From Confusional Arousal to Automatic Behaviors during Sleep

August 27th, 2011

Stanford Sleep Epidemiology Research Center (SSERC)

Scope of the Meeting

Sleep drunkenness, or Confusional Arousal, or Excessive Sleep Inertia is a sleep disorder characterized by periods of mental confusion occurring upon wakening at night or in the morning or during the day after a nap.

The individual presents an alteration of cerebral reactivity to external stimuli which occurs in the transitional period from NREM sleep to wakefulness (Broughton, 1968). The affected subject appears awake but behavior may be very inappropriate, with memory deficits, disorientation in time and space and slow mentation and speech.

Laboratory studies have shown it exists a period of sleep inertia that occurs upon the awakening (Achermann et al., 1995; Balkin & Badia, 1988; Jewett et al., 1999). This period is characterized by a reduced vigilance and impaired cognitive response which return to normal within 30 minutes to more than one hour. The severity of sleep inertia or the time course of its dissipation is not related to the sleep stage when the awakening occurs (Jewett et al., 1999). In animals, sudden awakenings by an external stimuli from non-REM sleep, provoke a reduction of the pre-pulse inhibition of the startle reflex which is not observed in spontaneous arousals. This mechanism would play a protective role for the survival of the animal that needs to response quickly to potential threats when it is suddenly aroused (Horner et al., 1997).

From an epidemiological perspective:

In a representative sample from the United Kingdom, Germany and Italy (13057 subjects - Ohayon et al, 2000)
- Confusional Arousals were reported by 2.9% of the sample;
- 1% of the sample also presented memory deficits (53.9%), disorientation in time and/or space (71%) or slow mentation and speech (54.4%);
- 1.9% (1.7% to 2.1%) reported confusional arousals without associated features.
- Younger subjects (< 35 years) and shift or night workers were at higher risk of reporting confusional arousals.
In a U.S. representative sample (15929 subjects, Ohayon 2011), we confirmed the results of our previous epidemiological study: Confusional Arousals are associated with hallucinatory phenomena that could be responsible for Automatic Behaviors or Violent Behaviors (Ohayon & Schenk, 2010).

This Symposium will address the issue of Confusional Arousals and the place of Automatic Behaviors in Sleep Medicine (Disorder of Sleep or Disorder of Arousal or Dissociative Disorder). Participants will discuss biological, genetic, clinical, pharmacological evidences and implications.

Program

Saturday, August 27th, 2011

08:15 - 08:30	Maurice Ohayon, MD, DSc, PhD, Chair Welcome / Overview of the meeting

08:30 - 09:10	Maurice Ohayon, MD, DSc, PhD From Confusional Arousals to Automatic Behaviors in the US General Population

09:10 - 09:50	Yun Kwok Wing, MD, PhD Automatic Behaviors During Sleep Among Psychiatric Populations

09:50 - 10:05	Discussion Are longitudinal and familial surveys able to identify predictive factors and/or vulnerability factors of Automatic Behaviors during Sleep ? Confusional Arousals and Automatic Behaviors: Prevalence and risk factors. Are Mental Disorders a risk factor? Confusional Arousals, Sleep Inertia, Automatic Behaviors: a same entity?

10:05 - 10:20	Break

10:20 - 11:00	Christina Gurnett, MD, PhD Sleepwalking And Genetics

11:00 - 11:40	David Spiegel, MD Unwelcome Arousal: Parasomnias and PTSD

11:40 - 12:20	Andrew Krystal, MD, MSc Are Psychotropic Drugs Triggers for Automatic Behaviors During Sleep?

12:20 - 12:35	Discussion Genetic, mental and iatrogenic vulnerability for Automatic Behaviors during Sleep Is Automatic Behavior a Dissociative Disorder? Psychotropic Drugs: Therapeutic agents or Automatic Behavior triggers?

