Non-24 Research Articles

Improvement in non-24-h sleep-wake rhythm disorder in a sighted individual treated with a melatonin receptor agonist

Non-24-hour sleep-wake rhythm disorder (N24SWD) typically presents in patients with visual impairments that disrupt the ability to entrain to the 24 hour solar cycle. We discuss a 43 year old sighted man who presented with periodic daytime hypersomnia and nighttime insomnia, occasionally leading to <3 hours of sleep per day. Previous polysomnography showed an apnea hypopnea index of 6.2 events per hour. A sleep log of 3 months showed irregular time of sleep onset, and an average of 3 hours of sleep per day. Wrist actigraphy confirmed N24SWD. A trial of tasimelteon 20 mg/day resulting in improved daytime hypersomnia (pre-Epworth Sleepiness Scale (ESS) = 21/24, post-ESS = 5/24; a score of > 10/24 is considered sleepy). Follow-up actigraphy showed marked resolution of phase delay with an average of five hours of sleep. The case demonstrates that tasimelteon is a possible treatment for N24SWD in sighted individuals.

Sandman Send Me a Dream: Case of Non-24-Hour Sleep-Wake Disorder in a Sighted Pediatric Patient (P11-9.005)

<h3>Objective:</h3> Non-24-hour sleep-wake disorder (N24SWD) is a circadian rhythm disorder that leads to the inability to consistently sync the sleep wake (SW) pattern to the 24 hour day night cycle. Patients with N24SWD have progressively delayed SW patterns that occur in a cyclic fashion leading to significant interruptions to daily life. N24SWD is most commonly observed in non-sighted individuals impacting an estimated 50% of that population. It is exceedingly rare in patients with sight, with the first published case in 1971. Furthermore, this is even rarer, if ever, previously described in the pediatric population. <h3>Background:</h3> A 12-year-old male was referred for excessive daytime sleepiness and abnormal sleeping patterns. His bedtime is progressively more delayed each day. During periods of unrestricted sleep, sleep onset delays 2–3 hours each night, with a sleep latency of about 30 minutes and 8–10 hours of sleep duration. Return to a normal bedtime of 9:00pm occurs every 7–10 days. There was no other significant sleep history. He denies sleep paralysis, hypnogogic and hypnopompic hallucinations, and snoring. Melatonin had inconsistent success and adverse effects. The patient’s neurological examination was unremarkable. <h3>Design/Methods:</h3> NA <h3>Results:</h3> Actigraphy confirmed the diagnosis of N24SWD demonstrating cycling of SW when allowed a free sleep schedule. Brain MRI without contrast was unremarkable. The patient was initiated on tasimelteon which led to significant improvements in his ability to maintain a consistent bedtime. <h3>Conclusions:</h3> This case demonstrates that not only can N24SWD occur in sighted individuals, but it can certainly be present in the sighted pediatric population. If not identified, it can lead to long term effects on a child’s life, affecting their development and education. This case also demonstrated the benefits of selective melatonin agonists in the treatment of this condition. <b>Disclosure:</b> Dr. Hart has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Morse has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Jazz Pharmaceuticals. Dr. Morse has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Avadel. Dr. Morse has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Jazz Pharmaceuticals. Dr. Morse has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Jazz Pharmaceuticals. Dr. Morse has received personal compensation in the range of $50,000-$99,999 for serving as an Expert Witness for Hayes solicitors. The institution of Dr. Morse has received research support from NIH.

