Report to the NIH Sleep Disorders Research Advisory Board (SDRAB) December 2005
Kleine-Levin Syndrome (“KLS’) explained
KLS is an uncommon sleep disorder characterized by recurrent and unusually long episodes (lasting weeks to months) of hypersomnia, associated with behavioral/cognitive disturbances and often megaphagia. KLS primarily strikes adolescents and the cessation of episodes typically occurs in early adult life.
The cause of KLS is unknown. All diagnostic test results on KLS patients to date have been normal. However, nearly half of the patients experience a non-specific, flu-like infectious disease a few days before the onset of their first KLS episode. There are a few reports of co-affected familial relationships.
The Kleine-Levin Syndrome Foundation, Inc
The Kleine-Levin Syndrome Foundation, Inc., established in 1999, has become an important network to identify and support individuals and families affected by KLS. The Foundation exchanges information with patients and the medical community to help in the diagnosis and care of those affected by KLS.
The Foundation continues to raise awareness of KLS. Fox TV News affiliate in Los Angeles aired a show on KLS on November 15th. Fox News came to the house of a 15 year-old boy while he was in a KLS hypersomnia episode and then to his football practice two days after his episode was over for interviews and filming. It was a well-done piece demonstrating a dramatic contrast in sleep state (see http://www.fox11.com/sections/news/onair.asp/). This story has already sparked interest by other TV network news on KLS and sleep disorders.
KLS Research Program Progress
The KLS Foundation has partnered with the Stanford University Sleep Center to establish a basic and clinical research program on KLS under the direction of Dr. Mignot.
A comprehensive review article on KLS has just been published (I. Arnulf, et al, Kleine-Levin syndrome: a systematic review of 186 cases in the literature, Brain, October 17, 2005,http://brain.oxfordjournals.org/cgi/content/abstract/awh620v1).
In KLS, the association of an infection before the onset of disease, young age at onset, recurrence of symptoms and possible genetic predisposition is suggestive of a possible autoimmune component. Ongoing studies are designed to look for the involvement of HLA, genetic or viral factors in KLS pathobiology.
To pursue this line of research, Stanford University has conducted a systematic study of new KLS cases. Blood samples and extensive clinical data were collected from 108 patients with KLS, most identified through the KLS Foundation. Parent samples were also collected (totaling 80 sets of patient plus both parent, termed “trios”), together with age-match controls. Diagnostic interviews by phone or in person were conducted in all cases.
While this data is still being analyzed, several new findings have already been made, including an increased ethnic predisposition of KLS: 15% of U.S. patients were of Jewish Ashkenazi heritage, a highly significant difference when compared to the 2% population frequency for this group in the United States(p
<0.001). This strongly suggests a genetic founder effect in the Jewish population.
Preliminary HLA typing results of the samples has lead to a possible linkage effect in an HLA allele using transmission disequilibrium analysis of the family trios.
These results have spawned further research interests from groups in France and Israel.
Stanford continues to collect KLS blood samples (see
Two KLS medical research resources have been established: (1) A large blood sample collection of KLS patients and parents for laboratory investigations and (2) a comprehensive database of KLS patients and parents, based on the collated questionnaire information. These resources are now available for KLS investigations and will hopefully foster further research interest by clinicians and scientists in the field of sleep medicine.
A scientific session on KLS is being organized for the June 2006 meeting of the Associated Professional Sleep Societies.
Report to the NIH Sleep Disorders Research Advisory Board (SDRAB) June 2005
The Kleine-Levin Syndrome Foundation is pleased to submit this third report to the NIH SDRAB, with a progress report on the KLS research program underway at Stanford University.
Kleine-Levin Syndrome (“KLS”) is a sleep disorder characterized by recurrent and unusually long episodes of hypersomnia, associated with behavioral/cognitive disturbances, megaphagia and rarely sexual disinhibition. These serious episodes last weeks to months and alternate with asymptomatic periods of normal sleep and behavior lasting months to years. KLS primarily strikes adolescents and the cessation of episodes typically occurs in early adult life.