12:35 - 13:45	Lunch

13:45 - 14:25	Phyllis Zee, MD, PhD

14:25 - 15:05	Yves Dauvilliers, MD, PhD Clinical aspects and pathogenesis of sleepwalking

15:05 - 15:45	Jacques Montplaisir, MD, PhD Sleepwalking: sleep disorder or disorder of arousal?

15:45 - 16:05	Discussion How to explain Sleepwalking and other Automatic Behaviors during Sleep? Automatic Behaviors: Sleep Disorder or Arousal Disorder? Sleepwalking and its treatment - Sleepwalking as an effect of the medications

16:05 - 16:25	Break

16:25 - 17:05	Christian Guilleminault, MD Sexual Behavior During Sleep

17:05 - 17:45	Michael Vitiello, PhD Confusional Arousals and Automatic Behaviors during Sleep: Risk Factors in the older adult population

17:45 - 18:05	Discussion Sexual Behaviors during Sleep and their association with Mental Disorders? Are Sexual Disorders during sleep, Eating Disorders during sleep similar to Sleepwalking? How to characterize the Confusional Arousals of Elderly people? Role of the medications?

18:05 - 18:40	Associate participants Report about their presentations

18:40 - 19:10	Maurice Ohayon, MD, DSc, PhD, Chair General Discussion Place of Confusional Arousals and Automatic Behaviors in the DSM-5 From Confusional Arousals to Automatic Behaviors: future directions Conclusions

Sunday, August 28th, 2011

08:00 - 08:15	Overview of the Symposium

08:15 - 10:00	General Discussion

10:00 - 10:30	Closing Statements

Abstracts

From Confusional Arousals to Automatic Behaviors in the US. General population
Maurice Ohayon, MD, DSc, PhD
The prevalence rates of confusional arousals were investigated in a sample of 15,929 individuals aged between 18 and 102 years. This sample was representative of the U.S. general population. Weekly occurrence of confusional arousals was reported by 0.9% of the sample and monthly occurence by 2.6%. Confusional arousals significantly decreased with age but were not gender-related. Circadian Rhythm Sleep Disorders, Obstructive Sleep Apnea Syndrome, Insomnia Disorders are strongly associated with confusional arousals. Among psychotropic drugs, tricyclic and SARI antidepressants are more frequently associated with confusional arousals than other types of psychotropics. Confusional arousals often occurred with other parasomnia arousal disturbances: as many as 31.9% reported hypnagogic hallucinations, 24% automatic behaviors during sleep and 43.9% automatic behaviors during the daytime.

Automatic Behaviors During Sleep Among Psychiatric Populations
Yun Kwok Wing, MD, PhD
Automatic behaviors during sleep (ABS) mostly refer to parasomnia characterized by sleep-related movements or behaviors, such as confusional arousal , Sleepwalking, and sleep-related eating disorder (SRED). There are several cases reports on ABS among psychiatric patients. Warnings have been added for the the use of psychotropics, especially hypno-sedatives, regarding on their risk of potential effect on ABS. However, most of the published evidences were case reports or series with limited data on the clinical epidemiology of ABS. Given the potential serious outcome such as sleep related injuries among subjects with ABS, its prevalence and associated risk factors have to be investigated further. Two recent clinical epidemiological studies in psychiatric populations reported that the prevalence of ABS ranged from 40% to 15% [1, 2]. Various risk factors, including co-morbid sleep disturbances, and use of psychotropics were associated with ABS [1].
Sleepwalking, one of the common ABS encountered in psychiatric patients, was found to have more adult onset, diverse clinical features, and associated with high prevalence of sleep-related injuries in psychiatric patients [3].
SRED was also found to be prevalent among patients of mental illnesses. Among various associated factors, SRED has the strongest association with the regular use of zolpidem, a non-benzodiazepine hypnotics [1]. One out of seven subjects taking zolpidem could develop SRED symptoms, and most of the subjects were taking therapeutic dosage regularly [1]. The precipitating role of zolpidem was further strengthened by a follow-up open interventional study that cessation of zolpidem could result in immediate and sustained disappearance of SRED [4].
Althought the exact reason on the susceptibility of psychiatric patients towards ABS remains elucidated, current findings suggested that the aetiologies are likely to be complex and multifactorial. Personal vulnerability, predisposing effect of co-morbid sleep disturbances, stress, psychopathologies, and the use of psychotropics, could have joint effect in contribution to the occurrence of ABS in psychiatric populations [1].
References
1. Lam SP, Fong SYY, Ho CKW, et al. Parasomnia among psychiatric outpatients: a clinical epidemiologic, cross-sectional survey. J Clin Psychiatry 2008; 69: 1374-1382.
2. Hwang TJ, Ni HC, Chen HC, Lin YT, Lia. SC. Risk predictors for hypnosedative-related complex sleep behaviors: a retrospective, cross-sectional pilot study. Clin J Psychiatry 2010: 71: 1331-1335
3. Lam SP, Fong SYY, Yu MWM, Li SX, Wing YK. Sleepwalking in psychiatric patients: a comparison of childhood and adult onset. Aust N Z J Psychiatry 2009; 43: 428-32.
4. Wing YK, Lam SP, Li SX, Zhang J, Yu MWM. Sleep-related eating disorder and zolpidem - an open interventional cohort study. J Clin Psychiatry 2010: 71 (5): 653-656