Non-24-Hour Sleep–Wake Disorder and Tasimelteon: A Review for Practitioners Who Work With Blind People

Introduction This narrative review summarizes the biology of human circadian rhythms; details the epidemiology, clinical manifestation, and diagnosis of non-24-hour sleep–wake disorder (N24SWD); and reviews the efficacy of possible treatments. Methods Searches of targeted phrases, such as “non-24-hour sleep–wake disorder” and “tasimelteon,” were conducted on PubMed between December 2016 and March 2020. Results As the world’s population ages, health practitioners frequently work with people who are blind. Damage to the retinal ganglion cells that signal environmental irradiance levels to the suprachiasmatic nucleus prevents many of these individuals from synchronizing their internal clocks to the 24-hour day. As a result, they experience a condition called N24SWD, where the body’s circadian rhythms fall in and out of phase with the solar cycle. The ability to fall asleep and remain asleep is a complex process that depends on many variables, including the release of the neurohormone melatonin. Melatonin is produced at night and is a key regulator of regular sleep cycles. Periods of interrupted sleep, increased sleep latency, and reduced total sleep time occur when melatonin production peaks during daytime. Thus, many persons with N24SWD have difficulty maintaining normal schedules due in part to the mistimed release of melatonin. Randomized clinical trials have shown that melatonin receptor agonist tasimelteon is an effective therapy for individuals with N24SWD. Other treatments have varying efficacy profiles. Conclusions Although rare, N24SWD is a serious condition that can impair quality of life for blind persons. Tasimelteon appears to be a safe and efficacious treatment option. Implications for Practitioners Practitioners can use this information to better understand why blind persons often report difficulties sleeping and to realize that therapeutic options are available to these individuals.

Sleep deprivation therapy to reset the circadian pacemaker in a non-24-hour sleep-wake disorder: a case report

Subscription RequiredCase ReportsSleep deprivation therapy to reset the circadian pacemaker in a non-24-hour sleep-wake disorder: a case report Kelly Guichard, MD, MS, Jean-Arthur Micoulaud-Franchi, MD, PhD, Pierre Philip, MD, PhD, Jacques Taillard, PhD Kelly Guichard, MD, MS Address correspondence to: Kelly Guichard, MD, MS, Clinique du Sommeil, Bordeaux University Hospital, Hôpital Pellegrin, Place Amélie Raba-Léon, 33000 Bordeaux, France; Email: E-mail Address: [email protected] Clinique du Sommeil, Bordeaux University Hospital, Bordeaux, France Université de Bordeaux, Sommeil - addiction - neuropsychiatrie SANPSY, Bordeaux, France Nouvelle Clinique Bel Air, Bordeaux, France Search for more papers by this author , Jean-Arthur Micoulaud-Franchi, MD, PhD Clinique du Sommeil, Bordeaux University Hospital, Bordeaux, France Université de Bordeaux, Sommeil - addiction - neuropsychiatrie SANPSY, Bordeaux, France Centre National de la Recherche Scientific (CNRS), unité de service et de recherche 3413, SANPSY, Bordeaux, France Search for more papers by this author , Pierre Philip, MD, PhD Clinique du Sommeil, Bordeaux University Hospital, Bordeaux, France Université de Bordeaux, Sommeil - addiction - neuropsychiatrie SANPSY, Bordeaux, France Centre National de la Recherche Scientific (CNRS), unité de service et de recherche 3413, SANPSY, Bordeaux, France Search for more papers by this author , Jacques Taillard, PhD Université de Bordeaux, Sommeil - addiction - neuropsychiatrie SANPSY, Bordeaux, France Centre National de la Recherche Scientific (CNRS), unité de service et de recherche 3413, SANPSY, Bordeaux, France Search for more papers by this author Published Online:July 1, 2021https://doi.org/10.5664/jcsm.9294

Circadian tau differences and rhythm associations in delayed sleep-wake phase disorder and sighted non-24-hour sleep-wake rhythm disorder.

