Through fundraising events, grant distribution and engagement with the patient community, WUN acts both a facilitator and an anchor bringing life, stability and encouragement to people affected by narcolepsy.
Until the late 1990’s, narcolepsy was a complete mystery. Doctors suspected that the problem lay within the hypothalamus, a part of the brain that regulates arousal, sleep, hunger and other functions, but the specific problem was unknown. The discovery that narcolepsy is caused by a loss of the orexin (hypocretin)-producing neurons has substantially improved our understanding of this often-disabling disorder and has enabled researchers to move much closer to better therapies.
With support from Wake Up Narcolepsy, Dr. Scammell’s research group has helped define which brain circuits give rise to cataplexy and sleepiness using mouse models of narcolepsy. Cataplexy is episodes of muscle weakness triggered by strong, generally positive emotions, and Dr. Scammell’s group has found that the amygdala is a key brain region for cataplexy. The amygdala is considered a brain region where “emotion meets motion”. For example, the amygdala helps produce emotional reflexes such as freezing with fear or smiling at a friend. It is now clear that in mice with narcolepsy, positive emotions (in response to tasty treats such as chocolate) are relayed by the amygdala to the brainstem, resulting in episodes of muscle weakness.
The amygdala is a complicated brain region, and Dr. Scammell’s research group will use this generous support from Wake Up Narcolepsy to define just which amygdala neurons mediate cataplexy. They anticipate that this will enable development of drugs that target just this brain circuit without causing side effects. This funding will also help generate crucial pilot data that can leveraged to obtain larger research grants from the National Institutes of Health and other organizations. Ultimately, a better understanding of these brain mechanisms will enable researchers and doctors to develop new methods to improve sleepiness, cataplexy, and other symptoms of narcolepsy.
Genetic predisposition of narcolepsy and a new sleep study diagnostic test
Dr. Emmanuel Mignot and his research team are proud to announce that they have recently completed a World Wide Genome Wide Association study to uncover why narcolepsy develops in some individuals but not others. The study was conducted in regular type 1 narcolepsy patients and also in patients who have developed narcolepsy following vaccination with the anti H1N1 swine flu vaccine pandemrix.
We analyzed multiethnic samples from Asians (Korea, Japan and China), African Americans, and Caucasians (Europe, USA) in 5,501 cases and 23,615 controls to study genetic associations with narcolepsy. We discovered overall significant associations in the HLA locus and in 12 other loci of which 6 are entirely new finings. The new findings include association with the Perforin PRF1, Langherin CD207, SIRPG, IL27 and ZFAND2A genes. Six other associations (T cell receptor TRA, TRB, cathepsin CTSH, interferon receptor IFNAR1, ZNF365 and P2RY11) have been reported in earlier studies. Most interestingly, TRA and CTSH genetic effects were stronger in vaccination-induced narcolepsy, while predisposing effects of IFNAR1, TCRB and CD207 were absent or opposite. Functional analysis in two cohorts revealed a functional role for TRA and TRB variants in regulating usage of TRAJ*24, TRAJ*28 and TRBV*4-2 respectively (P<10-8 ). In addition, we found that the IFNAR1 variant associated with narcolepsy increases response to influenza-A infection in dendritic cells. Finally, we found that partitioned narcolepsy heritability was mediated by immune cells, with functional analysis of ENCODE data indicating enrichment of functional elements in Th17, T regulatory and CD8+ T cells. Together these findings define narcolepsy as an autoimmune disease mediated through T cell receptor signaling, with involvement of influenza A (the flu) as a critical trigger. Interestingly, we are also now learning which genetic effects are related to flu infections (langherin, interferon receptor) versus core to the autoimmune process (PRF1, TCRA, HLA). The research is starting to build a detailed model on how the immune system is causing narcolepsy, with possible preventive applications. This research has been written and will be submitted very soon for publication. Additionally we used machine learning to create a probability score for narcolepsy in individuals suspected of having Type 1 narcolepsy, opening the possibility of diagnosing narcolepsy using an at home nighttime sleep study as opposed to current standard, a daytime nap study following a nocturnal sleep study called the Multiple sleep latency test that lasts 24 hrs. Analysis of sleep currently