A Protocol to Determine Circadian Phase by At-Home Salivary Dim Light Melatonin Onset Assessment.

Internal circadian phase assessment is increasingly acknowledged as a critical clinical tool for the diagnosis, monitoring, and treatment of circadian rhythm sleep-wake disorders and for investigating circadian timing in other medical disorders. The widespread use of in-laboratory circadian phase assessments in routine practice has been limited, most likely because circadian phase assessment is not required by formal diagnostic nosologies, and is not generally covered by insurance. At-home assessment of salivary dim light melatonin onset (DLMO, a validated circadian phase marker) is an increasingly accepted approach to assess circadian phase. This approach may help meet the increased demand for assessments and has the advantages of lower cost and greater patient convenience. We reviewed the literature describing at-home salivary DLMO assessment methods and identified factors deemed to be important to successful implementation. Here, we provide specific protocol recommendations for conducting at-home salivary DLMO assessments to facilitate a standardized approach for clinical and research purposes. Key factors include control of lighting, sampling rate, and timing, and measures of patient compliance. We include findings from implementation of an optimization algorithm to determine the most efficient number and timing of samples in patients with Delayed Sleep-Wake Phase Disorder. We also provide recommendations for assay methods and interpretation. Providing definitive criteria for each factor, along with detailed instructions for protocol implementation, will enable more widespread adoption of at-home circadian phase assessments as a standardized clinical diagnostic, monitoring, and treatment tool.

Circannual seizure provocation as the day lengthens in the northern and southern hemispheres.

Circannual status epilepticus (SE) patterns in communities near Earth's poles best test the hypothesis that SE susceptibility varies with light exposure because these communities are routinely subject to large changes in annual light exposure, which may result in changes to daily sleep time. We compared northern hemispheric circannual SE occurrence in Kivalliq, Canada (latitude-62.8° N) to southern hemispheric Auckland, New Zealand (latitude-36.9° S). Instead of peaking at a similar calendar time, SE peaked at a similar solar time during the increasing daylight phase after each region's respective winter solstice. This demonstrates that cumulative effects of increasing light exposure can mediate SE susceptibility.

Quantifying the impact of the Philips recall on patients with sleep apnea and clinicians.

STUDY OBJECTIVES: Philips Respironics issued a voluntary recall of positive airway pressure devices used to treat obstructive sleep apnea in June 2021. We surveyed sleep medicine clinicians from the American Academy of Sleep Medicine membership to assess the impact of the recall on clinicians and patients. METHODS: One hundred thirty-six clinicians participated between June 2022 and November 2022. Participants reported their treatment recommendations for patients affected by the recall, their patients' behaviors regarding the recall, the recall's impact on them as clinicians and on their patients, and the approximate time their patients were waiting for a replacement device. RESULTS: Clinicians most commonly reported first learning about the recall from Philips (25.0%), and patients most commonly first heard about the recall from news sources (34.5%). Most clinicians (62.4%) reported that they recommended patients continue using a recalled device. In comparison, only 9.3% of clinicians reported encouraging patients to stop using their recalled device. Clinicians reported that 59.9% of patients continued treatment with their recalled device, whereas 26.5% stopped treatment. Clinicians reported that over one-third of their patients were still waiting for a replacement machine. Most (86.8%) clinicians reported their stress levels were affected due to the recall, and 91.5% of clinicians reported the recall affected their patients' health and well-being. Most (83.3%) clinicians reported the recall affected their patients' trust in medicine. CONCLUSIONS: Clinicians reported that the Philips recall impaired the vast majority of their patients' health and trust in medicine and that many patients were still waiting for replacement devices. CITATION: Robbins R, Epstein LJ, Pavlova MK, et al. Quantifying the impact of the Philips recall on patients with sleep apnea and clinicians. J Clin Sleep Med. 2023;19(9):1677-1683.

Objective Diagnosis of Circadian Rhythm Disorders.

SUMMARY: Circadian sleep-wake disorders are common. Because they represent conflict between the timing of the patient's endogenous rhythms and desired timing of sleep, the presenting complaints may include both difficulty of sleep initiation or maintenance and undesired or unplanned daytime or early evening sleepiness. Therefore, circadian disorders may be misdiagnosed as either a primary insomnia or a hypersomnia disorder, depending on which complaint is more troublesome for the patient. Objective information about sleep and wake patterns over long periods is crucial for accurate diagnosis. Actigraphy provides long-term information about the rest/activity pattern about an individual. However, caution should be applied in interpretation of the results because the information provided only includes information of movements, and activity is only an indirect circadian phase marker. Timing of light and melatonin therapy is critical for successful treatment of circadian rhythm disorders. Therefore, results of actigraphy are useful and should be used in conjunction with additional measurements, including 24 hours sleep-wake history, sleep log, and melatonin measurements.