We investigated biological and behavioral rhythm period lengths (i.e. taus) of delayed sleep-wake phase disorder (DSWPD) and non-24-hour sleep-wake rhythm disorder (N24SWD). Based on circadian phase timing (temperature and dim light melatonin onset), DSWPD participants were dichotomized into a circadian-delayed and a circadian non-delayed group to investigate etiological differences. Participants with DSWPD (n = 26, 17 m, age: 21.85 ± 4.97 years), full-sighted N24SWD (n = 4, 3 m, age: 25.75 ± 4.99 years) and 18 controls (10 m, age: 23.72 ± 5.10 years) participated in an 80-h modified constant routine. An ultradian protocol of 1-h "days" in dim light, controlled conditions alternated 20-min sleep/dark periods with 40-min enforced wakefulness/light. Subjective sleepiness ratings were recorded prior to every sleep/dark opportunity and median reaction time (vigilance) was measured hourly. Obtained sleep (sleep propensity) was derived from 20-min sleep/dark opportunities to quantify hourly objective sleepiness. Hourly core body temperature was recorded, and salivary melatonin assayed to measure endogenous circadian rhythms. Rhythm data were curved using the two-component cosine model. Patients with DSWPD and N24SWD had significantly longer melatonin and temperature taus compared to controls. Circadian non-delayed DSWPD had normally timed temperature and melatonin rhythms but were typically sleeping at relatively late circadian phases compared to those with circadian-delayed DSWPD. People with DSWPD and N24SWD exhibit significantly longer biological circadian rhythm period lengths compared to controls. Approximately half of those diagnosed with DSWPD do not have abnormally delayed circadian rhythm timings suggesting abnormal phase relationship between biological rhythms and behavioral sleep period or potentially conditioned sleep-onset insomnia.

Le traitement par la lumière des troubles circadiens du rythme veille-sommeil

Phototherapy is one treatment of circadian sleep-wake disorders, which is based on consensual and numerous scientific and clinical evidences. Phototherapy efficiency depends on several light characteristics based on intensity, length of exposure, time of exposure and wavelength. Phototherapy is potentially indicated in the following circadian disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), jet-lag and night-shift work sleep-wake disorders (NSSWD). Phototherapy, acting via the retina, may be avoided in patients with retina disorders, an ophthalmologist should be consulted.

Circadian Rhythm Disturbances in the Blind.

Sleep timing, quantity, and quality are controlled by homeostatic and circadian systems. Circadian clock systems are present in all cells and organs and their timing is determined by a transcriptional-translational feedback loop of circadian genes. Individual cellular clocks are synchronized by the central body clock, situated in the suprachiasmatic nucleus, which communicates with them through humoral and neural signals including melatonin. The circadian system controls both the circadian period: (i.e., the length of the intrinsic clock), but also the circadian phase (i.e., the clock timing). An important determinant of the circadian system is light exposure. In most humans, the circadian period is slightly longer than 24h and without regular resetting it tends to drift, leading to progressively later bedtimes and wake times and a tendency to cycle though periods of normal and abnormal sleep. Blind patients are thus at an increased risk of abnormal circadian function. The purpose of this article is to review recent research and clinical management of circadian rhythm disorders in blind patients. Blind patients can present delayed and advanced sleep phase disorders but the most common abnormality in totally blind patients without light perception is non-24-hour sleep-wake disorder (N24SWD). This is rare in the general population but may affect up to 50% of blind patients without light perception. The diagnosis of a circadian rhythm disorder in the blind is complex. New screening tools have been developed but actigraphy and repeated melatonin profiles over 24h remain essential. Circadian disorders in the blind are frequent, especially in the patients without light perception. They require accurate diagnosis in order to target treatment. Determining the precise nature of a sleep disorder in blind patients with a suspected circadian rhythm abnormality is complex and requires a detailed clinical history with sleep diaries and the use of actigraphy and melatonin profiles.

