Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder.

OBJECTIVE: To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder. METHODS: The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS: 172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinson's disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimer's disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features. CONCLUSIONS: In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.

Prevalence and comorbidity of nocturnal wandering in the U.S. adult general population.

OBJECTIVE: To assess the prevalence and comorbid conditions of nocturnal wandering with abnormal state of consciousness (NW) in the American general population. METHODS: Cross-sectional study conducted with a representative sample of 19,136 noninstitutionalized individuals of the U.S. general population ≥18 years old. The Sleep-EVAL expert system administered questions on life and sleeping habits; health; and sleep, mental, and organic disorders (DSM-IV-TR; International Classification of Sleep Disorders, version 2; International Classification of Diseases-10). RESULTS: Lifetime prevalence of NW was 29.2% (95% confidence interval [CI] 28.5%-29.9%). In the previous year, NW was reported by 3.6% (3.3%-3.9%) of the sample: 1% had 2 or more episodes per month and 2.6% had between 1 and 12 episodes in the previous year. Family history of NW was reported by 30.5% of NW participants. Individuals with obstructive sleep apnea syndrome (odds ratio [OR] 3.9), circadian rhythm sleep disorder (OR 3.4), insomnia disorder (OR 2.1), alcohol abuse/dependence (OR 3.5), major depressive disorder (MDD) (OR 3.5), obsessive-compulsive disorder (OCD) (OR 3.9), or using over-the-counter sleeping pills (OR 2.5) or selective serotonin reuptake inhibitor (SSRI) antidepressants (OR 3.0) were at higher risk of frequent NW episodes (≥2 times/month). CONCLUSIONS: With a rate of 29.2%, lifetime prevalence of NW is high. SSRIs were associated with an increased risk of NW. However, these medications appear to precipitate events in individuals with a prior history of NW. Furthermore, MDD and OCD were associated with significantly greater risk of NW, and this was not due to the use of psychotropic medication. These psychiatric associations imply an increased risk due to sleep disturbance.

Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease.

REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of normal skeletal muscle atonia during REM sleep with prominent motor activity accompanying dreaming. The terminology relating to RBD, and mechanisms underlying REM sleep without atonia and RBD based on data in cat and rat are presented. Neuroimaging data from the few published human cases with RBD associated with structural lesions in the brainstem are presented, in which the dorsal midbrain and pons are implicated. Pharmacological manipulations which alter RBD frequency and severity are reviewed, and the data from human neuropathological studies are presented. An anatomic framework and new schema for the pathophysiology of RBD are proposed based on recent data in rat regarding the putative flip-flop switch for REM sleep control. The structure in man analogous to the subcoeruleus region in cat and sublaterodorsal nucleus in rat is proposed as the nucleus (and its associated efferent and afferent pathways) crucial to RBD pathophysiology. The association of RBD with neurological disease ('secondary RBD') is presented, with emphasis on RBD associated with neurodegenerative disease, particularly the synucleinopathies. The hypothesized pathophysiology of RBD is presented in relation to the Braak staging system for Parkinson's disease, in which the topography and temporal sequence of synuclein pathology in the brain could explain the evolution of parkinsonism and/or dementia well after the onset of RBD. These data suggest that many patients with 'idiopathic' RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented. We suggest that additional clinicopathological studies be performed in patients with dementia or parkinsonism, with and without RBD, as well as in patients with idiopathic RBD, to further elucidate the pathophysiology and also characterize the clinical and pathophysiological relevance of RBD in neurodegenerative disease. Furthermore, longitudinal studies in patients with idiopathic RBD are warranted to characterize the natural history of such patients and prepare for future therapeutic trials.

Rem sleep without atonia--from cats to humans.

Basic science research observations often lead to unexpected surprises. It is likely that in 1965 when Dr. Michel Jouvet placed bilateral peri-locus coeruleus lesions in cats and observed REM sleep without atonia (RWA) and "oneiric" behavior that could only be explained by "acting out dreams" (or "dreaming out acts"), he recognized that it was an important observation, but had little inkling of its true significance. Nor could he even imagine that it would lead to such greater understanding of wake/sleep phenomena in humans. Likely also, the first observation of REM sleep behavior disorder (RBD) in humans was felt to be interesting and novel - again with no true appreciation of what this seemingly simple observation would lead to important clinical relationships with numerous neurodegenerative disorders. The identification of RBD in humans also buttressed the concept of state dissociation, which has served to explain many previously unexplainable human behavioral phenomena.

Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism.

OBJECTIVE: To determine if synucleinopathy pathology is related to REM sleep behavior disorder (RBD) plus dementia or parkinsonism. METHODS: The clinical and neuropathologic findings were analyzed on all autopsied cases evaluated at Mayo Clinic Rochester from January 1990 to April 2002 who were diagnosed with RBD and a neurodegenerative disorder. Ubiquitin and/or alpha-synuclein immunocytochemistry was used in all cases. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS: Fifteen cases were identified (14 men). All had clear histories of dream enactment behavior, and 10 had RBD confirmed by polysomnography. RBD preceded dementia or parkinsonism in 10 (66.7%) patients by a median of 10 (range 2 to 29) years. The clinical diagnoses included dementia with Lewy bodies (DLB) (n = 6); multiple-system atrophy (MSA) (n = 2); combined DLB, AD, and vascular dementia (n = 1); dementia (n = 1); dementia with parkinsonism (n = 1); PD (n = 1); PD with dementia (n = 1); dementia/parkinsonism/motor neuron disease (n = 1); and AD/Binswanger's disease (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD) in 12 (neocortical in 11 and limbic in 1) and MSA in 3. Three also had argyrophilic grain pathology. In the LBD cases, concomitant AD pathology was present in six (one also with Binswanger's pathology, and one also with multiple subcortical infarcts). CONCLUSION: In the setting of degenerative dementia or parkinsonism, RBD often reflects an underlying synucleinopathy.

Evolving concepts of human state dissociation.

The concept of state dissociation in humans was made possible only by applying information obtained from basic science animal research studies to the human condition--without which these often dramatic, and treatable conditions would have remained in the mystical, supra-natural, or psychiatric arenas, without appropriate or effective treatment options. Sleep or wakefulness occurring asynchronously in bits and pieces of the brain is a most useful concept. From our standpoint, the basic science work in the function and mechanism of sleep is pertinent, not only adding to our knowledge in these important areas for the sake of knowledge, but also in providing clinicians with important information that is of immense clinical importance. The payoff of such research has been great, and demands that it should be ongoing. The field of sleep research and sleep medicine is in a unique position to foster close interactions between basic scientists and clinicians, the result being basic science answers to clinical questions, and unanswered clinical questions guiding the direction of and reinforcing the basic science research. The clinical conditions discussed above underscore the value of close cooperation among those working at all levels: molecular, cellular, multi-cellular, and clinical. Continued study of state dissociation by both basic scientists and clinicians will undoubtedly identify and explain even more of these fascinating conditions, with important therapeutic implications. The reciprocal benefits of close collaboration between basic scientists and clinicians will continue to be realized.

Severe, childhood-onset, idiopathic, life-long insomnia responding selectively to opiate therapy: case report with 19 year follow-up.

BACKGROUND: Idiopathic (primary) insomnia can be difficult to treat; only two prior cases responsive to opiate therapy have been reported. A case is now presented of severe, idiopathic, childhood-onset, familial insomnia, with increased libido, absence of psychopathology, tardive emergence of restless legs syndrome (RLS), and selective response to opiate therapy. CASE REPORT: A 39-year-old woman was referred in 1981 by her physician who had discovered 3 years earlier that propoxyphene treatment of migraines also controlled her chronic insomnia. She had experienced severe insomnia since childhood, and during early adulthood the insomnia intensified, as she would sleep 0-3 h nightly and never napped. Daily generalized motor restlessness resulted in her frequently walking around the house while feeling exhausted. The quality of her life was considerably compromised by her insomnia, motor restlessness, and by an increased libido that was present since puberty and that was only partially relieved by having sex repeatedly with her husband. RESULTS: Nightly opiate therapy for 19 years has controlled the insomnia, motor restlessness, and excessive libido without affecting her normal libido. The insomnia had not responded to treatment with >25 agents covering >10 pharmacologic categories. During her first (unmedicated) polysomnographic (PSG) study in 1981, she slept 0 min while spending 436 min in bed. In 1984, four consecutive PSG studies were conducted in a design that confirmed the efficacy of propoxyphene therapy of her insomnia. In 1990, an ambulatory PSG revealed two runs of EEG rhythmic paroxysmal activity arising from sleep and wakefulness, without clinical correlate. Neurologic history was negative for seizures, but positive for complete right carotid artery occlusion and three transient ischemic attacks. At age 55 years, typical RLS emerged that was controlled with levodopa therapy, and a concurrent relapse of insomnia was controlled with oxycodone replacing propoxyphene. CONCLUSIONS: Nightly opiate therapy of severe idiopathic (primary) insomnia can remain effective during very long-term clinical follow-up. Guidelines are provided for when to consider such an unusual treatment in other cases of severe, chronic insomnia.

