Usefulness and Limits of Clinical and Biological Tools to Evaluate Excessive Sleepiness


Scope of the Meeting


Goal
Excessive Sleepiness is a symptom that affects nearly 25% of the general population. However, this symptom has not been widely studied; instruments to assess it are rare and were developed before 1995. Our understanding of the symptom has since then changed considerably. The goal of this symposium is to inform the attendees on the new research development in the acquisition of knowledge related to excessive sleepiness; the evolution of the concept of excessive sleepiness and to familiarize attendees with the legal, clinical and diagnostic implications of the existing tools used to measure excessive sleepiness. More specifically, usefulness and limits of current tools will be discussed along with the avenues to improve the assessment of excessive sleepiness.

Objectives

  1. What are the legal implications of excessive sleepiness in terms of legal issues (responsibility in accidents related to excessive sleepiness) and work-related issues (risks for the individuals and for the population)
  2. What are the clinical implications in terms of evaluation and treatment. How accurate are the existing biological and clinical tools to determine when sleepiness is excessive and how it evolves over the time.
  3. What is the place of excessive sleepiness in current classifications (DSM-5 and ICSD-3): Differences and similarities between DSM-5 and ICSD-3 for Excessive sleepiness

Program

Friday, November 14th, 2014

08:30 - 08:45 Maurice Ohayon, MD, DSc, PhD
Welcome / Overview of the day

Laura Roberts, MD, MA
Population Sciences in the Department of Psychiatry at Stanford
 
08:45 - 09:20 Maurice Ohayon, MD, DSc, PhD
Excessive Sleepiness and Excessive Sleep Duration: Why Hypersomnolence is a better terminology than Hypersomnia from an epidemiological perspective?
 
09:20 - 09:55 David Dinges, PhD
What are the neurobehavioral manifestations of sleepiness?
 
09:55 - 10:30 Michael Thorpy MD
Limitations of Current Diagnostic Criteria for Hypersomnolence Disorders
 
10:30 - 10:35 Discussion
Sleep Duration and Mortality
Excessive Sleepiness as an epidemic in the US population
Sleeping Too much: Are Mental Disorders a risk factor?
Medical Disorders associated with Hypersomnolence
Which could be the recommendations for Sleep Duration to the Public?
 
10:35 - 10:45 Break
 
10:45 - 11:20 Antonio Vela-Bueno, MD, PhD
Fatigue versus Sleepiness
 
11:20 - 11:55 Edward Bixler, PhD
Daytime Sleepiness: Mechanisms, Risk Factors & Natural History
 
11:55 - 12:10 Discussion
How Fatigue and Sleepiness overlap?
Is fatigue a predictor of sleepiness?
Evolution of Daytime Sleepiness and Neurological Diseases
Are the measures of fatigue indicative of the risks of Sleepiness?
Is actimetry a good way to evaluate fatigue? Sleepiness?
 
12:15 - 13:30 Lunch
 
13:30 - 14:05 Giuseppe Plazzi, MD, PhD
Objective sleepiness measures to identify narcolepsy: from a laboratory perspective to epidemiology
 
14:05 - 14:40 Diane Guinta, PhD
Assessment of Sleepiness with the ESS and MWT in Narcolepsy Drug Trials
 
14:40 - 15:15 Yves Dauvilliers, MD, PhD
Role of the hypothalamic histamine system in narcolepsy
 
15:15 - 15:25 Discussion
 
15:25 - 15:40 Break
 
15:40 - 16:15 Michael Vitiello, Ph.D
Self-Reported Excessive Sleepiness in Older Adults: With what is it Associated?
 
16:15 - 16:50 Seung Chul Hong, MD, PhD
Sleep Loss and Daytime Consequences in the Korean Population
 
16:50 - 17:15 Jed Black, MD
Narcolepsy and Comorbities
 
17:15 - 17:45 Leon Rosenthal, MD
The Subjective Assessment of Sleepiness: the Good, the Bad and the Ugly
 
17:45 - 18:00 Maurice Ohayon, MD, DSc, PhD
General Discussion
Future directions of Research
Conclusions

Abstracts

Daytime Sleepiness: Mechanisms, Risk Factors & Natural History
Edward Bixler, PhD
It is commonly assumed that sleepiness is associated with the amount of sleep. Basic physiologic mechanisms of sleepiness have been established which have identified cytokines as a mediating factor. In addition, there are time of day and age associated influences on sleepiness. Subjective estimates of sleep are less accurate than estimates associated with sleepiness. In our adult population sample, we have shown that depression is a strong risk factor for sleepiness followed by obesity and age with somewhat similar findings observed in our child sample. Incident sleepiness showed a risk factor pattern consistent with the cross sectional data while weight gain was associated with both persistent and incident sleepiness and weight loss with remission. Thus, sleepiness is a complex multifactorial issue.