requires visual inspection by trained scoring technicians. We used neural networks in over 3,000 sleep recordings from 10 locations to automate sleep stage scoring, producing a hypnodensity graph – a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated on 70 subjects assessed by six sleep scorers, forming a more accurate standard for comparison. Our best model performed better than any individual scorer and reached an accuracy of 0.87, while average scorers only reached 0.81. When predictions were weighed by scorer agreement, performance rose to 0.95, indicating a higher consensus in areas of scorer agreement. The method also reliably scores sleep stages down to 5 second epochs instead of the conventional 30 second scoring-epochs. Accuracy did not vary by sleep disorder except for narcolepsy, suggesting scoring difficulties. A narcolepsy biomarker was thus extracted based on unusual sleep-stage overlaps. Validation of the biomarker in an independent dataset of 105 type-1 narcoleptics versus 331 controls and other patients produced a specificity of 0.96 and a sensitivity of 0.91. Similar performances were obtained when tested against a high pretest probability sample of patients with type-2 narcolepsy or idiopathic hypersomnia. Addition of HLADQB1*06:02 typing information (a frequently used genetic marker of type-1 narcolepsy) further increased specificity to 0.99. Our method could reduce costs by decreasing time spent in sleep clinics and automating the diagnosis of narcolepsy. It also opens the possibility of diagnosing narcolepsy using home sleep studies.
This research is under review in nature communication, and also available as a preprint at https://nature-research-under-consideration.nature.com/users/37265-naturecommunications/posts/21655-the-use-of-neural-networks-in-the-analysis-of-sleep-stages-and-thediagnosis-of-narcolepsy
A recent article citing Dr. Mignot’s career in narcolepsy: https://www.theatlantic.com/health/archive/2017/10/narcolepsy-sleep-disorder-stillunsolved/543717/
Thank you for your generous support!
The Behavioral Sleep Medicine Lab at Northwestern University, led by Jason Ong, has been very active in research aimed at improving the health-related quality of life in people with narcolepsy and idiopathic hypersomnia. In January 2020, our paper from a study that was funded by WUN was accepted for publication at Behavioral Sleep Medicine. This study involved a series of interviews with PWN to better understand how the symptoms of narcolepsy impact quality of life and to seek patient input on how to provide more relevant mental health services for PWN. In December 2021, we published our first study using a novel cognitive-behavior therapy for hypersomnia (CBT-H) in the Journal of Clinical Sleep Medicine. CBT-H is a 6-session telehealth program using techniques such as following a regular daytime and nighttime schedule, managing depression and anxiety associated with hypersomnia, and improving self-efficacy, which refers to the ability to achieve a goal. We found that 40% of participants showed a significant reduction in depressive symptoms and the telehealth delivery allowed participants from around the US to participate.
In addition to these publications, we have two current projects. One project aims to develop an app specifically designed to monitor and manage symptoms of hypersomnia based on our CBT-H program. The first beta version is nearly ready for testing. The second project is an NIH-funded study examining the use of mindfulness meditation to help reduce depression and anxiety symptoms in people with narcolepsy. This project is currently recruiting participants.
Dr. Jason Ong says, “We greatly appreciate the support from WUN, which has allowed us to carry out and complete these projects during the pandemic. We hope that our work will provide evidence-based strategies using digital and tele-health delivery to improve the mental health and quality of life among PWN.”
Our research team at Boston Children’s Hospital are working on many projects to improve the care of children, adolescent and young adults with narcolepsy. Diagnostic delays in narcolepsy are unfortunately common. We are working on a screening tool that can be used by health care providers and school-based professionals to identify patients with narcolepsy symptoms and direct them towards to appropriate diagnostic tests. We are also working on developing and validating patient-reported outcomes for pediatric narcolepsy. These outcome measures are important to identify what symptoms and functions are important to people with narcolepsy in order to guide treatments. Last, disrupted nighttime sleep (DNS) is a common problem for people with narcolepsy. We are studying DNS in pediatric narcolepsy and assessing its effect on memory, mood, and attention.