Sleepwalking And Genetics
Christina Gurnett, MD, PhD
Twin and family studies suggest that sleepwalking is highly heritable. Despite recent advances in the genetic basis of many sleep disorders, including narcolepsy, restless leg syndrome , And REM behavior disorder, very little is known about the genetic basis of sleepwalking. One study reported an association of sleepwalking with with human leukocyte antigen (HLA) DQB1*0501, but no other susceptibility genes have been reported.
In order to identify genetic susceptibility factors for sleepwalking, a large 4 generation family was ascertained in which sleepwalking segregates as an autosomal dominant condition with reduced penetrance. Linkage analysis revealed a region of markers on chromosome 20 that were shared among all 9 affected individuals. This sleepwalking linkage region on chromosome 20 contains more than 28 genes, including adenosine deaminase.
Next-generation sequencing methods are ideal methods for studying mendelian forms of sleep disorders when they occur in large families. Therefore, exome sequencing was performed on the proband from this family, revealing >300 novel and <200 rare (MAF <0.05) genetic variants. Additional sleepwalking families are being studied for replication, most of which demonstrate autosomal dominant inheritance with incomplete penetrance.
Recommendations for future study include:
1. Establishing the genetic relationship between various parasomnias
2. Developing diagnostic criteria useful for genetic studies, and
3. Collecting large parasomnia patient DNA cohorts for future genome-wide association studies and sequencing studies.

Unwelcome Arousal: Parasomnias and PTSD
David Spiegel, MD
Parasomnias, including nightmares, poor sleep efficiency, and sleepwalking, are common symptoms of Post-Traumatic Stress Disorder (PTSD). The symptoms of PTSD as they will likely be defined in DSM-5 will be reviewed, along with the typical abnormalities in the two major stress responses systems in the body, the hypothalamic-pituitary-adrenal axis, and the sympathomedullary axis.
Sleep is characterized by dominance of parasympathetic activity, so the adrenergic hyperarousal and abnormal cortisol levels typical of PTSD tend to disrupt it, triggering parasomnias.
Treatments for them will be reviewed, including antidepressants and benzodiazepines. Promising evidence that prazosin, an alpha-1 adrenoreceptor antagonist, reduces nightmares and other PTSD-related parasomnias, will be presented. These treatments in the context of overall psychotherapeutic treatment for PTSD will be examined.