Narcolepsy and Comorbidities: Real? Related to Sleepiness?
Jed Black
Recent large data-base analyses have suggested higher-than-control rates of medical comorbidities in patients with narcolepsy. While prior smaller studies have identified increased comorbid rates of obstructive sleep apnea, REM-sleep behavior disorder, restless legs syndrome, periodic leg movement syndrome, depression, anxiety and obesity, these more recent larger datasets identify comorbidities across most types of medical conditions, including cardiovascular, neuromuscular, and psychiatric. Some database experts view these findings as real and very valid; others are skeptical and are concerned about potential systematic bias. Prospective and post-hoc validation activities with two of these databases have been unsuccessful in identifying potential sources of error. In this presentation, the authors present data from the four large narcolepsy databases that have been published worldwide, review issues of validity, and consider the association of narcolepsy, sleepiness and medical comorbidity.


Role of the hypothalamic histamine system in narcolepsy
Yves Dauvilliers, MD, PhD
Narcolepsy with cataplexy is caused by a loss of orexin/hypocretin neurons in brain. One key target of these neurons is the histaminergic system, a major player in wake control with neurons originating from the hypothalamic tuberomamillary nucleus and projecting to the whole brain. How these two wake-promoting systems interact ? Are the histaminergic neurons affected in narcolepsy ? Could pharmacological modulation of histaminergic neurons constitute a novel therapeutic approach in narcolepsy and other types of vigilance deficits ?


Sleep Loss and Daytime Consequences in the Korean Population
Seung Chul Hong, MD, PhD, Jong-Hyun Jeong, MD and Maurice M. Ohayon, MD, DSc, PhD
Introduction: Sleep deprivation is a modern phenomenon. The deprivation can be voluntarily to accommodate lifestyle but it can be also the result of a sleep disorder, a mental disorder or a medical condition. This study examines the daytime consequences associated with sleep loss.
Methods: The study was performed using a representative sample of 2,537 individuals aged 15 years or older representative of the general population of South Korea.. The participants were interviewed by telephone using the Sleep-EVAL system. The interviews covered sleep habits, sleep symptomatology, physical and psychiatric illnesses. DSM-IV sleep and psychiatric disorder diagnoses were also assessed.
Results:
After adjusting for age and sex, people sleeping < 5hours/night (AOR: 4.7 (2.5-8.8)) and those sleeping 5 to 6 hours/night (AOR: 2.6 (1.5-4.5)) were more likely to report excessive sleepiness than those sleeping more than 7 hours/night. Similarly, people sleeping < 5hours/night were more likely to report fatigue (AOR: 8.5 (3.9-18.3)), cognitive difficulties (AOR: 6.6 (2.6-16.6)) and mood swings (irritability, anxiety or feeling depressed) (AOR: 5.7 (2.1-15.4)) than those sleeping more than 7 hours/night. People sleeping 5 to 6 hours/night also had the same problems. Sleeping less than 5 hours/night was associated with a greater risk of Insomnia Disorder (AOR: 6.2 (3.2-11.9)) and of OSAS (AOR: 3.1 (1.3-7.3)). Sleep 5 to 6 hours/night was only associated with a greater risk of Insomnia Disorder (AOR: 2.1 (1.1-4.2)). Conclusions: Nearly 12% of the Korean population is sleep deprived. As our results shown, sleep deprivation has important daytime consequences affecting different areas of functioning.


