS. In some cases it is quickly evident that the symptoms are very typical. We also get many calls from people who seems to have some of the typical symptoms but not all of them. What are the typical symptoms ?
Typically starts in adolescence with the first episode following an illness, trauma or other stress event
KLS is cyclical
Episodes last from a few days to months
The frequency of episodes varies from every other week to several years in between

18. KLS Medical Research Additional Challenges
Etiology (‘cause of illness’) unknown
Nature of illness (episodic, attenuates over time)
Small patient population, obtaining clinical samples
Accurate diagnosis
Funding

19. KLS Medical Research Working Hypotheses
Ethnic prevalence; Multiplex cases
Genetic?
Viral-like prodrome; Cyclical nature
Viral?
Clinical presentation; HLA
Immune mediated?
Brain imaging data; Age of onset
Neuro-anatomical?
Sporadic clinical findings
Hormonal?
Environmental?
Other?
A number of possibilities have been considered including hypothalamic damage, autoimmunity, and infectious triggers.
Hormonal: reports of prolactin, hGH, hypocretin out of normal range.

20. KLS patients & families
Who?
KLS Foundation
KLS patients & families
Research Community *
Treatments and cure
Funds
* Academia,
clinical centers, physicians,
healthcare industry,

21. Some KLS Research Efforts
August 12-14th 2011
Some KLS Research Efforts
Lead Researcher
Location
Main Area of KLS Research
Emmanuel Mignot, MD, PhD*
California, USA
Genetics
Isabelle Arnulf, MD, PhD*
Paris, France
Clinical investigations
Yu-Shu Huang, MD
Taiwan, RoC
Long term studies
Han Fang, MD*
China
Hypocretin, biomarkers
Anne-Marie Landtblom, MD, PhD*
Sweden
Neuro-anatomical imaging
Geert Mayer, MD
Germany
Hypocretin, lithium treatments
Yakov Sivan, MD *
Israel
Environmental
Charles Chiu, MD, PhD*
California
Viral Infections
Francesca Cañellas Dols, MD*
Spain
Autoimmunity to brain proteins
In 1999/2000 we first connected with Dr Mignot and helped sponsor some of his initial research focused on collecting and summarizing past research. This led to additional work including collecting blood samples from patients and their families. We have subsequently provided seed funding for a number of research projects and where little research was being conducted 15 years ago there is now a number of studies being performed globally in the US, Europe and Asia. Many of these researchers are with us today and we will be able to hear from them about the work they are doing.
* recipient of KLS Foundation research support

22. KLS Research Volunteers
THANK YOU!
For those who have not yet participated, the Stanford Center for Narcolepsy & KLS Research seeks individuals who have KLS, as well as siblings when possible, for studies investigating the genetic basis of KLS Candidates with a diagnosis of KLS must be willing to: ● complete a detailed medical questionnaire ● provide a one-time blood sample For more info see: med.stanford.edu/narcolepsy/KLS.html At this conference contact: Gaylene Grossman, RN (KLS Foundation) Ling Lin, PhD (Sr. Research Scientist, Stanford University)

23. Understanding Research Publications Seeking Information about KLS
Scientific (‘peer-reviewed’) vs. general media
TV shows, news sources & popular magazines, press, social media, internet
‘Single case’ reports vs. large cohort studies
Quality (Impact Factor & citations)
Primary research vs. review articles
Technical –
Secondary – TV shows, news outlets & general interest magazines, lay press, social media, internet

24. Medical publications about KLS have steadily increased the past 20 years
2016: 16 papers
190 journal articles, case reports, reviews (32), letters/comments, et al

25. Importance of cohort size and participation in KLS research
August 12-14th 2011
Importance of cohort size and participation in KLS research
Cohort size in a published study
There are now more informative KLS studies and review articles based on observations and conclusions from a larger cohort of individuals with KLS.
This plots published studies with n >5.
Year of publication

26. Medical Review Articles on KLS
Medical review (summary) articles are valuable for researchers, healthcare providers, KLS families, school/work support needs
There are several good review articles on KLS:
Arnulf et al. “Kleine-Levin syndrome: a systematic review of 186 cases in the literature” Brain (2005)
Billiard et al. “Recurrent hypersomnia: a review of 339 cases” Sleep Med Rev. (2011)
Arnulf et al. “Diagnosis, disease course, and management of patients with Kleine-Levin syndrome” Lancet Neurology (2012)
Miglis & Guilleminault, “Kleine-Levin syndrome: a review” Nature & Science of Sleep (2014)

27. “Kleine-Levin syndrome: A systematic review of 186 cases in the literature” (Arnulf, et al, 2006, Brain)
Number citations/year*
* ResearchGate; 210 total citations

