Association of eszopiclone, zaleplon, or zolpidem with complex sleep behaviors resulting in serious injuries, including death.

PURPOSE: To identify and analyze postmarketing cases of complex sleep behaviors (CSBs) resulting in serious injuries, including death, associated with eszopiclone, zaleplon, or zolpidem (Z-drugs). METHODS: Retrospective analysis of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from 16 December 1992 through 27 February 2018 and medical literature using PubMed and EMBASE. We used random sampling and descriptive statistics. RESULTS: We identified 66 cases that met inclusion and exclusion criteria, four of which were identified in the medical literature. Twenty cases reported death and 46 cases reported serious injuries in association with CSBs occurring after the use of a Z-drug. Fatal cases described events, such as carbon monoxide poisoning, drowning, falls, hypothermia, motor vehicle collisions, and apparent completed suicide. Nonfatal cases resulting in serious injuries described events, such as accidental overdoses, falls, gunshot wounds, hypothermia, third-degree burns, and self-injuries or suicide attempts. Twenty-two cases reported a previous episode of a CSB while taking a Z-drug prior to the event reported in this case series. CONCLUSIONS: The FAERS and medical literature cases support the need for increased awareness of the consequences that may occur because of CSBs associated with the use of Z-drugs. Therefore, to protect public health, regulatory actions were taken, including adding a Boxed Warning, a Contraindication in patients who have experienced a prior episode of a CSB with a Z-drug, and updating the existing Warnings and Precautions. An FDA Drug Safety Communication was also disseminated to alert healthcare professionals and the public of this potential risk.

Adrenergic reactions during N3 sleep arousals in sleepwalking and sleep terrors: The chicken or the egg?

To understand the mechanisms of N3 sleep interruptions in patients with sleepwalking episodes and/or sleep terrors (SW/ST), we evaluated whether autonomic reactions preceded or accompanied behavioural arousals from NREM sleep stage N3. In 20 adult patients with SW/ST and 20 matched controls without parasomnia, heart rate and pulse wave amplitude were measured beat-to-beat during the 10 beats preceding and during the 15 beats succeeding a motor arousal from N3 sleep. Respiratory rate and amplitude were measured during the same 25 successive beats. In patients with SW/ST, the N3 arousals were associated with a 33% increase in heart rate, a 57% decrease in pulse wave amplitude (indicating a major vasoconstriction), a 24% increase in respiratory rate and a doubling of respiratory amplitude. Notably, tachycardia and vasoconstriction started 4 s before motor arousals. A similar profile (tachycardia and vasoconstriction gradually increasing from the 4 s preceding arousal and post-arousal increase of respiratory amplitude, but no polypnea) was also observed, with a lower amplitude, during the less frequent 38 quiet N3 arousals in control subjects. Parasomniac arousals were associated with greater tachycardia, vasoconstriction and polypnea than quiet arousals, with the same pre-arousal gradual increases in heart rate and vasoconstriction. Autonomic arousal occurs 4 s before motor arousal from N3 sleep in patients with SW/ST (with a higher adrenergic reaction than in controls), suggesting that an alarming event during sleep (possibly a worrying sleep mentation or a local subcortical arousal) causes the motor arousal.

The neurophysiological and neurochemical effects of alcohol on the brain are inconsistent with current evidence based models of sleepwalking.

The DSM-5 and ICSD-3 have removed alcohol from the list of potential triggers for sleepwalking due to the lack of empirical evidence. Recent imaging and EEG based studies of sleepwalking and confusional arousals have provided a more data-based method of examining if alcohol is compatible with what is known about the neurophysiology and neurochemistry of sleepwalking. These studies have demonstrated a deactivation of the frontal areas of the brain, while the cingulate or motor cortex remains active and characterized activation in the form of beta EEG. This increase in activation is attributed to a decrease in the inhibitory activity the neurotransmitter GABAA. This cerebral excitability of the cingulate cortex of sleepwalkers is also present in the brains of sleepwalkers during wakefulness compared to normal controls. Alcohol is well established to have an inhibitory effect on the brain and specifically on the motor areas via the inhibitory effects of increased GABAA activity. Thus, the empirical data show sleepwalking is characterized by a decrease in the inhibitory activity of GABAA - permitting or facilitating motor activity while alcohol has the opposite effect of increasing GABAA and inhibiting motor activity. This is inconsistent with theories that alcohol is somehow a trigger or facilitator for sleepwalking.