Are Psychotropic Drugs Triggers for Automatic Behaviors During Sleep?
Andrew Krystal, MD
A number of reports link hypnotic medications to parasomnias such as somnambulism, confusional arousals, and sleep eating. However, little systematic research has been carried out to to determine if the risks of these events are increased as a result of taking hypnotic medications.
In this work, we review recent findings on the epidemiology of these types of parasomnias including the risks associated with hypnotic medications. These data are then contextualized in terms of clinical experience with hypnotics, small studies reporting a link between non-REM parasomnias and particular hypnotic medications, and data from all of the available placebo-controlled trials of hypnotic medications.
We then discuss the implications of the new epidemiologic data for:
1. Clinical practice,
2. Regulatory agencies, and
3. Research

Clinical aspects and pathogenesis of sleepwalking
Yves Dauvilliers, MD, PhD
Sleepwalking (SW) is an arousal parasomnia of non-rapid eye movement (NREM) sleep where movement behaviors usually confined to wakefulness are displayed during sleep. It occurs in 2-14% of children and 1.6-2.4% of adults.
We may dissociate primary sleepwalking often associated with sleep terrors and confusional arousals, and secondary or comorbid sleepwalking due to drug (mainly Zolpidem and Lithium) or substance (Alcohol) or due to medical condition (Parkinson 'disease and psychiatric conditions) and sleep disorder conditions (including OSAS, UARS, PLMD and RLS-PLMS).
Sleepwalking is the result of factors that predispose or precipitate the episodes. Pathophysiology is still unclear with an inability to sustain slow wave sleep being the most probable hypothesis that may be genetically determined. The presence of hypersynchronous slow delta has been regularly reported in sleepwalkers, but their significance is controversial. SW is a common and highly heritable sleep disorder with a familial component in up to 80% of cases.
Twin studies reported higher concordance for SW in monozygotic than in dizygotic twins (50% against 10-15%). We have reported a significant excess transmission for HLA DQB1*05 and *04 alleles in familial cases of SW. A recent study described an autosomal dominant inheritance pattern of sleepwalking with reduced penetrance in a 4-generation family. Linkage analysis for sleepwalking showed the first genetic locus for sleepwalking at chromosome 20q12-q13.12 (maximum odds score of 3.44). A recent study also reported overlap between parasomnias and sleep-disordered breathing within similar families.
SW may lead to serious injuries but other consequences need to be evaluated in term of daytime sleepiness, fatigue, depressive symptoms and quality of life. Management of SW required the treatment of the triggering factors (stress, use of alcohol or drugs, sleep deprivation or fever) that may result in resolution of sleepwalking without medication.
If sleepwalking is caused significant distress in spite of safe measures, a medical treatment of sleepwalking is indicated. medical treatment is Indicated. No powered rigorous controlled trials exist for the treatment of sleepwalking, but case reports and clinical experience revealed good efficacy of clonazepam.

Sexual Behavior During Sleep
Christian Guilleminault, MD
Violence, during sleep or out of sleep, related to abnormal alertness has received more attention during the past 10 years.
Absence of full alertness and impairment of brain function due to associated sleep disorders has been considered as a legal defense in crimes and homicides [1, 2]. Sleep Medicine experts have been requested to testify in medical legal cases. Educational efforts have been made to attract the attention of physicians about the problem, medical-legal implications, and the need to have appropriate documentation of the medical problems associated with the reported violence.
A general population survey has shown that sleep-related violence is much more common than known by physicians. Two percent of the general population reported the occurrence of sleep-related violence [3]. However, report and surveys have provided little information on "atypical sexual behavior" during or out of sleep, which may present as an annoying but tolerable problem to the bed partner. It may be an aggressive, harmful behavior during sleep, often called "rape" or "rape-like" behavior by the bed partner. This behavior, also called "sleep sex" by some bed partners, is therefore poorly documented. In our experience, it is also not often mentioned to physicians, due to the feelings of shame of patients and bed partners.
This work presents a series of patients who we exhibited different behaviors that we labeled "atypical sexual behavior during sleep".
Two of these cases led to police intervention, and one of them had charges of "rape" against a teenager and was seen as a medical-legal case. The 11 case-vignettes are briefly presented to outline the range of the problems.
The work-up performed, objective findings, treatment approaches, and follow-up outcome are presented.
The goal is to outline some of the medical implications that may hide behind “atypical sexual behavior” from clinical information collected during sleep structured interviews, and to suggest tests and investigations that may be done to find the underlying sleep abnormalities leading to the behavior.
References:
1. Moldofsky H, Gilbert R, Lue FA, MacLean AW. Sleep related violence. Sleep, 1995, 18:731-39
2. Guilleminault C, Moscovitch A, Leger D. Forensic Sleep Medicine: Nocturnal wandering and violence. Sleep. 1995; 18: 740-48.3.
3. Ohayon MM, Caulet M, Priest RG. Violent behavior and sleep J. Clin. Psychiatr. 1997; 58: 369-78.
4. Guilleminault C, Moscovitch A, Yuen K. Poyares D, Atypical Sexual Behavior During Sleep, Psychosomatic Medicine 2002/64:328-336

