Kleine Levin Syndrome Foundation
Toward a better definition of the clinical syndrome of KLS
Dr. Arnulf (Hospital Pitié-Salpétrière in Paris, France) conducted a metanalysis of the KLS literature during a sabbatical year at Stanford University. This landmark publication is now available in the medical journal called Brain (Arnulf et al., 2005), and can be provided to physicians who know little about the disorder. A total of 195 published reports about KLS from 1962-2004 were collected and those in foreign language translated. Cases not consistent with true KLS were excluded. Clinical data for a remaining 186 cases were compiled to produce the first comprehensive summary statistics for the disorder. Primary KLS cases were found mostly in men (68%) and occurred sporadically worldwide. The median age of onset was 15 years (81% during the second decade of life) and the syndrome lasted 8 years, with seven episodes of 10 days, recurring every 3.5 months (median values). The disease lasted longer in women and in patients experiencing less frequent episodes during the first year. An important finding of this analysis was
the unappreciated observation that KLS is not simply a sleep disorder characterized by hypersomnia, hyperphagia and hypersexuality. Indeed, beside increased sleep amounts during episodes, cognitive and perceptual abnormalities were always reported, most typically described by the patient as being in a fog, underwater, almost in a dream, or somehow separated from the surrounding reality. This under-appreciated symptom was found to be more consistent than hyperphagia or hypersexuality, symptoms often overemphasized because of their dramatic value. Hyperphagia and hypersexuality are in fact present only in some episodes, mild or not present at all. The diversity of symptoms reported by KLS patients suggests that the pathology affects a large portion of the brain. Indeed, this picture is consistent with a recent brain imaging study that showed a hypoperfusion of the thalamus (a sleep and sensory gating area) during episodes, and inconsistent hypoperfusion in the hypothalamus (controlling sleep, appetite and instinctual behaviors) and in multiple cortical regions (responsible for perception and cognition).
A second finding was the lack of efficacy for most reported attempted therapies. Indeed, it was found that the only agent that may have more effect than doing nothing was Lithium, but the response rate in preventing recurrence was only 41% and this was based only on 29 reports (our second, as yet unpublished study, actually suggests a lower response rate of approximately 20%). Similarly, stimulants were found to be active on sleepiness, but as they did not act on abnormal cognition, and were often not helpful if not deleterious.
A registry of active KLS cases
More recently, thanks to the KLS Foundation, we have been able to collect new clinical data and genetic material on a large number of KLS cases. A KLS questionnaire was created, with the aim of gathering further clinical information and to explore other potential predisposing and causal factors. Age, sex and ethnically matched controls were studied using a similar questionnaire. Finally, we collected blood samples from patients and from healthy controls to create a registry of samples for research studies.
Thanks to the dedication of patients, amazing help from the KLS Foundation and hard work from our staff, particularly Isabelle Arnulf and Jennifer File (patient coordinator), we were able to collect over 100 new KLS cases. In many instances we also collected blood samples from parents, which will help future genetic analysis. For us, this surprising success meant that a lot of patients were starving for help, and that the disease is probably more frequent than believed. The prevalence of less than 1 case of KLS per million typically quoted is in my opinion a gross underestimation. A detailed report is now under review for publication in a prestigious scientific journal, Annals of Neurology.
New Insights into KLS:
The systematic collection of clinical data in a new series of KLS patients in comparison with healthy controls led to a few additional insights.
First, we found that disease duration was longer than in the metanalysis, a median of 12 years instead of 8 years.
Second, as in the prior study, we found that treatments were generally ineffective and in this case lithium or other mood stabilizers such as anticonvulsivants had similarly poor response rates (20%).
Third, we found that patients in between episodes were quite normal; indeed, we found that patients were only slightly more anxious and overweight versus age, sex and ethnically matched controls. Most notably, patients were not more depressed, and did not have increased family history for depression or other psychiatric and neurological disorders. This last finding is important because some psychiatrists still think KLS is a variant of bipolar disorder due to the recurrence pattern, the hypersomnia and the possible beneficial effect of Lithium or other mood stabilizers.
