Images: "Too much heat for my non-24-hour sleep-wake disorder!" A case report.

The non-24-hour sleep-wake disorder (N24SWD) is a rare condition, sometimes associated with blindness or with suprachiasmatic nuclei lesions, resulting in a free-running rhythm or hypernycthemeral syndrome. Synchronizers, such as light, when light perception remains, melatonin, food intakes, physical activity, social interactions, and temperature, play a key role in the treatment of N24SWD. In this report, we describe a case illustrating the impact of outdoor temperature in a 34-year-old man with N24SWD effectively treated through a combination of chronotherapy interventions. During 3 consecutive heat waves, he experienced a recurrence of his natural 25.5-hour free-running rhythm, with a consistent bedtime phase delay caused by temperature, resulting in the discontinuation of chronotherapy. After these heat waves, he was able again to resynchronize his rhythms with the combination of chronotherapeutics. This case report highlights that patients with N24SWD may be particularly at risk of relapse during heat waves, with direct implications for monitoring and reinforcing chronotherapies. CITATION: Garrivet J, d'Ortho M-P, Frija-Masson J, et al. "Too much heat for my non-24-hour sleep-wake disorder!" A case report. J Clin Sleep Med. 2024;20(2):329-333.

The Effect of Blindness on Biological Rhythms and the Consequences of Circadian Rhythm Disorder.

Various physiological systems and behaviors such as the sleep-wake cycle, vigilance, body temperature, and the secretion of certain hormones are governed by a 24-hour cycle called the circadian system. While there are many external stimuli involved the regulation of circadian rhythm, the most powerful environmental stimulus is the daily light-dark cycle. Blind individuals with no light perception develop circadian desynchrony. This leads to non-24-hour sleep-wake rhythm disorder, which is associated with sleep-wake disorders, as well as mood disorders and loss of appetite and gastrointestinal disturbances due to disrupted circadian hormone regulation. As the diagnosis is often delayed because of under-recognition in clinical practice, patients must cope with varying degrees of social and academic dysfunction. Most blind individuals report that non-24-hour sleep-wake rhythm disorder affects them more than blindness. In the treatment of totally blind patients suffering from non-24-hour sleep-wake rhythm disorder, the first-line management is behavioral approaches. Drug therapy includes melatonin and the melatonin agonist tasimelteon. Diagnosing blind individuals' sleep disorders is also relevant to treatment because they can be improved with the use of melatonin and its analogues or by phototherapy if they have residual vision. Therefore, assessing sleep problems and planning treatment accordingly for individuals presenting with blindness is an important issue for ophthalmologists to keep in mind.

Attention-Deficit/Hyperactivity Disorder and Delayed Sleep Phase Syndrome in Adults: A Randomized Clinical Trial on the Effects of Chronotherapy on Sleep.

Delayed sleep phase syndrome (DSPS) is the most common sleep disturbance in adults with attention-deficit/hyperactivity disorder (ADHD). We previously showed that chronotherapy with melatonin effectively advanced the dim-light melatonin onset (DLMO), a biomarker for the internal circadian rhythm, by 1.5 h and reduced ADHD symptoms by 14%. Melatonin combined with bright light therapy (BLT) advanced the DLMO by 2 h, but did not affect ADHD symptoms. This article explores whether sleep times advanced along with DLMO, leading to longer sleep duration and better sleep in general, which might explain the working mechanism behind the reduction in ADHD symptoms after treatment with melatonin. This article presents exploratory secondary analysis on objective and self-reported sleep characteristics from a three-armed double-blind randomized placebo-controlled clinical trial (RCT), which included 49 adults (18-55 years) with ADHD and DSPS. Participants were randomized to receive sleep education and 3 weeks of (1) 0.5 mg/day placebo, (2) 0.5 mg/day melatonin, or (3) 0.5 mg/day melatonin plus 30 min of bright light therapy (BLT) between 0700 and 0800 h. Sleep was assessed at baseline, directly after treatment, and 2 weeks after the end of treatment. Objective measures were obtained by actigraphy, self-reported measures by various sleep questionnaires and a sleep diary. Melatonin with or without BLT did not advance sleep times, improve sleep in general, or strengthen wake-activity rhythms. So even though the DLMO had advanced, sleep timing did not follow. Adding extensive behavioral coaching to chronotherapy is necessary for advancing sleep times along with DLMO and to further alleviate ADHD symptoms.