Confusional Arousals during Sleep: Risk Factors in the Older Adult Population
Michael V. Vitiello, PhD
Maurice Ohayon, MD, DSc, PhD
Confusional Arousal (CA), a phenomenon also referred to as sleep drunkenness or excessive sleep inertia, is a fairly common sleep disorder occurring in 2.9% of the general population (1). CA is an awakening from sleep characterized by a period of mental confusion, including lack judgment and spatial / temporal disorientation. Individuals with sleep disorders, such as sleep apnea and insomnia, are more likely to experience CA, as are those with psychiatric illnesses and memory deficits (1). Medical illness and psychoactive prescription medications may also predispose to CA. While in the general population CA occurs most frequently in younger (<35 yrs) individuals and those on shift and night work (1), its prevalence and associated risk factors within the older adult population are unclear. Many of the factors associated with CA occur with increasing prevalence in older adults suggesting that older adults may be risky for CA. Indeed CA may itself be a risk factor for nighttime, and possibly post-nap, falls, a significant cause of morbidity And mortality in the older adult population. Here we report the prevalence of CA and its risk factors in a group of 2,721 older (>65 yrs) adults drawn from a randomized stratified sample of 15,929 individuals representative of the US general population. They were interviewed by telephone using Sleep-EVAL expert system. The prevalence of CA (> 1/mo) in older adults was 1.6% and did not differ by age or gender, African Americans were at higher risk of CA (3.7%, OR: 3.5 [1.2-10.3]) than other ethnic groups (White: 1.2%, Hispanic, 2.1%, and Asian: 1.9%). Higher prevalence of CA was associated with CRSD (7.3%, OR 5.8 [1.8.18.11]), OSAS (6.0%, OR: 3.8 [1.3-11.3]), RLS (OR: 8.2% [1.8-17.1]) and Excessive Sleepiness ( 4.5%, OR: 3.5 [1.1-10.9]), but not Insomnia Higher prevalence of CA was associated with PTSD (8.1% OR: 5.0 [1.4-20.7]), and Panic Disorder (10.7%, OR: 6.1 [1.3-28.1]), but not Organic Diseases, and with SSRIs (3.5%; OR: 2.6 [1.0-6.7]), but with no other psychoactive medications.
These findings demonstrate that CA, while less prevalent than in younger populations nevertheless is common (prevalence=1.6%) in older adults and is unaffected by gender and advancing age. The risk for CA is increases significantly in African Americans and in those with sleep disorders, such as PTSD, Panic Disorder and taking SSRIs. It should be noted that these prevalences and risk factors are associated with CA in community dwelling older adults and may not be the same for the large population of older adults living in the considerably different environment of long-term care settings.
References:
1. Ohayon et al. The Place of Confusional Arousals in Sleep and Mental Disorders. J. Nerv Meant Dis 2000; 188:340-3.48

This activity is supported by an Educational Grant from Neurocrine Biosciences to Stanford University.

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