0701 CIRCADIAN TAU DIFFERENCES IN BIOLOGICAL, BEHAVIOURAL AND SLEEPINESS RHYTHMS IN DELAYED SLEEP-WAKE PHASE DISORDER AND NON-24-HOUR SLEEP-WAKE RHYTHM DISORDER PATIENTS

In this study we investigated biological, sleepiness and behavioural rhythm period lengths (i.e., taus) of Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD) patients and healthy control sleepers. We also ran cross-correlation analyses between different rhythm variables to examine phase angle of entrainment. The aim was to explore if behavioural rhythms, in addition to the biological circadian rhythms contribute to misalignments of sleep timing symptomatic of DSWPD and N24SWD. Twenty-six DSWPD participants who met diagnostic criteria (17m, 9f, age: 21.85 ± 4.97 years) and 18 controls (10m, 8f, age: 23.72 ± 5.10 years) participated in an 80-hour modified constant routine. Additionally, 4 full-sighted patients (3m, 1f, age: 25.75 ± 4.99 years) were diagnosed with N24SWD and included as a discrete study group. A forced-desynchrony ultradian protocol of 1-hour ‘days’ in dim light, controlled conditions alternated 20-minute sleep opportunities with 40-minute enforced wakefulness. Subjective sleepiness ratings were recorded prior to every sleep opportunity and median reaction time (vigilance) was measured hourly. Amount of sleep obtained (sleep propensity) was derived from 20-minute sleep opportunities to quantify hourly objective sleepiness. Hourly core body temperature was recorded and salivary melatonin assayed to measure endogenous circadian rhythms. Rhythm data were curved using the 2-component cosine model. DSWPD and N24SWD patients had significantly longer melatonin and temperature taus compared to controls. There were no significant tau differences between groups as measured by subjective sleepiness, sleep propensity and vigilance rhythms. However, DSWPD patients showed a greater interval between maximum sleep propensity and minimum core body temperature. Their sleep propensity rhythms lagged core temperature rhythms by an hour more compared to controls’ sleep propensity and core temperature rhythms. The findings provide further evidence that delayed circadian rhythms in DSWPD may result from larger phase angles between core body temperature and sleep propensity. This interval may result in later sleep timing in DSWPD patients relative to their circadian timing thus masking their light exposure during a time that is critical to phase-advancing the circadian system. This project was funded by the Australian Research Council.

Evaluation of circadian phenotypes utilizing fibroblasts from patients with circadian rhythm sleep disorders

We evaluated the circadian phenotypes of patients with delayed sleep–wake phase disorder (DSWPD) and non-24-hour sleep–wake rhythm disorder (N24SWD), two different circadian rhythm sleep disorders (CRSDs) by measuring clock gene expression rhythms in fibroblast cells derived from individual patients. Bmal1-luciferase (Bmal1-luc) expression rhythms were measured in the primary fibroblast cells derived from skin biopsy samples of patients with DSWPD and N24SWD, as well as control subjects. The period length of the Bmal1-luc rhythm (in vitro period) was distributed normally and was 22.80±0.47 (mean±s.d.) h in control-derived fibroblasts. The in vitro periods in DSWPD-derived fibroblasts and N24SWD-derived fibroblasts were 22.67±0.67 h and 23.18±0.70 h, respectively. The N24SWD group showed a significantly longer in vitro period than did the control or DSWPD group. Furthermore, in vitro period was associated with response to chronotherapy in the N24SWD group. Longer in vitro periods were observed in the non-responders (mean±s.d.: 23.59±0.89 h) compared with the responders (mean±s.d.: 22.97±0.47 h) in the N24SWD group. Our results indicate that prolonged circadian periods contribute to the onset and poor treatment outcome of N24SWD. In vitro rhythm assays could be useful for predicting circadian phenotypes and clinical prognosis in patients with CRSDs.

A Pre-Screening Questionnaire to Predict Non-24-Hour Sleep-Wake Rhythm Disorder (N24HSWD) among the Blind.