Dr. Kiran Maski says, “I am incredibly grateful for the support of Wake Up Narcolepsy, our wonderful research participants, and our dedicated research staff that make this work possible!”
Narcolepsy and idiopathic hypersomnia usually begin in early adolescence, but diagnostic delays ranging 5-10 years are common, impacting disease burden. To improve early identification of these treatable conditions, Dr. Kiran Maski, Boston Children’s, developed and validated the Pediatric Hypersomnolence Survey (PHS). This is a screening tool that can be used in clinical offices and the community to assess sleepy kids and teens. We hope this survey can help triage kids/teens with narcolepsy/idiopathic hypersomnia more directly to sleep medicine providers for timely diagnosis.
This work was just accepted by the journal Neurology https://pubmed.ncbi.nlm.nih.gov/35314496/.
The development of the PHS was funded by Covery Health Care and Wake Up Narcolepsy.
1. Helped Masters student finish her Masters in Narcolepsy and depression
2. Started second large study qualitatively evaluating symptoms of Narcolepsy in kids.
3. Published paper on clinical manifestations of Narcolepsy.
4. Adolescent medicine Staff dedicated to the Narcolepsy clinic to help navigate the issues some adolescents face with Narcolepsy.
5. Hosted a family event.
Dr. Indra Narang from Sick Kids-
Clinical Manifestations of Childhood Narcolepsy.
We evaluated symptoms of children who presented with symptoms of Narcolepsy and were
subsequently diagnosed with Narcolepsy. These data were obtained just after diagnosis of Narcolepsy in
33 children prior to any child commencing medications to alleviate their symptoms. The mean age at
diagnosis was 10.4 years, the youngest age being 3.9 years and oldest 17 years of age. All children had
excessive daytime sleepiness. Of these children, 64% had cataplectic facies such as tongue protrusion,
facial droop, facial grimacing and/or head rolling. The remaining 36% had characteristic cataplexy with
muscle weakness of limbs and /or falling to the ground with laughter/excitement. Interestingly, children
with cataplectic facies tended to be younger and had higher body weights. At presentation, the study
also found that 21% of children had hallucinations and 9% had sleep paralysis.
All brain scans (MRI brain) and all testing for epilepsy using an EEG were negative for this group of
children. This study has increased awareness of Narcolepsy in children and highlighted the different
manifestations of Narcolepsy in children. Link to the published study.
Depressive Symptoms, Sleep Patterns and Physical Activity in Adolescents with Narcolepsy
In this study, our group were interested to understand the association between depressive symptoms,
sleep patterns (duration and quality), excessive daytime sleepiness and physical activity in adolescents
with narcolepsy and to compare them to controls. We recruited 30 adolescents with a mean age of 13.8
years diagnosed with Narcolepsy and 30 controls subjects.
Adolescents completed many questionnaires evaluating how 1) sleepy they were 2) the presence of
depressive symptoms, 3) sleep disturbance, 4) physical activity levels. They also used wrist based
actigraphy for one week to measure total sleep time.
This study showed that adolescents with Narcolepsy had more depressive symptoms than adolescents
who did not have Narcolepsy. Depressive symptoms were associated with excessive daytime sleepiness,
more night time sleep disturbance and lower physical activity levels.
This study has re-inforced a multi-disciplinary care approach to adolescents with Narcolepsy ensuring
that mental health issues are addressed early in the consultation process. Further, we have emphasized
the message that improving nocturnal sleep quality and good sleep hygiene as well as promoting
physical activity may provide an opportunity to reduced depressive symptoms in adolescents with
Narcolepsy. This study has not been published yet but is under review.
Qualitative Evaluation of symptoms of Narcolepsy
This study which we have just commenced is evaluating which specific symptoms impact patients with
Narcolepsy. We are also interested to know how these symptoms may affect their daily lives.