Does snoring predict sleepiness independently of apnea and hypopnea frequency?

Obstructive apneas and hypopneas during sleep are a well recognized cause of excessive daytime sleepiness. Snoring is also associated with excess sleepiness, although it is not known whether this reflects an independent effect of snoring or whether snoring is simply a marker for obstructive sleep apnea. To further explore the relation of snoring to sleepiness, we conducted a cross-sectional cohort study of community-dwelling adults participating in the Sleep Heart Health Study. The study sample comprises 2,737 men and 3,040 women with a mean age of 64 (SD 11) yr. Sleepiness was quantified using the Epworth Sleepiness Scale (ESS). Snoring history was obtained via a self-completion questionnaire. The respiratory disturbance index (RDI), defined as the number of apneas plus hypopneas per hour of sleep, was measured during in-home polysomnography. The ESS score increased progressively with increasing RDI, from a mean of 7.1 (4.2) in subjects with RDI < 1.5 to 8.8 (4.8) in subjects with RDI >/= 15 (p < 0.001). A progressive increase in ESS score was also seen across five categories of snoring frequency, from 6.4 (4.2) in current nonsnorers to 9.3 (4.8) in subjects who snored six to seven nights per week (p < 0.001). The prevalence of excessive daytime sleepiness, defined as an ESS score >/= 11, increased from 15% in never-snorers to 39% in those who snored six to seven nights per week. The relation of snoring to sleepiness was seen at all levels of RDI, with no significant change in the relation of snoring to ESS score after adjustment for RDI in multivariate models. The effects of snoring and RDI on sleepiness were little affected by adjustment for age, sex, race, body mass index, or questionnaire evidence of insufficient sleep time or nocturnal leg jerks or cramps. We conclude that both snoring and RDI are independently associated with excess sleepiness in community-dwelling, middle-aged and older adults.

Eyes wide shut. The dangers of sleepy driving.

Most Americans are chronically sleep-deprived. However, few people are aware of the extent to which sleep deprivation impairs cognitive functioning. In the United States, at least 56,000 motor vehicle crashes (MVCs) each year, resulting in 1,550 deaths and thousands more nonfatal injuries, are attributed to sleepiness behind the wheel. As lawsuits from fall-asleep MVCs mount, individuals, the transportation industry, public policymakers, and the legal profession are starting to take notice.

Diagnosis and management of parasomnias.

Parasomnias are unpleasant or undesirable behavioral or experiential phenomena that occur predominately or exclusively during sleep. These phenomena were initially thought to represent a unitary event, often attributed to psychiatric disease. Recent clinical and polygraphic analysis has revealed that they are, in fact, the result of a large number of very different conditions, most of which are diagnosable and treatable. In fact, most are not the manifestation of psychiatric disorders, and they are far more prevalent than previously suspected. Although there are many parasomnias (1,2), from a practical standpoint only the few that comprise the overwhelming majority will be discussed in this review. These include disorders of arousal, rapid-eye-movement sleep behavior disorder, nocturnal seizures, and restless legs syndrome. Most parasomnias are readily diagnosable and, more importantly, are treatable.

What is causing excessive daytime sleepiness? Evaluation to distinguish sleep deprivation from sleep disorders.

Many people have a temporary spell, often in early afternoon, when they feel drowsy. This passing desire for a quick nap is completely different from excessive daytime sleepiness, which is a much more significant problem. Considering the potentially dire personal and economic consequences of falling asleep unintentionally or at inappropriate times, excessive daytime sleepiness must be taken very seriously. A thorough evaluation, as described by Dr. Mahowald, virtually always leads to a specific underlying cause, allowing effective treatment recommendations.