Treatment of a patient with a circadian sleep-wake disorder using a combination of melatonin and metoprolol.

CITATION: Circadian rhythm sleep-wake disorders result from the lack of synchronization between endogenous circadian rhythms and daily environmental or behavioral cycles. Current treatment of circadian rhythm sleep-wake disorders relies on strengthening normal zeitgebers, or temporal cues, through the combination of strict behavioral modification, controlled light exposure, and supplemental melatonin or melatonin receptor agonists. These therapies can be difficult to maintain and are supported with only limited clinical outcome data. The effectiveness of exogenous melatonin, in particular, may be reduced by the patient's continued production of endogenous melatonin with a temporal pattern that is not conducive to the desired sleep schedule. Here we describe the case of a single, sighted patient with a circadian rhythm sleep-wake disorder who benefited from the combined use of a beta blocker to suppress endogenous melatonin secretion along with the timed administration of exogenous melatonin. We suggest that the positive results obtained justify further study of this mechanism-guided approach. CITATION: Gehrman PR, Anafi RC. Treatment of a patient with a circadian sleep-wake disorder using a combination of melatonin and metoprolol. J Clin Sleep Med. 2021;17(10):2121-2124.

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

NONE: Non-24-hour sleep-wake disorder is 1 of several chronic circadian rhythm sleep-wake disorders. It is defined as progressive daily shifts in sleep onset and wake times. It mainly affects patients who are sight-impaired, is relatively rare in sighted patients, and is difficult to treat, with no guidelines. This case report discusses non-24-hour sleep-wake disorder in a sighted young man who complained of alternating severe insomnia and excessive sleepiness, with a sleep agenda and actigraphic data showing a daily delay of approximately 2 hours. A novel therapy by total sleep deprivation followed by a combination of morning light therapy and nocturnal melatonin administration was efficient in stopping his free-running sleep-wake pattern both immediately and in the long term. The treatment combination for 6 months resulted in stable circadian entrainment to a 24-hour cycle. Compliance with chronotherapy was maintained over the course of follow-up.

The role of the circadian system in the etiology and pathophysiology of ADHD: time to redefine ADHD?

Attention-deficit/hyperactivity disorder (ADHD) is highly associated with the delayed sleep phase disorder, a circadian rhythm sleep-wake disorder, which is prevalent in 73-78% of children and adults with ADHD. Besides the delayed sleep phase disorder, various other sleep disorders accompany ADHD, both in children and in adults. ADHD is either the cause or the consequence of sleep disturbances, or they may have a shared etiological and genetic background. In this review, we present an overview of the current knowledge on the relationship between the circadian rhythm, sleep disorders, and ADHD. We also discuss the various pathways explaining the connection between ADHD symptoms and delayed sleep, ranging from genetics, behavioral aspects, daylight exposure, to the functioning of the eye. The treatment options discussed are focused on improvement of sleep quality, quantity, and phase-resetting, by means of improving sleep hygiene, chronotherapy, treatment of specific sleep disorders, and by strengthening certain neuronal networks involved in sleep, e.g., by sensorimotor rhythm neurofeedback. Ultimately, the main question is addressed: whether ADHD needs to be redefined. We propose a novel view on ADHD, where a part of the ADHD symptoms are the result of chronic sleep disorders, with most evidence for the delayed circadian rhythm as the underlying mechanism. This substantial subgroup should receive treatment of the sleep disorder in addition to ADHD symptom treatment.

Promoting nighttime sleep in the intensive care unit: Alternative strategies in nursing.