What are the neurobehavioral manifestations of sleepiness?
David F. Dinges, PhD
Excessive sleepiness is a risk factor in healthy adults as well as people suffering from disorders that degrade the stability of waking alertness. There is extensive scientific evidence that both acute total and chronic partial sleep loss, are risk factors for deficits in cognitive, affective, and neurobehavioral functions thought to be associated with excessive sleepiness. These neurobehavioral deficits pose risks to the safety and health of humans. The cognitive deficits associated with elevated sleep pressure include degradation of alertness, attention, working memory, problem solving, reaction time, situational awareness, risk taking, etc. The deficits in attention, in particular, appear to reflect what we have referred to as neurobiological "wake state instability". The sleepiness mediated pressure for these effects is dynamically controlled by the interaction of sleep homeostatic drive and circadian regulation. In recent years, however, our experiments have established that the homeostatic sleep-dependent process has at least two components:
(1) Process S balances sleep propensity by tracking recent sleep history, such that as wakefulness increases, homeostatic drive increases the propensity for sleep (2)
(2) Process U monitors sleep-wake on a longer time scale, tracking the buildup of sleep debt over several days.
(3) Thus, both the cumulative build up of sleepiness and its "dissipation" by so called "recovery" sleep are complex dynamic processes occurring over days, weeks, months and perhaps even years. Moreover, we and others have also established that there are phenotypic (heritable) differences among people in the extent to which their waking neurobehavioral functions are sensitive to sleep loss (i.e., elevated sleep pressure).
Finally we note that some of the changes induced by sleep loss, such as decreases in muscle tone (which are often overlooked), pose particularly serious risks to people with uncontrolled excessive sleepiness by way of accidents and falls. In this presentation we will illustrate these dynamics in human neurobehavioral functions affected by sleep pressure; and show that the frequency and duration of neurobehavioral deficits are often not tracked by self-report estimates of sleepiness, which raises provocative questions about the value af asking people how sleepy they are or how likely they are to fall asleep.
1. Lim, J., Dinges, D.F.: Sleep deprivation and vigilant attention. Molecular and Biophysical Mechanisms of Arousal, Alertness, and Attention. Annals of the New York Academy of Sciences, 1129:305-322, 2008. PMID: 18591490
2. Daan S, Beersma DGM, Borbely AA. Timing of human sleep – recovery process gated by a circadian pacemaker. Am J Physiol. 1984;246:R161–R178.
3. McCauley P, Kalachev LV, Smith AD, et al. A new mathematical model for the homeostatic effects of sleep loss on neurobehavioral performance. J Theor Biol. 2009;256:227–239.


Assessment of Sleepiness with the ESS and MWT in Narcolepsy Drug Trials
Diane Guinta, PhD
The Epworth Sleepiness Scale and the Maintenance of Wakefulness Test are complementary tools used for assessing sleepiness in narcolepsy. Different stimulant and stimulant like medications have been studied using these tools. Can the results of these studies tell us anything about their value?


Objective sleepiness measures to identify narcolepsy: from a laboratory perspective to epidemiology
Giuseppe Plazzi, MD, PhD
Sleepiness assessment is a complex task for the multifaceted aspects of the sleepiness phenomenon itself. Sleepiness is indeed a physiological inner sensation informing the subject on the need for sleep, has different correlates in males and women of different age, but should differentiated from excessive daytime sleepiness (or hypersomnolence) that is a pathological condition. The latter can result from several sleep disorders that can be screened by means of questionnaires and easily confirmed with home monitoring devices, but is also the cardinal symptom of central disorders of hypersomnolence. Several objective approaches are available to confirm pathological sleepiness, most notably the MSLT where mean sleep latency and number of sleep onset RERM periods (SOREMPs) are tell tales to distinguish idiopathic hypersomnia from the narcoleptic spectrum. However, recent advances suggested the research utility of additional measurements to identify sleepy patients and in particular those suffering from narcolepsy type 1 (NT1). First, actigraphic monitoring seemed a reliable to distinguish NT1 from both controls and idiopathic hypersomnia by combining indexes of nocturnal motor hyperactivity and daytime immobility, thus resuming the widespread nyctemeral imbalance of the disease. Concerning daytime testing, different studies suggested that the MSLT can provide additional measures to distinguish different sleepiness phenotypes. Indeed, the sleep onset profile can be dissected considering the occurrence of sustained sleep versus the first epoch of sleep stage 1 and the difference between these sleep latencies well identified patients with idiopathic hypersomnia. Moreover, the occurrence of SOREMP from sleep stage 1 appeared quite specific of narcolepsy (mostly type 1) versus insufficient sleep syndrome. Finally, continuous daytime monitoring well distinguished NT1 patients for the occurrence of multiple spontaneous SOREMPs and correlation between increased daytime sleep (especially in circadian time forbidden for sleep) and high sleep propensity at the MSLT. However, daytime testing is highly time and resources consuming, while nocturnal polysomnography is routinely performed in all laboratories worldwide thus encouraging efforts to screen for central disorders of hypersomnolence and leave daytime testing for more difficult cases. Indeed, SOREMP occurrence was specific to identify NT1 patients, but its low sensitivity leaves approximately 50% of the patients for MSLT. Similarly, sleep stage transition analysis seemed not adding diagnostic power when combined with SOREMP, but may be useful to further dissect patients into the narcoleptic spectrum. New data on high sleep stage transitions across nocturnal sleep were indeed associated with cataplexy or hypocretin deficiency within narcolepsy, adding power to the potential of nocturnal sleep macrostructure utility from a dynamic standpoint. We are actually running a study on the utility of SOREMP, sleep stage transitions, and timing of stable sleep stages across nocturnal sleep in the differential diagnosis of central disorders of hypersomnolence. We are disclosing that NT1 patients can be reliably identified by high sleep instability (transitions between wakefulness, non REM sleep stage 1, non REM sleep and REM sleep) accompanied by low sleep stability (time spent durably in sleep stage 1) and occurrence of SOREMp. These data appeared stable across diagnostic groups in two consecutive nights and their combination seemed reliable to identify NT1 in the setting of diagnostic assessment of central disorders of hypersomnolence, thus against narcolepsy type 2, idiopathic hypersomnia and subjects suffering from subjective sleepiness in the absence of high sleep propensity at the MSLT and normal nocturnal sleep. Finally, our ability to objectively study sleepiness still have limitations. Indeed, recent evidences disclosed a poor test-retest reliability of MSLT data in the borderland of narcolepsy (i.e.narcolepsy type 2, idiopathic hypersomnia) on one hand, and on the other hand the possibility of rare cases with slow progression of symptoms in parallel with decreasing hypocretinergic transmission should be kept in mind.