Familial predisposition and a possible increased risk in Ashkenazi Jews
One of the surprising findings of this study was the observation that in 5 cases out of 108, more than one family member was affected with KLS. This is surprising considering how rare KLS is believed to be. More than 20 such families with multiple cases of KLS are known to the KLS Foundation, suggesting either a genetic predisposition (genes passed from the parents to several children in the family) or shared environmental factors (for example being exposed to the same virus within the same family).
Further, we found that 14% of the KLS cases recruited in the United States were Jewish Ashkenazi. This figure is much higher than the 2% proportion of such individuals in the general US population and was also much higher than Jewish patients in our database of subjects with other sleep disorders. This was only partially a surprise, as one of the largest previously published case series of KLS cases was from Israel (Gadoth et al., 2001). To us, this result suggest that Ashkenazi Jews, who are known to carry special genetic changes because of their origin from a relatively small number of individuals 4,000 years ago, may have a specific genetic factor predisposing to KLS. Importantly however, many more cases were non-Jewish and it is always possible that the inflated value is the result of a recruitment bias, for example if the American Jewish population is more aware of the disorder than other populations. To illustrate this point, very few African Americans and Latinos were found in our recently collected KLS sample, possibly because they did not come to our attention due to socioeconomic differences.
KLS, HLA and autoimmunity: a disappointing hypothesis
Many possible etiologies have been suggested for KLS. The presence of flu-like symptoms at the onset of the disease in many cases suggests a possible infectious cause or at least an infectious trigger. In 2002, Dauvilliers et al. made an exciting finding, reporting on the observation that 47% of his KLS cases in Europe, 30 in total, were Human Leukocyte Antigen (HLA)-DQB1*02 positive in contrast to approximately 25% of controls. HLA are proteins that are very important for regulating the immune system, the system that fights infections in our body. Most diseases with an HLA association are autoimmune diseases, conditions where the immune system mistakenly attacks one’s own self, for example in multiple sclerosis where the immune system attacks insulating components in our nerves. The hypothesis was very appealing, as many autoimmune diseases have a characteristic remitting-relapsing course like KLS, corresponding to periods of sudden immune activation, and may be initiated by environmental or infectious triggers. To further test this hypothesis, we examined the HLA-DR and DQ associations in our large sample of recently collected KLS patients, but were unable to find a correlation, suggesting that the first report was a chance finding. Dr. Arnulf, in Paris, France, also tried immune related therapies, most notably intravenous immunoglobulin (a therapy effective in some autoimmune diseases) but did not observe consistent effects.
The environment/genetic interaction hypothesis and the search for a possible pathogen causing KLS
As mentioned above, our working hypothesis is that of a genetic predisposition to an infectious process that may affect the brain and would result in a waxing and waning brain infection/inflammation thereby producing KLS episodes. After several years, the immune system could successfully keep the process at bay and the disease would terminate. In some aspect, KLS could be similar to herpes infections, which often reoccur in life.
To address this issue, we are now collecting nasal swab samples from patients at the beginning of a KLS episode. We hope these samples will identify a possible viral agent that could be involved in KLS. We have now collected approximately 10 samples, and are hoping to obtain 20 such samples in order to initiate a molecular analysis by Dr. DeRisi at UCSF, who specializes in identifying unknown viruses. In parallel, we are sending serum samples to screen for the presence of a number of viruses known to affect the brain, such as the recently identified HHV-6.
Collaboration with Israel
The observation that KLS preferentially affects Ashkenazi Jews offers a unique research opportunity. Indeed, if this is the case, it is likely that whatever genetic factor is involved in predisposing to KLS, it is enriched in this population. Further, as this ethnic group descends from a relatively smaller number of individuals, it is more likely that only one or few genetic subtypes are involved in this population, which greatly increases the probability of finding a genetic culprit.