Sleep apnea phenotyping and relationship to disease in a large clinical biobank.

OBJECTIVE: Sleep apnea is associated with a broad range of pathophysiology. While electronic health record (EHR) information has the potential for revealing relationships between sleep apnea and associated risk factors and outcomes, practical challenges hinder its use. Our objectives were to develop a sleep apnea phenotyping algorithm that improves the precision of EHR case/control information using natural language processing (NLP); identify novel associations between sleep apnea and comorbidities in a large clinical biobank; and investigate the relationship between polysomnography statistics and comorbid disease using NLP phenotyping. MATERIALS AND METHODS: We performed clinical chart reviews on 300 participants putatively diagnosed with sleep apnea and applied International Classification of Sleep Disorders criteria to classify true cases and noncases. We evaluated 2 NLP and diagnosis code-only methods for their abilities to maximize phenotyping precision. The lead algorithm was used to identify incident and cross-sectional associations between sleep apnea and common comorbidities using 4876 NLP-defined sleep apnea cases and 3× matched controls. RESULTS: The optimal NLP phenotyping strategy had improved model precision (≥0.943) compared to the use of one diagnosis code (≤0.733). Of the tested diseases, 170 disorders had significant incidence odds ratios (ORs) between cases and controls, 8 of which were confirmed using polysomnography (n = 4544), and 281 disorders had significant prevalence OR between sleep apnea cases versus controls, 41 of which were confirmed using polysomnography data. DISCUSSION AND CONCLUSION: An NLP-informed algorithm can improve the accuracy of case-control sleep apnea ascertainment and thus improve the performance of phenome-wide, genetic, and other EHR analyses of a highly prevalent disorder.

Circannual incidence of seizure evacuations from the Canadian Arctic.

OBJECTIVES: Emerging evidence suggests that circadian rhythms affect seizure propensity in addition to, and possibly independent of, sleep-wake states. Subject to extreme seasonal changes in light and dark, the northerly Arctic can serve as a "natural experiment" to assess the real-life impact of environmental influences on seizure severity. Therefore, we evaluated the timing of seizure evacuations over 11.25 years in a well-defined region of the Canadian Arctic. METHODS: Retrospective review of EEG database and patient records at the single "bottleneck" hospital to which all patients from the Kivalliq Region in Nunavut, Canada are evacuated for seizure emergencies. We calculated the mean resultant length (MRL) of circular data for circannual analysis, and conducted Rayleigh's test to assess for a statistical departure from circular uniformity. RESULTS: Screening 40,392 EEGs, we found 117 medical evacuations from 99 distinct individuals from September 2009 to November 2020. Most evacuations occurred month-wise in May (19%); week-wise within a 7-day period in February (5%), June (5%), or November (5%); and day-wise within a 24-hour period in June (3%) or November (3%). Maximal MRL clustering occurred in April no matter if analyzed by day (0.16333, p = 0.04), week (0.16296, p = 0.04), or month (0.1736, p = 0.03). CONCLUSIONS: A relative circannual increase in seizure evacuations between the winter and summer solstices may be related to increasing sleep loss when day length grows. Fewer evacuations between the summer and winter solstices may be related to decreased daylight and "catching up" on sleep when night length grows. Additional factors likely also play a role in circannual variation of seizure evacuations in the Arctic, which warrants further research.

Evaluation and Management of First-Time Seizure in Adults.

First seizures are often perceived as devastating events by patients and their families due to the fear of having a life-long disease. One in 10 people experiences one or more seizures during their lifetime, while 1 in 26 people develops epilepsy. Acute symptomatic seizures are often related to a provoking factor or an acute brain insult and typically do not recur. Careful history and clinical examination should guide clinicians' management plans. Electroencephalography and brain imaging, preferably with epilepsy-specific magnetic resonance imaging, may help characterize both etiology and risk of seizure recurrence. Antiepileptic drugs should be initiated in patients with newly diagnosed epilepsy. In patients without an epilepsy diagnosis, the decision to prescribe drugs depends on individual risk factors for seizure recurrence and possible complications from seizures, which should be discussed with the patient. Counseling about driving and lifestyle modifications should be provided early, often at the first seizure encounter.

Proceedings of the Sleep and Epilepsy Workgroup: Section 2 Comorbidities: Sleep Related Comorbidities of Epilepsy.