There is currently no questionnaire-based pre-screening tool available to detect non-24-hour sleep-wake rhythm disorder (N24HSWD) among blind patients. Our goal was to develop such a tool, derived from gold standard, objective hormonal measures of circadian entrainment status, for the detection of N24HSWD among those with visual impairment. We evaluated the contribution of 40 variables in their ability to predict N24HSWD among 127 blind women, classified using urinary 6-sulfatoxymelatonin period, an objective marker of circadian entrainment status in this population. We subjected the 40 candidate predictors to 1,000 bootstrapped iterations of a logistic regression forward selection model to predict N24HSWD, with model inclusion set at the p < 0.05 level. We removed any predictors that were not selected at least 1% of the time in the 1,000 bootstrapped models and applied a second round of 1,000 bootstrapped logistic regression forward selection models to the remaining 23 candidate predictors. We included all questions that were selected at least 10% of the time in the final model. We subjected the selected predictors to a final logistic regression model to predict N24SWD over 1,000 bootstrapped models to calculate the concordance statistic and adjusted optimism of the final model. We used this information to generate a predictive model and determined the sensitivity and specificity of the model. Finally, we applied the model to a cohort of 1,262 blind women who completed the survey, but did not collect urine samples. The final model consisted of eight questions. The concordance statistic, adjusted for bootstrapping, was 0.85. The positive predictive value was 88%, the negative predictive value was 79%. Applying this model to our larger dataset of women, we found that 61% of those without light perception, and 27% with some degree of light perception, would be referred for further screening for N24HSWD. Our model has predictive utility sufficient to serve as a pre-screening questionnaire for N24HSWD among the blind.

Non-24-Hour Sleep-Wake Rhythm Disorder in Sighted and Blind Patients.

Non-24-hour sleep-wake rhythm disorder (N24SWD) is a cyclic debilitating circadian rhythm sleep disorder characterized by an inability to sleep on a 24-hour schedule. Individuals isolated from a 24-hour light-dark cycle exhibit sleep-wake cycles different from 24hours. Relatively rare in sighted patients, it may be associated with delayed sleep-wake rhythm disorder or psychiatric disorders. It is more common in totally blind individuals owing to the lack of light information reaching the circadian pacemaker in the hypothalamus. We review the clinical characteristics of patients with N24SWD, discuss the biological mechanisms that may underlie its development, and describe treatment strategies.

Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial.

IntroductionMelatonin, secreted by the pineal gland during the night phase, is a regulator of the biological clock and sleep tendency. Totally blind subjects frequently report severe, periodic sleep problems, with 50%–75% of cases displaying non-24-hour sleep–wake disorder (N24HSWD) due to inability to synchronize with the environmental day–night cycle. Melatonin immediate-release preparations are reportedly effective in N24HSWD. Here, we studied the efficacy and safety of prolonged-release melatonin (PRM), a registered drug for insomnia, for sleep disorders in totally blind subjects living in normal social environments. The primary endpoint was demonstration of clinically meaningful effects on sleep duration (upper confidence interval [CI] limit >20 minutes whether significant or not) to allow early decision-making on further drug development in this indication.Trial registrationClinicalTrials.gov registry – NCT00972075.MethodsIn a randomized, double-blind, placebo-controlled proof-of-principle study, 13 totally blind subjects had 2 weeks’ placebo run-in, 6 weeks’ randomized (1:1) PRM (Circadin®) or placebo nightly, and 2 weeks’ placebo run-out. Outcome measures included daily voice recorded sleep diary, Clinical Global Impression of Change (CGIC), WHO-Five Well-being Index (WHO-5), and safety.ResultsMean nightly sleep duration improved by 43 minutes in the PRM and 16 minutes in the placebo group (mean difference: 27 minutes, 95% CI: −14.4 to 69 minutes; P=0.18; effect size: 0.82) meeting the primary endpoint. Mean sleep latency decreased by 29 minutes with PRM over placebo (P=0.13; effect size: 0.92) and nap duration decreased in the PRM but not placebo group. The variability in sleep onset/offset and latency tended to decrease during PRM but not placebo treatment. The potentially beneficial effects of PRM persisted during the 2 weeks of discontinuation period, consistent with clock stabilizing effects. PRM was well-tolerated, adverse events were of mild or moderate severity and similar between PRM and placebo.ConclusionNightly use of PRM may potentially improve patient-reported sleep difficulties in totally blind individuals trying to adhere to normal social lifestyle. A larger study powered to demonstrate a statistically significant effect is warranted.