Parasomnias. Managing bizarre sleep-related behavior disorders.

Sleep can be a troubling experience for persons plagued by nocturnal disorders known as parasomnias. While they are "asleep," such persons may be walking, screaming in terror, rearranging furniture, eating odd food concoctions, or wielding weapons. Or they may be unable to fall asleep because of the unpleasant sensations of restless legs syndrome. Although these disorders are indeed bizarre, effective treatments are available. In this article, Drs Schenck and Mahowald discuss the evaluation and treatment of parasomnias and provide illustrative patient vignettes from their extensive experience at a sleep disorders center.

Sleep in a community sample of elderly war veterans with and without posttraumatic stress disorder.

BACKGROUND: Although sleep disturbances are commonly reported by individuals with posttraumatic stress disorder (PTSD), objective findings have been inconsistent, due in part to small sample sizes, comorbid psychiatric disorders, variations in the recentness of trauma exposure, and the use of PTSD subjects involved in psychiatric treatment. METHODS: A community sample of elderly males (n = 59) exposed to war trauma 28-50 years ago and free from sleep-affecting medications and disorders other than PTSD completed 3 nights of polysomnography. Of these participants, 30 met criteria for current PTSD; three were receiving supportive outpatient psychotherapy. RESULTS: Two statistically significant differences were observed: Those with PTSD had a higher percentage of rapid eye movement (REM) sleep and fewer arousals from non-REM sleep. The perceptions of sleep quality among the participants with PTSD were lower than the perceptions of non-PTSD participants. Although participants with untreated obstructive sleep apnea and sleep movement disorders were not included in the sample, many cases were detected on initial screening. Treatment resulted in improved sleep and increased feelings of well being. CONCLUSIONS: Alterations in REM and arousals characterized PTSD in this sample. When comorbid sleep disorders were ruled out, sleep was clinically similar across the groups. Trauma-related sleep disturbances that subjects reported as arising early in the course of the disorder appear to have declined over time.

Medical-legal aspects of sleep medicine.

Sleepiness and sleep disorders are increasingly raising interesting and important medical-legal issues in three areas: violent or injurious behavior arising from the sleep period, accidents or errors in judgment caused by sleepiness behind the wheel or in the workplace, and disability determinations caused by sleepiness-induced work impairment. Sleep-related violence may be caused by many conditions, most of which are diagnosable and treatable. Legal issues raised by these behaviors are usually enigmatic. The nature of such behaviors may be extremely complex, and documenting that a given violent act was caused by such a behavior, after the fact, may be difficult. Guidelines for the medical-legal evaluation of such behaviors have been developed and are evolving. Culpability determination in sleepiness-related industrial or motor vehicle accidents is in the developmental stage, and varies by jurisdiction. Disability determination for workplace sleepiness caused by sleep disorders is in its infancy, and poses a challenge, given the erroneous but pervasive societal attitude that sleepiness is a manifestation of laziness, depression, sloth, work-avoidance behavior, or a defect of character.

Polysomnographic sleep is not clinically impaired in Vietnam combat veterans with chronic posttraumatic stress disorder.

BACKGROUND: Because sleep is typically disturbed in posttraumatic stress disorder (PTSD), this study was undertaken to evaluate a group of Vietnam combat veterans with the disorder using clinical polysomnographic techniques. METHODS: Eighteen Vietnam combat veterans with PTSD and 10 healthy non-combat-exposed Vietnam era veterans participated in 2 nights of polysomnographic study and a multiple sleep latency test. RESULTS: No significant differences between subjects and controls were noted except for greater sleep onset latency to stage 2 (p < .03), and lower arousals/hour from stages 3 & 4 (p < .04) on night 2, and lower subjectively estimated total sleep time on night 1 (p < .005) in the case of PTSD subjects. Otherwise, results from the second night served to replicate those from the first, and no significant differences appeared on 2 successive nights for any polysomnographic variable. No daytime hypersomnolence was detected. CONCLUSIONS: Polysomnographically recorded sleep was notably better than expected in the presence of clinically significant PTSD with typical histories of disrupted sleep. In these subjects, there is no clinically significant sleep disorder or typical pattern of sleep disturbance detectable by standard polysomnography.