Based on the above, our first goal has been to collect as many KLS cases in this ancestry as possible in the US and elsewhere. In this endeavor, we have been extremely fortunate to recruit Dr. Yakov Sivan from Israel. Thanks to him, we now have more than 40 cases and controls from this ethnic subgroup. A genome wide association is currently ongoing with these samples.
A need for education
Another area where we feel much remains to be done is in education. Indeed, very little exists in term of diagnostic and therapeutic guidelines. We believe that to fill this gap we need to publish intensively in high impact journals. The publications mentioned above, published in Brain (mostly European readership) and under revision at Annals of Neurology, will be extremely effective. We are also trying to publish commentaries on this intriguing disease as frequently as possible.
KLS International research team
Principal investigators and staff:
Emmanuel Mignot MD, PhD, Director, Center for Narcolepsy and Hypersomnia research, Stanford University USA
Isabelle Arnulf, MD, PhD, Fédération des Pathologies du Sommeil, Hôpital Pitié-Salpêtrière, Paris, France
Juliette Faraco, PhD, Center for Narcolepsy and Hypersomnia research, Stanford University
Joachim Hallmayer, MD, PhD, Stanford University, USA
Neil Risch, PhD Genetic epidemiology, University of California, San Francisco, USA
Yakov Sivan, MD, Dana-Children’s Hospital, Tel-Aviv, Israel
Clinical patient coordinators:
USA: Jacob Markovitz, Stanford University, USA
Israel: Esti Cohen Gabizon, Dana-Children’s Hospital. Tel-Aviv, Israel
Europe: Isabelle Arnulf, Hôpital Pitié-Salpêtrière, Paris, France
Arnulf I, Zeitzer JM, File J, Farber N, Mignot E. Kleine-Levin syndrome: a systematic review of 186 cases in the literature. Brain. 2005 Dec;128(Pt 12):2763-76.
Dauvilliers Y, Mayer G, Lecendreux M, Neidhart E, Peraita-Adrados R, Sonka K, et al. Kleine–Levin syndrome: an autoimmune hypothesis based on clinical and genetic analyses. Neurology 2002; 59: 1739–45.
Gadoth N, Kesler A, Vainstein G, Peled R, Lavie P. Clinical and polysomnographic characteristics of 34 patients with Kleine–Levin syndrome. J Sleep Res 2001; 10: 337–41.
Huang YS, Guilleminault C, Kao PF, Liu FY. SPECT findings in the Kleine-Levin syndrome. Sleep. 2005 Aug 1;28(8):955-60.
Mignot E., A step forward for restless legs syndrome. Nat Genet. 2007 Aug;39(8):938-9.
STANFORD UNIVERSITY KLS RESEARCH PROJECT
Scientific Research Program
A KLS research program has been established at Stanford University under the direction of Dr. Emmanuel Mignot MD, PhD and co-investigator Dr. Isabelle Arnulf. Studies will focus on possible immune, infectious, neurological and genetic bases for the syndrome. The program will use a range of medical and basic research methods, working together with a multidisciplinary team studying hypersomnia and other sleep disorders at Stanford. The research program has begun establishing a comprehensive medical information database about KLS and the first large scale KLS blood sample collection. While the vast majority of cases are sporadic and cases have been reported in all continents, a few very intriguing cases of co-affected family relationships within this rare disease population have been identified. The first investigations will examine HLA and possible other genetic factors predisposing to KLS. This study is part of a larger Stanford study of HLA predisposing genes in various disorders of excessive daytime sleepiness
Objective of the Research Program
Information about KLS is scattered among approximately 100+ published case reports. To obtain a better understanding of the disease, a comprehensive review article is in preparation and a questionnaire has been prepared to accumulate patient data to better characterize KLS symptoms and look for commonalities among patients.A blood sample collection of up to 200 KLS patients and families (with age, sex and ethnic-matched controls) is being established so that various hypotheses about the possible causes of KLS can be readily tested. This blood sample collection will also be a resource available for other investigations and will hopefully foster further research interest in KLS by clinicians and scientists. A consent form has been approved by the Panel for Human Subjects in Medical Research at Stanford which participants will be required to complete to provide samples to the program.