Epilepsy is a chronic disease with multiple, complex comorbidities. Bidirectional relationships exist among seizures, sleep, circadian rhythms, and diseases within and outside of the central nervous system. Seizures fragment sleep and can contribute to development of sleep disorders, which in turn leads to worse overall health and more seizures. Moreover, treatment options are often limited by interactions with anti-seizure medications. Advances in the fields of epilepsy and in sleep medicine have been made separately, and therefore treating patients with these comorbidities necessitates interdisciplinary approach. The focus of this section of the Sleep and Epilepsy Workgroup was to identify methods of collaboration and outline investigational, educational, and treatment priorities to mutually advance what we consider a combined field.

Proceedings of the Sleep and Epilepsy Workshop: Section 3 Mortality: Sleep, Night, and SUDEP.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Likely pathophysiological mechanisms include seizure-induced cardiac and respiratory dysregulation. A frequently identified feature in SUDEP cases is that they occur at night. This raises the question of a role for sleep state in regulating of SUDEP. An association with sleep has been identified in a number of studies with patients and in animal models. The focus of this section of the Sleep and Epilepsy Workshop was on identifying and understanding the role for sleep and time of day in the pathophysiology of SUDEP.

Proceedings of the Sleep and Epilepsy Workshop: Section 1 Decreasing Seizures-Improving Sleep and Seizures, Themes for Future Research.

Epileptic seizures, sleep, and circadian timing share bilateral interactions, but concerted work to characterize these interactions and to leverage them to the advantage of patients with epilepsy remains in beginning stages. To further the field, a multidisciplinary group of sleep physicians, epileptologists, circadian timing experts, and others met to outline the state of the art, gaps of knowledge, and suggest ways forward in clinical, translational, and basic research. A multidisciplinary panel of experts discussed these interactions, centered on whether improvements in sleep or circadian rhythms improve decrease seizure frequency. In addition, education about sleep was lacking in among patients, their families, and physicians, and that focus on education was an extremely important "low hanging fruit" to harvest. Improvements in monitoring technology, experimental designs sensitive to the rigor required to dissect sleep versus circadian influences, and clinical trials in seizure reduction with sleep improvements were appropriate.

Sleep assessment by means of a wrist actigraphy-based algorithm: agreement with polysomnography in an ambulatory study on older adults.

The purpose of the present work is to examine, on a clinically diverse population of older adults (N = 46) sleeping at home, the performance of two actigraphy-based sleep tracking algorithms (i.e., Actigraphy-based Sleep algorithm, ACT-S1 and Sadeh's algorithm) compared to manually scored electroencephalography-based PSG (PSG-EEG). ACT-S1 allows for a fully automatic identification of sleep period time (SPT) and within the identified sleep period, the sleep-wake classification. SPT detected by ACT-S1 did not differ statistically from using PSG-EEG (bias = -9.98 min; correlation 0.89). In sleep-wake classification on 30-s epochs within the identified sleep period, the new ACT-S1 presented similar or slightly higher accuracy (83-87%), precision (86-89%) and F1 score (90-92%), significantly higher specificity (39-40%), and significantly lower, but still high, sensitivity (96-97%) compared to Sadeh's algorithm, which achieved 99% sensitivity as the only measure better than ACT-S1's. Total sleep times (TST) estimated with ACT-S1 and Sadeh's algorithm were higher, but still highly correlated to PSG-EEG's TST. Sleep quality metrics of sleep period efficiency and wake-after-sleep-onset computed by ACT-S1 were not significantly different from PSG-EEG, while the same sleep quality metrics derived by Sadeh's algorithm differed significantly from PSG-EEG. Agreement between ACT-S1 and PSG-EEG reached was highest when analyzing the subset of subjects with least disrupted sleep (N = 28). These results provide evidence of promising performance of a full-automation of the sleep tracking procedure with ACT-S1 on older adults. Future longitudinal validations across specific medical conditions are needed. The algorithm's performance may further improve with integrating multi-sensor information.

Objectively measured sleep-wake patterns in patients with drug-resistant epilepsy - Interaction with quality of life and antiepileptic treatment.