Tasimelteon for Non-24-Hour Sleep–Wake Disorder

The melatonin receptor agonist tasimelteon has been approved to treat non-24 sleep–wake disorder in totally blind individuals, the FDA has announced. The drug should be taken each night before bedtime. In two placebo-controlled clinical trials comprising roughly 100 totally blind patients …

An Unusual Cause of Insomnia Following IED-Induced Traumatic Brain Injury

A 20-year-old man presented to the sleep disorders clinic for evaluation of recurrent episodes of sleeping difficulties and a diagnosis of insomnia made by his primary care physician. Approximately 6 months prior to his initial presentation, he sustained multiple injuries following an improvised explosive device (IED) blast while serving in Operation Iraqi Freedom, including a mild-moderate traumatic brain injury and penetrating injuries to both eyes. His ophthalmologic trauma resulted in enucleation of his right eye and significantly reduced vision in his left. Since his injuries, he reports recurrent periods during which he is unable to initiate sleep at a desired time. During these periods, he experiences significant fatigue and daytime somnolence when trying to keep a normal sleep-wake schedule. He stated that these periods resolved slowly but then recurred without an identifiable precipitating cause. He had no significant past medical history and denies any sleep complaints prior to his injury. He was diagnosed with depression but stated that his symptoms worsened after starting a selective-serotonin reuptake inhibitor. Similarly, non-benzodiazepine sedative-hypnotics did not significantly improve his insomnia and resulted in worsening of his daytime fatigue. Physical examination demonstrated an enucleated right eye and left visual acuity of 20/200, but was otherwise unremarkable; laboratory studies, including thyroid function testing, a complete blood count, and serum electrolytes were within normal limits. Nocturnal polysomnography revealed a sleep latency of 42 minutes, sleep efficiency of 96%, and preserved sleep architecture. The patient completed a sleep diary over the course of a month (Figure 1). Treatment was then initiated, and the patient reported marked improvements in sleep latency, sleep consolidation, and daytime sleepiness during a follow-up evaluation two months later. A repeat sleep diary showed normalization of his sleep-wake cycle (Figure 2). Figure 1 Sleep diary pre-treatment. Figure 2 Sleep diary post-treatment. Q: WHAT IS THE DIAGNOSIS AND HOW WOULD YOU INITIATE THERAPY? A: CIRCADIAN RHYTHM SLEEP DISORDER, FREE-RUNNING TYPE (NON–24-HOUR SLEEP WAKE SYNDROME). BOTH EVENING MELATONIN ADMINISTRATION AND MORNING PHOTOTHERAPY HAVE BEEN SHOWN TO IMPROVE SYMPTOMS.

Daily activity and persistent sleep-wake schedule disorders

Ohta Tatsuro, Tokihisa Iwata, Yuhei Kayukawa and Tamotsu Okada: Daily Activity and Persistent Sleep-Wake Schedule Disorders. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(4):529–537. 1. 1. Patients with disorders of entrainment to external time cues such as delayed sleep phase syndrome (DSPS) and non24-hour sleep-wake syndrome (HNS) were treated with non-pharmacological interventions and/or pharmacological agents. 2. 2. Resetting the circadian clock with chronotherapy was easy in all DSPS patients, but it was not as easy to maintain the reset rhythm without additional therapy. Triazolam was effective in treating the phase delay that reappeared after chronotherapy. 3. 3. Vitamin b 12 (methylcobalamin) was strikingly effective in some patients with DSPS or HNS. 4. 4. All the adolescent patients who complained of inability to attend school finally returned to their classes after treatment. Maintaining the reset rhythm in adolescent patients was easier than in adults.