The Subjective Assessment of Sleepiness: the Good, the Bad and the Ugly.
Leon Rosenthal, MD
Excessive Wake-Time Sleepiness (EWS) constitutes one of the cardinal symptoms in Sleep Medicine. The current definition is based on the heightened propensity to fall asleep manifested by an individual. This conceptual understanding of EWS has enabled the characterization of populations with EWS using both subjective and polysomnographic tests. Currently, the most widely used subjective scale is the Epworth Sleepiness Scale (ESS). While it is easy to administer, it has inherent psychometric and clinical limitations. In this context, the Time of day Sleepiness Scale (ToDSS) and the Sleep-Wake Activity Inventory (SWAI) offer additional features that are advantageous. The ToDSS uses the same items included in the ESS and asks subjects to rate their propensity to fall asleep in the morning, afternoon and evening. Thus, the scale derives 3 scores reflecting the subjective ratings of EWS across the day. Using this scale, increasing levels of subjective sleepiness have been demonstrated across the day. The SWAI is a multi-factorial scale, which includes six factors. Among them, the excessive sleepiness and the nocturnal sleep factors have been extensively tested. While these two factors have shown psychometric strength, the incorporation of the full scale in clinical and research studies has not been realized. Despite the significant advance in our understanding of EWS, all available subjective scales have objectionable aspects. While some of these features are inherent to subjective scales, psychometric and conceptual challenges are ripe for improvements in the assessment of EWS.


Limitations of Current Diagnostic Criteria for Hypersomnolence Disorders
Michael Thorpy, MD
The diagnostic criteria for the hypersomnias have evolved over the years but have we done patients a disservice? Are the diagnostic criteria too exclusionary? They may be ideal for research purposes, but are they of limited usefulness in helping the clinician to reach a diagnosis? The current DSM-V and ICSD3 hypersomnia diagnostic criteria, and the narcolepsy criteria in particular, will be discussed with a focus on their strengths and limitations.


Fatigue vs Sleepiness
Antonio Vela-Bueno, MD, PhD
Fatigue and sleepiness are frequent complaints in clinical practice and in the general population. Both patients and clinicians often have difficulties in differentiating between them. Also both terms are often used interchangeably in the literature, in spite of the differences in pathophysiologic and clinical expression. Contributing to the lack of a good semantic and clinical distinction between fatigue and sleepiness is the fact that, whereas the assessment of sleepiness is based on both subjective and validated objective methods, there is lack of well-validated biological markers of fatigue, with its assessment being based on clinical history and the use of scales. Fatigue and sleepiness are associated (one or the other, or both) with various sleep disorders, with conditions such as sleep deprivation and with a vast array of other clinical conditions. An adequate differential diagnosis is crucial for establishing a rational treatment plan. Thus far there are more pharmacologic and non - pharmacologic resources available for sleepiness than for fatigue. In this presentation we briefly overview the problems related to the differentiation between fatigue and sleepiness.


Self-Reported Excessive Sleepiness in Older Adults: With what is it Associated?
Michael V. Vitiello, PhD
The daytime sleepy, nodding off older adult is a classic stereotype of aging and reinforces the assumption that excessive sleepiness is common in older adults. Here we examine two study cohorts of older adults for associates of excessive sleepiness. The VITAL cohort provides an examination of the relationship of nighttime and daytime (including excessive sleepiness) sleep complaints with a number of potential associates including illnesses and overall medical burden. The 2003 NSF Poll cohort, examines potential predictors of frequent napping. Analyses from these two cohorts indicate that:
1) excessive sleepiness declines rather than increases with advancing age, and
2) excessive sleepiness is associated with individual medical and psychiatric illnesses, with general medical burden and with frequent napping, but not with aging, per se.


This Activity is supported by an Unrestricted Educational Grant from Jazz Pharmaceuticals to Stanford University.