Sleepwalking.

Arnulf describes the fascinating behavior of sleepwalking and its associated parasomnias.

Altered brain perfusion patterns in wakefulness and slow-wave sleep in sleepwalkers.

Study Objectives: The present study assessed brain perfusion patterns with single-photon emission computed tomography (SPECT) during sleepwalkers' post-sleep deprivation slow-wave sleep (SWS) and resting-state wakefulness. Methods: Following a 24 hr period of sleep deprivation, 10 sleepwalkers and 10 sex- and age-matched controls were scanned with a high-resolution SPECT scanner. Participants were injected with 99mTc-ethylene cysteinate dimer after 2 min of stable SWS within their first sleep cycle as well as during resting-state wakefulness, both after a subsequent 24 hr period of sleep deprivation. Results: When compared with controls' brain perfusion patterns during both SWS and resting-state wakefulness, sleepwalkers showed reduced regional cerebral perfusion in several bilateral frontal regions, including the superior frontal, middle frontal, and medial frontal gyri. Moreover, reduced regional cerebral perfusion was also found in sleepwalkers' left postcentral gyrus, insula, and superior temporal gyrus during SWS compared with controls. During resting-state wakefulness compared with controls, reduced cerebral perfusion was also found in parietal and temporal regions of sleepwalkers' left hemisphere, whereas the right parahippocampal gyrus showed increased regional cerebral perfusion. Conclusions: Our results reveal patterns of reduced regional cerebral perfusion in sleepwalkers' frontal and parietal areas when compared with controls, regions previously associated with SWS generation and episode occurrence. Additionally, reduced perfusion in the dorsolateral prefrontal cortex and insula during recovery SWS is consistent with the clinical features of somnambulistic episodes, including impaired awareness and reduced pain perception. Altered regional cerebral perfusion patterns during sleepwalkers' resting-state wakefulness may be related to daytime functional anomalies in this population.

Medication induced sleepwalking: A systematic review.

Medications that trigger sleepwalking may inadvertently put the patient at risk of injury to themselves and/or others, and contribute to poor treatment adherence. The aim of this study was to systematically review the literature to identify drugs that may increase the risk of sleepwalking. A search of CINAHL, EMBASE, PsycINFO, PubMed, and ScienceDirect was conducted with the keywords 'sleepwalking' OR 'somnambulism'. Of the original 83 sourced papers, 62 met the inclusion criteria and were subsequently included for review. Twenty-nine drugs, primarily in four classes-benzodiazepine receptor agonists and other gamma aminobutyric acid (GABA) modulators, antidepressants and other serotonergic agents, antipsychotics, and ß-blockers-were identified as possible triggers for sleepwalking. The strongest evidence for medication-induced sleepwalking was for zolpidem and sodium oxybate. All other associations were based on case reports. This research highlights the importance of considering sleepwalking in risk profiles in clinical trials, particularly for drugs that enhance GABA activity at the GABAA receptor, enhance serotonergic activity, or block the activity of noradrenaline at ß receptors. The results also have implications for prescribers to consider sleepwalking as a potential adverse effect and ensure that: 1) the patient is educated about a safe sleep environment; 2) they are encouraged to report the onset or exacerbation of sleepwalking, and 3) alternative treatments are considered if sleepwalking occurs.

Adult-Onset Sleepwalking Secondary to Hyperthyroidism: Polygraphic Evidence.

ABSTRACT: Sleepwalking is a disorder characterized by complex motor behaviors arising from slow wave sleep usually occurring in children. The adult onset of sleepwalking suggests the presence of an external precipitating factor leading to the occurrence of the disorder. Hyperthyroidism has been reported to be the possible cause of sleepwalking in a few cases. We present the case of a 36-year-old man who reported a sudden appearance of nocturnal episodes of sleepwalking. He underwent a complete video polysomnography (VPSG), which showed a polygraphic pattern arising from stage N3 sleep related to the presence of simple motor behaviors. Routine blood tests showed a mild hyperthyroidism. After 4 months of thyrostatic treatment, the patient reported no more sleepwalking events. A VPSG performed at the last follow-up showed the absence of pathological electroclinical events arising from stage N3 sleep. Therefore, we hypothesize that there is a link between sleepwalking and thyroid dysfunction in our patient.