AIM: To identify if complementary interventions impacted on conscious intensive care patients' perception of stress factors and quality of sleep. RESEARCH METHODOLOGY: A non-controlled clinical study was undertaken on conscious patients in an intensive care unit in central Italy. Patients perception of stress factors and quality of sleep during the first night with usual medical and nursing treatments was measured using two questionnaires: the Stress Factors in Intensive Care Unit Questionnaire and the Modified Richards-Campbell Sleep Questionnaire. During the second night two specific treatments were administered: (1) receptive musical sounds and (2) a massage using sweet lavender/lemon-scented almond oil. The same variables were measured on the third day using the same questionnaires. RESULTS: The data of 74 patients were analysed. The patients' main concerns were "hearing unusual noises" (n = 46, 62.2%), "having people continuously working around the bed" (n = 53, 71.6%), "being worried" (n = 60, 81.1%) and "being unable to sleep" (n = 47, 63.5%). Fifty-three patients (71.6%) reported waking up in the middle of the night and 21 (28.3%) of them were unable to fall asleep again. Receptive musical sounds and massage using aromatherapy improved the quality of patients' sleep (t = 2.01, p = 0.047). CONCLUSION: Complementary interventions may reduce patients' perception of stress and improve their sleep. Further research is now needed.

A systematic review of circadian function, chronotype and chronotherapy in attention deficit hyperactivity disorder.

Reports of sleep disturbances in attention deficit hyperactivity disorder (ADHD) are common in both children and adults; however, the aetiology of such disturbances is poorly understood. One potentially important mechanism which may be implicated in disrupted sleep in ADHD is the circadian clock, a known key regulator of the sleep/wake cycle. In this systematic review, we analyse the evidence for circadian rhythm changes associated with ADHD, as well as assessing evidence for therapeutic approaches involving the circadian clock in ADHD. We identify 62 relevant studies involving a total of 4462 ADHD patients. We find consistent evidence indicating that ADHD is associated with more eveningness/later chronotype and with phase delay of circadian phase markers such as dim light melatonin onset and delayed sleep onset. We find that there is evidence that melatonin treatment may be efficacious in addressing ADHD-related sleep problems, although there are few studies to date addressing other chronotherapeutic approaches in ADHD. There are only a small number of genetic association studies which report linkages between polymorphisms in circadian clock genes and ADHD symptoms. In conclusion, we find that there is consistent evidence for circadian rhythm disruption in ADHD and that such disruption may present a therapeutic target that future ADHD research might concentrate explicitly on.

A double-blind randomized controlled trial to assess the effect of bright light therapy on depression in patients with Parkinson's disease.

BACKGROUND: A disturbed circadian rhythm seems to be a causal factor in the occurrence of depressive disorders in patients with Parkinson's disease (PD). The circadian rhythm can be restored with light. Therefore, Bright Light Therapy (BLT) might be a new treatment option for depression in PD patients. METHODS/DESIGN: In this double-blind controlled trial, 84 subjects with idiopathic PD are randomized to either BLT or a control light condition. The BLT condition emits white light with an intensity of 10,000 Lux, while the control device emits dim white light of 200 Lux, which is presumed to be too low to influence the circadian rhythm. Subjects receive 30 min of home treatment twice daily for three months. Timing of treatment is based on the individual chronotype. After finishing treatment, subjects enter a follow-up period of six months. The primary outcome of the study is the severity of depressive symptoms, as measured with the Hamilton Depression Rating Scale. Secondary outcomes are alternative depression measures, objective and subjective sleep measures, and salivary melatonin and cortisol concentrations. For exploratory purposes, we also assess the effects on motor symptoms, global cognitive function, comorbid psychiatric disorders, quality of life and caregiver burden. Data will be analyzed using a linear mixed models analysis. DISCUSSION: Performing a placebo-controlled trial on the effects of BLT in PD patients is challenging, as the appearance of the light may provide clues on the treatment condition. Moreover, fixed treatment times lead to an improved sleep-wake rhythm, which also influences the circadian system. With our study design, we do not compare BLT to placebo treatment, i.e. an ineffective control treatment. Rather, we compare structuring of the sleep-wake cycle in both conditions with additional BLT in the experimental condition, and additional dim light in the control condition. Participants are not informed about the exact details of the two light devices and the expected therapeutic effect, and expectancies are rated prior to the start of treatment. Ideally, the design of a future study on BLT should include two extra treatment arms where BLT and control light are administered at random times. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov on May 17th 2012 (ClinicalTrials.gov Identifier: NCT01604876 ).