How to Participate in the Research Program
The questionnaire is designed to collect information about:
· Personal and family medical history, including ethnic information
· History of KLS – symptoms, precipitating factors, kinetics of episodes
· Results of treatments tried, and medical and lab tests taken
After completion of the questionnaire, participants (typically the KLS patient and their parents) willing to provide blood samples will be required to complete a consent form allowing Stanford to use the samples and the data obtained from the samples. Once the form is complete blood sampling kits (with pre-paid FedEx return) will be sent.
In addition to helping fund this research, the KLS Foundation plays an important role in the program by providing contact information on KLS patients and in motivating compliance.
Dr. Mignot is an Associate Professor of Medicine, Stanford Medical School , Professor of Psychiatry and Behavioral Sciences, Director of the Stanford Center for Narcolepsy, and a Howard Hughes Institute investigator, who is very experienced in clinical and basic research in the area of sleep disorders medicine and is internationally recognized as having discovered the cause of narcolepsy. He has received numerous honors, is the co-author of more than 100 original scientific publications, and serves on the editorial board of scientific journals in the field of sleep disorders research.
Research Program FAQ’s
Please use the following link for questions on the Research project:
STANFORD UNIVERSITY KLS RESEARCH PROJECT PROGRESS REPORT: JUNE 2005
The KLS research program underway at Stanford University is progressing at a very impressive pace.
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 project began in the fall of 2004 in the laboratory of Emmanuel Mignot, MD, PhD, under the direction of Isabelle Arnulf, MD, PhD, working with a small support team.
The research program began with a thorough review of nearly 200 cases of KLS reported in the literature and a complete analysis of the symptoms, risk factors and treatment responses of patients. This comprehensive review has been submitted for publication.Two valuable resources for KLS medical research have been established:(1) the first large scale KLS blood sample collection for laboratory investigations(2) a comprehensive questionnaire of KLS patients and parents to create an information database on KLS.
Status of blood sample collection and questionnaire
Compliance has been excellent. To date, a total of 114 patients with KLS who meet the ICSD-2 Revised criteria have taken part in the study by submitting blood samples and completing a detailed questionnaire. In addition to the patients, 164 parents took part in the study, so complete sets of many patients with both parents are available for genetic and other studies. A collection of age, sex and ethnic matched controls of 115 subjects is complete. The patient database also contains families with multiple occurrences of KLS (siblings, father and son, first cousins).
Responses from the questionnaires have been entered in a large confidential Excel database, stored with restricted access at Stanford University. All data entered have been double-checked and cleaned. The questionnaire collected data about personal & family medical history, history of KLS (symptoms, risk factors, kinetics of episodes, many sleep related questions) and results of treatments tried and medical & lab tests taken.
Statistical analysis on KLS vs. controls questionnaire data has begun. Already a higher incident rate in one ethnic group and a correlation with one risk factor have been identified.
Investigations of the blood samples
From the hundreds of blood kits returned, samples of serum, plasma, and buffy coat cells have been prepared, DNA has been extracted and all stored in a blood bank. First studies are designed to look for possible genetic factors predisposing individuals to KLS.
Various autoimmune diseases are tightly linked to a specific human leukocyte antigen (HLA) type. For example, in narcolepsy, over 90% of the patients carry one specific HLA allele.
A first assay of 220 samples of KLS parents and patients has already been typed for a specific HLA allele 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.
In an additional project, the serum of approximately 100 KLS patients and controls has been prepared for measuring blood protein disease markers. Already, one serum protein, a marker of acute inflammation, has been shown to be twice as high in KLS patients than in controls.
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 which were collected during a KLS episode or had clear “infectious signs” at an KLS episode onset have been selected for analysis.
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.