What Does the Sleeping Brain Say? Syntax and Semantics of Sleep Talking in Healthy Subjects and in Parasomnia Patients.

Objectives: Speech is a complex function in humans, but the linguistic characteristics of sleep talking are unknown. We analyzed sleep-associated speech in adults, mostly (92%) during parasomnias. Methods: The utterances recorded during night-time video-polysomnography were analyzed for number of words, propositions and speech episodes, frequency, gaps and pauses (denoting turn-taking in the conversation), lemmatization, verbosity, negative/imperative/interrogative tone, first/second person, politeness, and abuse. Results: Two hundred thirty-two subjects (aged 49.5 ± 20 years old; 41% women; 129 with rapid eye movement [REM] sleep behavior disorder and 87 with sleepwalking/sleep terrors, 15 healthy subjects, and 1 patient with sleep apnea speaking in non-REM sleep) uttered 883 speech episodes, containing 59% nonverbal utterance (mumbles, shouts, whispers, and laughs) and 3349 understandable words. The most frequent word was "No": negations represented 21.4% of clauses (more in non-REM sleep). Interrogations were found in 26% of speech episodes (more in non-REM sleep), and subordinate clauses were found in 12.9% of speech episodes. As many as 9.7% of clauses contained profanities (more in non-REM sleep). Verbal abuse lasted longer in REM sleep and was mostly directed toward insulting or condemning someone, whereas swearing predominated in non-REM sleep. Men sleep-talked more than women and used a higher proportion of profanities. Apparent turn-taking in the conversation respected the usual language gaps. Conclusions: Sleep talking parallels awake talking for syntax, semantics, and turn-taking in conversation, suggesting that the sleeping brain can function at a high level. Language during sleep is mostly a familiar, tensed conversation with inaudible others, suggestive of conflicts.

Demographic, Clinical and Polysomnographic Characteristics of Childhood- and Adult-Onset Sleepwalking in Adults.

BACKGROUND: Sleepwalking (SW) is found to affect children predominantly, but it can persist or appear de novo even among adults. In this study, we assessed the demographic, clinical and polysomnographic profile, trigger factors and associated comorbidities of adult-onset (AO-SW) and childhood-onset (CO-SW) adult sleepwalkers. METHODS: In adult sleepwalkers, a structured clinical interview, a battery of questionnaires, video-polysomnography (v-PSG) and standard electroencephalography (EEG) were performed. RESULTS: Among 63 sleepwalkers, 45% had ≥1 episodes/month, 54% had partial recall of the episodes and 36% reported trigger factors for SW. Almost all subjects reported co-occurring parasomnias. In v-PSG, 4% exhibited episodes of SW, 17% confusional arousals, 21% had an increased apnea-hypopnea-index and 6% exhibited features of an overlap parasomnia disorder. In our cohort, 73% reported CO-SW and 27% AO-SW. In subjects with AO-SW, positive family history for parasomnias was found in 33% (vs. 49% in CO-SW), neurological comorbidities in 44% (vs. 14%), psychiatric comorbidities in 25% (vs. 33%), EEG abnormalities in 50% (vs. 29%). Violence during SW episodes was more frequent in males and in subjects with CO-SW (45% for self-injury and 44% for violent behaviour vs. 33 and 29% respectively in the AO-SW group). CONCLUSIONS: Adult SW represents a complex and potentially dangerous condition. The characteristics of AO-SW often differ from those of CO-SW.

Assessment and treatment of sleepwalking in clinical practice.

BACKGROUND: Sleepwalking is a relatively common and innocuous arousal disorder during non­rapid eye movement sleep. OBJECTIVE: This paper provides a review of the most recent science on sleepwalking to guide clinical decision-making. DISCUSSION: Most patients who sleepwalk do not require treatment, but comorbid sleep disorders that result in daytime tiredness, and behaviour and emotional problems require assessment and interventions. In the absence of clinical trials, tentative, low-risk treatments - scheduled waking and hypnosis - are suggested for sleepwalking that results in distress or violence towards others. People who sleepwalk and are violent may benefit from impulse-control interventions.

Gray matter abnormalities of the dorsal posterior cingulate in sleep walking.