28. Beware ‘Predatory’ publication
an exploitative open-access academic publishing business that charges fees to authors, without providing editorial review and publishing services of legitimate journals. Example:
From: Susan Johnson Sent: Tuesday, June 19, 2018 To: Subject: Re: "Sleep disorders Causing Neurological Disorders" Write a Clinical Image/Editorial for this Edition Greetings! Hope you’re doing well We are inviting submissions for upcoming issue focused on Sleep disorders. The journal covers all aspects of Cognitive Behavioral Therapy, Dream and Anxiety Disorders, Migraine, Psychiatric Disorders, Sleep Disturbance, Sleep Medicine, Insomnia, Depression Causing Sleep Disorders and Mental Illness, Sleep Apnea, etc. We are inviting researchers and authors to submit an original research/Review/Case Reports/Image/video (s) that explore latest research developments in “Sleep disorders". As it is invited one we would like to charge you only 150USD, there will not be any hidden charges involved for this edition. Please send your manuscript to …
Susan Johnson, Editorial office: Austin Journal of Sleep disorders

29. Need for accurate diagnosis
Diagnosis is a crucial aspect of medicine to establish whether a patient has or does not have a particular condition.
In research, a homogeneous group of subjects is essential when goal is to accurately understand a condition.
Misdiagnosis creates a cascade of negative outcomes – inaccurate research results and patients will receive inappropriate treatment that will likely not alleviate disease symptoms.

30. KLS - Diagnostic Criteria
Many definitions of KLS proposed in the literature
DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 2013)
Produced by the American Psychiatric Association
Standardized criteria for the classification of mental and sleep disorders.
Used by clinicians, researchers, drug regulation agencies, health insurance companies, etc.
Uses ICD codes:
ICD-10 (International Classification of Diseases, 2015)
Produced by WHO
U.S. health system standard list of codes to describe diagnoses.
Standardized codes improves consistency among physicians in recording patient
symptoms and diagnoses for purposes of reimbursement and clinical research.
ICSD-3 (International Classification of Sleep Disorders, 2014)
Produced by the American Academy of Sleep Medicine, in association with European Sleep Research Society, Japanese Society of Sleep Research and Latin American Sleep Society.
KLS is classified as a sleep disorder, specifically one of recurrent hypersomnia
The DSM is published by the American Psychiatric Association (APA) and offers a common language and standard criteria for the classification of mental disorders. It is used, or relied upon, by clinicians, researchers, psychiatric drug regulation agencies, health insurance companies, pharmaceutical companies, the legal system, and policy makers together with alternatives such as the ICD-10 Classification of Mental and Behavioural Disorders, produced by the WHO.[1]The ICD is produced by a global health agency WHO with a constitutional public health mission, while the DSM is produced by a single national professional association (American Psychiatric Association).

31. Diagnostic Codes from ICD-10 CM (2018) G47 Sleep disorders
G47.0 Insomnia
G47.1 Hypersomnia
 G47.10 unspecified
 G47.11 Idiopathic hypersomnia with long sleep time
 G47.12 Idiopathic hypersomnia without long sleep time
 G47.13 Recurrent hypersomnia
 G47.14 … due to medical condition
 G47.19 Other hypersomnia
 G47.2 Circadian rhythm sleep disorders
 G47.3 Sleep apnea
 G47.4 Narcolepsy and cataplexy
 G47.5 Parasomnia
 G47.6 Sleep related movement disorders
 G47.9 Sleep disorder, unspecified

32. ICD-10-CM Diagnosis Code for Recurrent hypersomnia
G47.1   Hypersomnia
G47.13 – Recurrent Hypersomnia: Kleine-Levin Syndrome
A condition characterized by recurrent hypersomnia and hyperphagia and marked by such symptoms as mental confusion, excessive sleep requirements, restlessness, and hallucinations.
A rare condition characterized by recurrent hypersomnias associated with hyperphagia, occurring primarily in males in the 2nd-3rd decade of life. Clinical features include mental confusion, excessive sleep requirements (approx 18hrs/day), restlessness, and in some cases hallucinations. Episodes have a duration of days to weeks, and may recur several times per year. This condition may resolve spontaneously over several years.
A rare disorder predominantly males. The individuals exhibit normal behavior between episodes.
ICD-10 (completed 1992; US has used ICD-10-CM [‘clinical modification’] since October 2015) is the 10th revision of the International Statistical Classification of Diseases and Related Health Problems, a medical classification list by the WHO. It contains codes for diseases, signs and symptoms, abnormal findings, complaints, social circumstances, and external causes of injury or diseases. The classification permits the tracking of many new diagnoses compared to ICD-9.  Some national editions expand the code set further.
G47.13 is a billable/specific ICD-10-CM code that can be used to indicate a diagnosis for reimbursement purposes.
The 2018 edition of ICD-10-CM G47.13 became effective on October 1, 2017.
This is the American ICD-10-CM version of G47.13 - other int’l versions of ICD-10 G47.13 may differ.