The cause of KLS is unknown. All diagnostic test results on KLS patients to date, including brain imaging, EEG, serum virus titers and CSF examination, have been normal. However, nearly half of the patients experience a non-specific, mainly flu-like infectious disease a few days before the onset of their first KLS episode. While the vast majority of cases are sporadic and cases appear on all continents, there are however a few reports of co-affected familial relationships. In KLS, the association of an infection before the onset of disease, young age at onset, recurrence of symptoms and possible genetic predisposition is suggestive of a possible autoimmune component.
Stanford University KLS Research Project
The KLS Foundation has partnered with sleep experts at the Stanford University Sleep Center to establish a basic and clinical research program on KLS. This began in the fall of 2004 in the lab of Emmanuel Mignot, MD, PhD (650-725-6517) under the direction of Isabelle Arnulf, MD, PhD, (650 724-8839) working with a small support team.
The research program began with a thorough review of 186 cases of KLS reported in the literature and a meta-analysis of the symptoms, risk factors and treatment responses in patients. This review has been submitted for publication.
Two medical KLS research resources have been established: (1) The first large scale KLS blood sample collection for laboratory investigations and (2) a comprehensive questionnaire of KLS patients and parents to create an information database on KLS.
Blood collection and questionnaire
Compliance has been excellent. To date, a total of 105 patients with KLS who meet the ICSD-2 Revised criteria have taken part in the study by submitting blood samples and a detailed questionnaire. The mean age of the KLS group was 26.1± 11.1 years (range 8 – 66 years) and 81 (77%) patients were male. Reported ethnicities include 88 Caucasian, 14 Jewish, 1 African (French Antilla), 1 Asian (Korean) and 1 Hispanic patient. In addition to the patients, 164 parents took part to the study, so the rate of trios is 78%. A collection of age-, sex- and ethnic-matched controls of 111 subjects is almost complete. The current KLS patient database contains 4 cases with the following family relationships: 2 siblings affected (n=2), father and son affected (n= 1) and first cousins affected (n= 1).
Responses from the questionnaires have been all entered in a large confidential Excel database, stored with restricted access at Stanford University. All data entered have been double-checked and cleaned. We are waiting for the last 2 controls to start statistics on KLS vs. controls questionnaire data.
DNA has been extracted from of all blood samples. Samples of serum, plasma, and buffy coat cells have been prepared. The blood sample bank is stored at –80°C.
Investigations of the blood samples
First studies are designed to look for HLA and possible other genetic factors predisposing to KLS.
Various autoimmune diseases are tightly linked to a specific human leukocyte antigen (HLA) type. For example, in narcolepsy, 88-98% of the patients carry one specific HLA allele (HLA-DQB1*0602), while the corresponding percentages in control populations vary from 12 to 38%. The HLA system has been poorly studied in KLS patients, however a study by Dr. Dauvilliers and Tafti in a limited number of KLS patients suggested a higher than control frequency of another HLA allele (HLA-DQB1*201).
A first assay of 220 samples of KLS parents and patients has already been phenotyped for HLA DQB1*602 and the percent positive is not different from that found in the normal population. These samples have been sent to the Stanford University HLA laboratory for full class-II genotyping. We will try to replicate the reported HLA finding of DQB1*02 association in KLS using a sample collection 3-4 times larger.
The serum of approximately 100 KLS patients and controls have been prepared for measuring blood protein disease markers.
We are also interested in examining a possible viral role in KLS pathology. To maximize the chance of finding viruses or viral markers, blood samples have been selected for analysis which were collected during a KLS episode, closed to the KLS onset and had clear “infectious signs” at KLS onset.
In addition to exploring possible hypothesis for the cause of Kleine-Levin Syndrome, these resources will be available for other KLS investigations and will hopefully foster further research interest by clinicians and scientists in the field of sleep medicine.
This pilot project has been funded by a small grant from the KLS Foundation and we are fortunate that Dr Isabelle Arnulf, the major investigator coordinating this project is on paid sabbatical from Europe. Our research goal has been to gather preliminary data for subsequent outside support in this area. NIH has not funded KLS research, despite the disabling nature of this disease. Although characterized as a rare sleep disorder, its real prevalence is unknown and the success of the Stanford recruitment indicates it may be more prevalent than conventionally thought.