OBJECTIVE: This study aimed to determine whether voxel-based analysis of T1 weighted magnetic resonance imaging (MRI) and diffusion tensor imaging is able to detect alterations of gray and white matter morphometry as well as measures of mean diffusivity and fractional anisotropy in patients with non-rapid eye movement parasomnia. METHODS: 3 Tesla MRI was performed in 14 drug-free, polysomnography-confirmed adult patients with non-rapid eye movement parasomnia (age: 29 ± 4.2 years; disease duration 19.2 ± 7.7 years) and 14 healthy subjects, matched for age and gender. Statistical parametric mapping was applied to objectively identify focal changes of MRI parameters throughout the entire brain volume. RESULTS: Statistical parametric mapping localized significant decreases of gray matter volume in the left dorsal posterior cingulate cortex (BA23) and posterior midcingulate cortex (BA24) in patients with non-rapid eye movement parasomnias compared to the control group (p < 0.001, corrected for multiple comparisons). No significant differences of mean diffusivity and fractional anisotropy measures were found between the non-rapid eye movement parasomnia group and the healthy control group. CONCLUSIONS: Recently, the simultaneous co-existence of arousal or wakefulness originating from the motor and cingulate cortices and persistent sleep in associative cortical regions was suggested as a functional framework of somnambulism. Gray matter volume decline in the dorsal posterior and posterior midcingulate cortex reported in this study might represent the neuroanatomical substrate for this condition.

Is there a common motor dysregulation in sleepwalking and REM sleep behaviour disorder?

This study sought to determine if there is any overlap between the two major non-rapid eye movement and rapid eye movement parasomnias, i.e. sleepwalking/sleep terrors and rapid eye movement sleep behaviour disorder. We assessed adult patients with sleepwalking/sleep terrors using rapid eye movement sleep behaviour disorder screening questionnaires and determined if they had enhanced muscle tone during rapid eye movement sleep. Conversely, we assessed rapid eye movement sleep behaviour disorder patients using the Paris Arousal Disorders Severity Scale and determined if they had more N3 awakenings. The 251 participants included 64 patients with rapid eye movement sleep behaviour disorder (29 with idiopathic rapid eye movement sleep behaviour disorder and 35 with rapid eye movement sleep behaviour disorder associated with Parkinson's disease), 62 patients with sleepwalking/sleep terrors, 66 old healthy controls (age-matched with the rapid eye movement sleep behaviour disorder group) and 59 young healthy controls (age-matched with the sleepwalking/sleep terrors group). They completed the rapid eye movement sleep behaviour disorder screening questionnaire, rapid eye movement sleep behaviour disorder single question and Paris Arousal Disorders Severity Scale. In addition, all the participants underwent a video-polysomnography. The sleepwalking/sleep terrors patients scored positive on rapid eye movement sleep behaviour disorder scales and had a higher percentage of 'any' phasic rapid eye movement sleep without atonia when compared with controls; however, these patients did not have higher tonic rapid eye movement sleep without atonia or complex behaviours during rapid eye movement sleep. Patients with rapid eye movement sleep behaviour disorder had moderately elevated scores on the Paris Arousal Disorders Severity Scale but did not exhibit more N3 arousals (suggestive of non-rapid eye movement parasomnia) than the control group. These results indicate that dream-enacting behaviours (assessed by rapid eye movement sleep behaviour disorder screening questionnaires) are commonly reported by sleepwalking/sleep terrors patients, thus decreasing the questionnaire's specificity. Furthermore, sleepwalking/sleep terrors patients have excessive twitching during rapid eye movement sleep, which may result either from a higher dreaming activity in rapid eye movement sleep or from a more generalised non-rapid eye movement/rapid eye movement motor dyscontrol during sleep.

EEG Functional Connectivity Prior to Sleepwalking: Evidence of Interplay Between Sleep and Wakefulness.

Study Objectives: Although sleepwalking (somnambulism) affects up to 4% of adults, its pathophysiology remains poorly understood. Sleepwalking can be preceded by fluctuations in slow-wave sleep EEG signals, but the significance of these pre-episode changes remains unknown and methods based on EEG functional connectivity have yet to be used to better comprehend the disorder. Methods: We investigated the sleep EEG of 27 adult sleepwalkers (mean age: 29 ± 7.6 years) who experienced a somnambulistic episode during slow-wave sleep. The 20-second segment of sleep EEG immediately preceding each patient's episode was compared with the 20-second segment occurring 2 minutes prior to episode onset. Results: Results from spectral analyses revealed increased delta and theta spectral power in the 20 seconds preceding the episodes' onset as compared to the 20 seconds occurring 2 minutes before the episodes. The imaginary part of the coherence immediately prior to episode onset revealed (1) decreased delta EEG functional connectivity in parietal and occipital regions, (2) increased alpha connectivity over a fronto-parietal network, and (3) increased beta connectivity involving symmetric inter-hemispheric networks implicating frontotemporal, parietal and occipital areas. Conclusions: Taken together, these modifications in EEG functional connectivity suggest that somnambulistic episodes are preceded by brain processes characterized by the co-existence of arousal and deep sleep.