33. Diagnostic (ICSD-3) criteria for KLS

34. KLS Foundation description
KLS is a rare and complex neurological disorder characterized by recurring periods of excessive amounts of sleep, altered behavior, and a reduced understanding of the world. The disorder strikes adolescents primarily but can occur in younger children and adults. At the onset of an episode the patient becomes progressively drowsy and sleeps for most of the day and night (hypersomnolence), sometimes waking only to eat or go to the bathroom. Each episode lasts days, weeks or months during which time all normal daily activities stop. Between episodes, there appears to be perfect health with no evidence of behavioral or physical dysfunction. KLS episodes may continue for 10 years or more.
KLS is characterized by clearly demarcated and recurrent episodes of excessive sleep and altered behavior.  KLS usually starts in the post-pubescent teenage years and episodes may continue to occur for a decade or longer.  Main symptoms are hypersomnia (18-22 hrs/day for weeks), cognitive impairment (confusion, de-realization, amnesia), disinhibited behavior and megaphagia (food cravings).  Between episodes there is normal sleep, understanding and behavior.  

35. KLS Research Summary
Over the past 15+ years, there has been a growing and networked international KLS research effort
Despite research challenges:
There is now a better understanding and medical description of KLS
A multi-disciplined research effort is underway to understand the medical cause of KLS
Emerging genetic results may provide a leap in KLS scientific studies
Key: Participation by individuals with KLS in research and funding

36. KLS Research Conference Schedule
Basic Research Presentations – Saturday
Talks oriented to research community
Plenary session :30 am
Dual track session :30 am – 3 pm
KLS families invited to listen to research talks
Opportunity to ask questions later during Q&A
Submit questions on index cards
Moderated Q&A ‘Research’ Panel for all 3 – 4 pm
Medications/Treatments (open) – Sunday
Overview at 10:00 am
Moderated Q&A ‘Clinician’ Panel 10:30-11:30 am
Researcher Workshops: Saturday – Managing KLS
Sunday – Future research agenda
Many of you are likely to have questions and at the same time we want to allow for the presenters to complete their presentations during the time allocated to them. There is scheduled a time at 3 pm today to have a facilitated research Q&A session. As part of the package you received when you checked in there were index cards on which we encourage you to write your questions. After the presentation I will be available to discuss your questions and collate the questions and try to answer as many of them as we can during the session later today.

37. KLS Research - Presentations
Presenter
Title
Neal Farber
Research Overview
Emmanuel Mignot *
Genetics of KLS
Aditya Ambati *
KLS Proteomics
David Rye
KLS viewed through the lens of hypersomnia
Guy Leschziner
Association between KLS and Migraines
Anne-Marie Landtblom*
Imaging Characteristics of KLS
Yu-Shu Huang
Actigraphy findings in KLS and development of predictive model
Fang Han *
Biomarkers
Smaranda Leu Semenescu
KLS Treatment
Isabelle Arnulf *
Clinical Picture
L-PGDS: LIPOCALIN-TYPE PROSTAGLANDIN D SYNTHASE
In 1999/2000 we connected with Dr Mignot and helped sponsor some of his initial research focused on collecting and summarizing past research. This led to additional work including collecting blood samples from patients and their families. We have subsequently provided seed funding for a number of research projects and where no research was being conducted 10 years ago there is now a number of studies being performed globally in the US, Europe and Asia. Many of these researchers are with us this weekend and we will be able to hear from them about the work they are doing.
We know that many of you are likely to have questions and at the same time we want to allow for the presenters to complete their presentations during the time we have allocated to them. We have scheduled some time at 5 pm today to have a facilitated Q&A session. As part of the package you received when you checked in there were index cards on which we encourage you to write your questions. After the presentation at about 4:30 I will be available to discuss your questions and collate the questions and try to answer as many of them as we can during the session after lunch today.
* recipient of KLS Foundation research support

38. First research talk – genetics
Epidemiological evidence suggests KLS not a genetic disease, however:
- Higher than expected incidence of KLS in one ethnic population
~ 5% multiplex families
Many diseases have a subset of affected individuals with a genetic component or pre-disposition
With the participation by > 650 individuals with KLS over 15 years, Mignot lab & collaborators have been searching for KLS genetic markers.

39. KLS Genetics
Dr. Emmanual Mignot

40. KLS proteomics
Dr. Aditya Ambati

41. Break

42. KLSF CONFERENCE

43. KLS in the context of hypersomnias
Dr. David Rye

44. Fundraising
Jenny Grossman

45. Collaborative Relationship with your Doctor
Hamper and Selak

46. Personal Reflections
Michael Hamper

47. Lunch

48. Amazon gives 5% of every purchase to the KLS Foundation if you use the KLS Foundation’s Amazon Smile Link:
Josh Riley to perform coming back from lunch
smile.amazon.com/ch/

49. Getting your education and working
Joey Dee

50. Break

51. “Your illness does not define you. Your strength & courage does.”

52. Creating the best life you can
Joy Selak

53. Researcher panel

54. 3RD INTERNATIONAL KLS CONFERENCE

55. Service dogs for KLS
Nancy Elfenbaum

56. Surviving and Thriving; navigating relationships with an invisible illness
Ilana Jaqueline (via skype)

57. 50% of all sales go to the KLS Foundation for Research
50% of all sales go to the KLS Foundation for Research

58. KLS treatment
Drs. Smaranda Leu-Semenescu and Isabelle Arnulf (via skype)

59. Break

60. THANK YOU TO OUR SPONSORS!

61. Researcher panel