Trastorno de retraso de la fase del sueño y del despertar. Síndrome de retraso de fase / Delayed sleep wake phase disorder (DSWPD)

El trastorno de retraso de la fase del sueño y del despertar o síndrome de retraso de fase (SRF) es la alteración del ritmo circadiano de sueño más frecuente y suele manifestarse en la adolescencia. Se caracteriza por un retraso estable, habitualmente de más de dos horas, del inicio y del final del sueño respecto a los horarios convencionales. Clínicamente los pacientes presentan insomnio a la hora de acostarse, con gran dificultad para levantarse por la mañana en la hora deseada. Entre semana, debido a las obligaciones escolares o sociales, los niños con SRF duermen pocas horas, generándose una privación crónica de sueño que se manifestará con somnolencia diurna, fatiga, falta de atención, afectación del rendimiento escolar o absentismo escolar. Característicamente, el fin de semana o durante las vacaciones, cuando están libres de horarios, retrasan el sueño, siendo este de características normales y levantándose descansados. Es importante realizar un diagnóstico precoz para iniciar un tratamiento temprano que minimice las consecuencias del SRF. Por la imposibilidad de seguir unos horarios regulares de estudio ni de trabajo, son jóvenes a los que se califica de noctámbulos o de vagos, a pesar de sus esfuerzos repetidos por adaptarse a unos horarios convencionales, lo que aboca en altos índices de depresión, ansiedad y abuso de sustancias. El retraso de fase de sueño se confirma mediante las agendas de sueño, la actigrafía y los marcadores de fase circadianos. La higiene del sueño, la cronoterapia, la fototerapia y la administración de melatonina son los posibles tratamientos del SRF (AU)

Delayed sleep wake phase disorder (DSWPD) or delayed sleep phase disorder is the most frequent circadian rhythm sleep disorder and is commonly seen in adolescents. DSWPD is characterized by habitual by sleep onset and wake times that are usually delayed more than two hours relative to conventional sleep-wake times. Clinically, affected subjects experience difficulty falling asleep and arising at socially acceptable wake time. Enforced conventional wake times (during the school or working days), may result in chronically insufficient sleep manifested as excessive daytime sleepiness, fatigue, repetitive school absences with negative impact on their attention and academic performance. When allowed to follow their preferred schedule (during the weekends or vacation periods), the patient’s timing of sleep is delayed with normal and restoring sleep. It is very important to make an early diagnosis to initiate treatments that minimize consequences of DSWPD. Although their repetitive attempts to adapt to conventional times, their difficulties to maintain regular school or work timings leads these adolescents to be seen as lazy and not motivated, which usually results in an increase in mood disorders and drug abuse. Delay sleep phase is demonstrated by sleep log, actigraphy monitoring and in the timing of other circadian rhythms. Sleep hygiene, chronotherapy, bright light therapy or melatonin administration are the most habitual treatment of the DSWPD (AU)

Cognitive Behavioral Therapy as an Adjunct Treatment to Light Therapy for Delayed Sleep Phase Disorder in Young Adults: A Randomized Controlled Feasibility Study.

Delayed sleep phase disorder (DSPD) is common among young people, but there is still no evidence-based treatment available. In the present study, the feasibility of cognitive behavioral therapy (CBT) was evaluated as an additive treatment to light therapy (LT) in DSPD. A randomized controlled trial with participants aged 16 to 26 years received LT for two weeks followed by either four weeks of CBT or no treatment (NT). LT advanced sleep-wake rhythm in both groups. Comparing LT+CBT with LT+NT, no significant group differences were observed in the primary endpoints. Although anxiety and depression scores were low at pretreatment, they decreased significantly more in LT+CBT compared to LT+NT. The results are discussed and some suggestions are given for further studies.

Therapeutic strategies for circadian rhythm and sleep disturbances in Huntington disease.

Aside from the well-known motor, cognitive and psychiatric signs and symptoms, Huntington disease (HD) is also frequently complicated by circadian rhythm and sleep disturbances. Despite the observation that these disturbances often precede motor onset and have a high prevalence, no studies are available in HD patients which assess potential treatments. In this review, we will briefly outline the nature of circadian rhythm and sleep disturbances in HD and subsequently focus on potential treatments based on findings in other neurodegenerative diseases with similarities to HD, such as Parkinson and Alzheimer disease. The most promising treatment options to date for circadian rhythm and sleep disruption in HD include melatonin (agonists) and bright light therapy, although further corroboration in clinical trials is warranted.