Night-waking trajectories and associated factors in French preschoolers from the EDEN birth-cohort.

Night waking in preschoolers has been associated with adverse health outcomes in cross-sectional studies, but has rarely been analyzed in a longitudinal setting. Therefore, little is known about the evolution of night waking in early childhood. The objectives of the present study were: to identify night-waking trajectories in preschoolers, and to examine the risk factors associated with those trajectories. Analyses were based on the French birth-cohort study EDEN, which recruited 2002 pregnant women between 2003 and 2006. Data on a child's night waking at the ages of two, three, and five, six years, and potential confounders, were collected through parental self-reported questionnaires. Night-waking trajectories were computerized using group-based trajectory modeling on 1346 children. Two distinct developmental patterns were identified: the "2-5 rare night-waking" (77% of the children) and the "2-5 common night-waking" pattern. Logistic regressions were performed to identify the factors associated with the trajectories. Risk factors for belonging to the "2-5 common night-waking" trajectory were: exposure to passive smoking at home, daycare in a collective setting, watching television for extended periods, bottle feeding at night, high emotionality, and low shyness. This approach allowed identification of risk factors associated with night waking during a critical age window, and laid the groundwork for identifying children at higher risk of deleterious sleep patterns. Those risk factors were mainly living habits, which indicated that prevention and intervention programs could be highly beneficial in this population.

Scalp and Source Power Topography in Sleepwalking and Sleep Terrors: A High-Density EEG Study.

STUDY OBJECTIVES: To examine scalp and source power topography in sleep arousals disorders (SADs) using high-density EEG (hdEEG). METHODS: Fifteen adult subjects with sleep arousal disorders (SADs) and 15 age- and gender-matched good sleeping healthy controls were recorded in a sleep laboratory setting using a 256 channel EEG system. RESULTS: Scalp EEG analysis of all night NREM sleep revealed a localized decrease in slow wave activity (SWA) power (1-4 Hz) over centro-parietal regions relative to the rest of the brain in SADs compared to good sleeping healthy controls. Source modelling analysis of 5-minute segments taken from N3 during the first half of the night revealed that the local decrease in SWA power was prominent at the level of the cingulate, motor, and sensori-motor associative cortices. Similar patterns were also evident during REM sleep and wake. These differences in local sleep were present in the absence of any detectable clinical or electrophysiological sign of arousal. CONCLUSIONS: Overall, results suggest the presence of local sleep differences in the brain of SADs patients during nights without clinical episodes. The persistence of similar topographical changes in local EEG power during REM sleep and wakefulness points to trait-like functional changes that cross the boundaries of NREM sleep. The regions identified by source imaging are consistent with the current neurophysiological understanding of SADs as a disorder caused by local arousals in motor and cingulate cortices. Persistent localized changes in neuronal excitability may predispose affected subjects to clinical episodes.

Sleepwalking episodes are preceded by arousal-related activation in the cingulate motor area: EEG current density imaging.

OBJECTIVE: To investigate local arousal fluctuations in adults who received ICSD-2 diagnosis of somnambulism. METHODS: EEG neuroimaging (eLORETA) was utilized to compare current density distribution for 4s epochs immediately preceding sleepwalking episode (from -4.0 s to 0 s) to the distribution during earlier 4s epochs (from -8.0 s to -4.0 s) in 20 EEG segments from 15 patients. RESULTS: Comparisons between eLORETA images revealed significant (t>4.52; p<0.05) brain activations before onset of sleepwalking, with greater current density within beta 3 frequency range (24-30 Hz) in Brodmann areas 33 and 24. CONCLUSIONS: Sleepwalking motor events are associated with arousal-related activation of cingulate motor area. SIGNIFICANCE: These results support the notion of blurred boundaries between wakefulness and NREM sleep in sleepwalking.