[Circadian rhythm sleep disorders in psychiatric diseases]. / Störungen des Schlaf-Wach-Rhythmus bei psychiatrischen Erkrankungen.

Circadian rhythm sleep disorders are prevalent among psychiatric patients. This is most probable due to a close relationship between functional disturbances of the internal clock, sleep regulation and mental health. Mechanisms on molecular level of the circadian clock and neurotransmitter signalling are involved in the development of both disorders. Moreover, circadian disorders and psychiatric diseases favour each other by accessory symptoms such as stress or social isolation. Actimetry to objectively quantify the rest-activity cycle and salivary melatonin profiles as marker for the circadian phase help to diagnose circadian rhythm sleep disorders in psychiatric patients. Chronotherapeutics such as bright light therapy, dark therapy, melatonin administration, and wake therapy are used to synchronise and consolidate circadian rhythms and help in the treatment of depression and other psychiatric disorders, but are still neglected in medicine. More molecular to behavioural research is needed for the understanding of the development of circadian disorders and their relationship to psychiatric illnesses. This will help to boost the awareness and treatment of circadian rhythm sleep disorders in psychiatry.

Circadian molecular clocks and cancer.

Physiological processes such as the sleep-wake cycle, metabolism and hormone secretion are controlled by a circadian rhythm adapted to 24h day-night periodicity. This circadian synchronisation is in part controlled by ambient light decreasing melatonin secretion by the pineal gland and co-ordinated by the suprachiasmatic nucleus of the hypothalamus. Peripheral cell autonomous circadian clocks controlled by the suprachiasmatic nucleus, the master regulator, exist within every cell of the body and are comprised of at least twelve genes. These include the basic helix-loop-helix/PAS domain containing transcription factors; Clock, BMal1 and Npas2 which activate transcription of the periodic genes (Per1 and Per2) and cryptochrome genes (Cry1 and Cry2). Points of coupling exist between the cellular clock and the cell cycle. Cell cycle genes which are affected by the molecular circadian clock include c-Myc, Wee1, cyclin D and p21. Therefore the rhythm of the circadian clock and cancer are interlinked. Molecular examples exist including activation of Per2 leads to c-myc overexpression and an increased tumor incidence. Mice with mutations in Cryptochrome 1 and 2 are arrhythmic (lack a circadian rhythm) and arrhythmic mice have a faster rate of growth of implanted tumors. Epidemiological finding of relevance include 'The Nurses' Health Study' where it was established that women working rotational night shifts have an increased incidence of breast cancer. Compounds that affect circadian rhythm exist with attendant future therapeutic possibilities. These include casein kinase I inhibitors and a candidate small molecule KL001 that affects the degradation of cryptochrome. Theoretically the cell cycle and malignant disease may be targeted vicariously by selective alteration of the cellular molecular clock.

The effectiveness of light/dark exposure to treat insomnia in female nurses undertaking shift work during the evening/night shift.

STUDY OBJECTIVES: The present study investigated whether bright light exposure during the first half of the evening/night shift combined with light attenuation in the morning is effective in improving sleep problems in nurses undertaking rotating shift work who suffer from clinical insomnia. METHODS: This was a prospective, randomized control study. The Insomnia Severity Index (ISI) and the Hospital Anxiety Depression Scale (HADS) were used to evaluate insomnia and anxiety/depression severity, respectively. Female hospital nurses on rotating shifts during the evening or night shift with an ISI score > 14 were enrolled. Subjects in the treatment group (n = 46) were exposed to bright light at 7,000-10,000 lux for ≥ 30 minutes. Exposure was continued for at least 10 days during 2 weeks, and the subjects avoided daytime outdoor sun exposure after work by wearing dark sunglasses. Subjects in the control group (n = 46) were not exposed to bright light, but also wore sunglasses after work. Statistical analyses were performed to examine group differences and differences across treatments. RESULTS: After treatment, the treatment group showed significant improvements in the ISI score and the HADS total and subscale scores as compared with pre-treatment. The ISI, HADS, and subscales of the HADS scores were significantly improved across treatments in the treatment group as compared with the control group. CONCLUSIONS: The design of this study is easy to put into practice in the real world. This is the first study to document that a higher intensity and briefer duration of bright light exposure during the first half of the evening/night shift with a daytime darkness procedure performed in rotating shift work female nurses suffering from clinical insomnia could improve their insomnia, anxiety, and depression severity.

Brief morning light treatment for sleep/wake disturbances in older memory-impaired individuals and their caregivers.

BACKGROUND: Scheduled exposure to bright light (phototherapy) has been used, with varying degrees of success, to treat sleep disruption in older individuals. Most of these studies have been done in institutional settings and have used several hours of daily light exposure. Such a regimen in the home setting may be untenable, especially when the individual with the sleep disruption has memory impairment and is being cared for by a family member. As such, we examined the effectiveness of a "user-friendly" phototherapy protocol that would be readily usable in the home environment. METHODS: We exposed a group of 54 older caregiver/care recipient dyads, in which the care recipient had memory impairment, to two weeks of morning bright light phototherapy. Dyads were exposed to either bright white (∼4200 lux) or dim red (∼90 lux) light for 30 min every day, starting within 30 min of rising. All subjects also received sleep hygiene therapy. Objective (actigraphy) and subjective measures of sleep and mood were obtained at baseline and at the end of the two weeks of phototherapy. RESULTS: In care recipients, actigraphy- and log-determined time in bed and total sleep time declined in the active condition (p<0.05, ANOVA); there was no corresponding change in subjective insomnia symptoms (p's>0.37, ANOVA). The decrease in the time in bed was associated with an earlier out of bed time in the morning (p<0.001, Pearson correlation). The decrease in the total sleep time was associated with a decrease in sleep efficiency (p<0.001, Pearson correlation) and an increase in wake after sleep onset (p<0.001, Pearson correlation). In caregivers, there were no differential changes in actigraphic measures of sleep (p's>0.05, ANOVA). Actigraphy-measured wake after sleep onset and sleep efficiency did, however, improve in both conditions, as did sleepiness, insomnia symptoms, and depressive symptomatology (p's<0.05, ANOVA). CONCLUSIONS: Exposure to this regimen of phototherapy diminished sleep in older individuals with memory impairments. Their caregivers, however, experienced an improvement in sleep and mood that appeared independent of the phototherapy and likely due to participation in this protocol or the sleep hygiene therapy.

Circadian rhythm sleep disorder, free-running type in a sighted male with severe depression, anxiety, and agoraphobia.

Circadian rhythm sleep disorder, free-running type (CRSD, FRT) is a disorder in which the intrinsic circadian rhythm is no longer entrained to the 24-hour schedule. A unique case of CRSD, FRT in a 67-year-old sighted male is presented. The patient had a progressively delayed time in bed (TIB) each night, so that he would cycle around the 24-h clock approximately every 30 days. This was meticulously documented each night by the patient over the course of 22 years. The patient's CRSD, FRT was associated with severe depression, anxiety, and agoraphobia. The agoraphobia may have exacerbated the CRSD, FRT. Entrainment and stabilization of his circadian rhythm was accomplished after treatment that included melatonin, light therapy, and increased sleep structure.

Bilateral thalamic stroke transiently reduces arousals and NREM sleep instability.

The vascularization of the human thalami is supplied by many perforating arteries, which exhibit complex distribution and many possible individual variations. One rare variant is the artery of Percheron that supplies the paramedian thalami bilaterally. Its ictal occlusion may result in a symmetric paramedian infarction, which generally leads to impairment of consciousness associated with hypersomnia. Our aim is to describe in detail sleep-wake schedules, sleep structure and microstructure in a 68-year-old patient with occlusion of Percheron's artery. EEG monitoring, performed 24 h after the onset of symptoms, showed severe disruption of the sleep-wake cycle, with episodes of sleep and wakefulness recurring irregularly during day and night. Thalamic nuclei are part of the human arousal system; medial thalamic nuclei play a pivotal role in sleep regulation at different levels. A diagnosis of paramedian thalamic infarction should be considered in patients who present with recurrent episodes of unresponsiveness.