RATIONALE: Patients with epilepsy experience frequent episodes of fragmented sleep which may contribute to chronic sleep loss. Enhancing sleep patterns might lead to improved quality of life in these patients. Currently, unlike some other antiepileptic drugs (AEDs), there are no data on the effects of clobazam, a novel AED on sleep. Therefore, we tested the hypothesis that patients with epilepsy will have longer, more consolidated sleep after treatment with clobazam. METHODS: In this prospective study, we included adults with drug-resistant epilepsy who were being considered for treatment with clobazam. Patients with known untreated moderate/severe sleep apnea or with major circadian rhythm disorders were excluded. We tested a set of the following subjective sleep measures: Pittsburgh Sleep Quality Inventory (PSQI), Epworth Sleepiness Scale (ESS), Karolinska Sleepiness Scale (KSS), Insomnia Severity Index (ISI), and Quality of Life in Epilepsy (QOLIE) prior to starting the treatment, as well as after achieving a stable clobazam dose. We also measured sleep pattern using wrist actigraphy - before starting therapy and after achieving stable dose. RESULTS: A total of 12 participants completed all parts of the study. After treatment, a lower number of awakenings and less wake after sleep onset (WASO) were seen, as well as a lower number of seizures. Average pretreatment bedtime was 23:45, and average wake time was 8:24. A higher seizure frequency significantly correlated with all subjective sleep measures, as well as with a higher amount actigraphy measured WASO and less total sleep time (TST) measured both by sleep log and by actigraphy. Those with higher baseline WASO by actigraphy also had more depressive symptoms, worse quality of life, longer duration of epilepsy, and a higher seizure frequency. CONCLUSION: Both objective and subjective sleep metrics correlate with depressive symptoms and quality of life. After treatment, there were fewer awakenings as well as fewer seizures.

Circadian-Like Rhythmicity of Extracellular Brain Glutamate in Epilepsy.

Seizures often exhibit striking circadian-like (~24-h) rhythms. While chronotherapy has shown promise in treating epilepsy, it is not widely used, in part because the patterns of seizure rhythmicity vary considerably among patients and types of epilepsy. A better understanding of the mechanisms underlying rhythmicity in epilepsy could be expected to result in more effective approaches which can be tailored to each individual patient. The excitatory neurotransmitter glutamate is an essential modulator of circadian rhythms, and changes in the extracellular levels of glutamate likely affect the threshold to seizures. We used a reverse translational rodent model of mesial temporal lobe epilepsy (MTLE) combined with long-term intracerebral microdialysis to monitor the hourly concentrations of glutamate in the seizure onset area (epileptogenic hippocampus) over several days. We observed significant 24-h oscillations of extracellular glutamate in the epileptogenic hippocampus (n = 4, JTK_CYCLE test, p < 0.05), but not in the hippocampus of control animals (n = 4). To our knowledge, circadian glutamate oscillations have not been observed in a seizure onset region, and we speculate that the oscillations contribute to the rhythmicity of seizures in MTLE.

Prevalence and correlates of periodic limb movements in OSA and the effect of CPAP therapy.

OBJECTIVE: We sought to assess the prevalence, correlates, and consequences of periodic limb movements of sleep (PLMS) in persons with obstructive sleep apnea (OSA) and the effect (worsening or improvement) of continuous positive airway pressure (CPAP) therapy on PLMS in a large prospective multicenter randomized controlled trial. METHODS: We performed retrospective analyses of data from the Apnea Positive Pressure Long-term Efficacy Study, a prospective multicenter randomized controlled trial. A total of 1,105 persons with OSA enrolled in this study underwent a polysomnographic investigation at baseline, another one for CPAP titration, and another study 6 months after randomization to either active CPAP or sham CPAP. RESULTS: Of all participants, 19.7% had PLM index (PLMI) ≥10/hour, 14.8% had PLMI ≥15/hour, 12.1% had PLMI ≥20/hour, 9.3% had PLMI ≥25/hour, and 7.5% had PLMI ≥30/hour. The odds of having a PLMI ≥10 were higher in older participants (odds ratio [OR] 1.03, p < 0.001), men (OR 1.63. p = 0.007), those using antidepressants (OR 1.48. p = 0.048), and those with higher caffeine use (OR 1.01, p = 0.04). After controlling for OSA and depression, PLMS were associated with increased sleep latency, reduced sleep efficiency, and reduced total sleep time. No significant relationships were noted between PLMS frequency and subjective sleepiness (Epworth Sleepiness Scale score) or objective sleepiness (Maintenance of Wakefulness Test). There was no differential effect of CPAP in comparison to sham CPAP on PLMS after 6 months of therapy. CONCLUSIONS: PLMS are common in patients with OSA and are associated with a significant reduction in sleep quality over and above that conferred by OSA. Treatment with CPAP does not affect the severity of PLMS.

Novel non-pharmacological insomnia treatment - a pilot study.

OBJECTIVE: The objective of this prospective pilot study was to examine the effects of a novel non-pharmacological device (BioBoosti) on insomnia symptoms in adults. METHODS: Subjects with chronic insomnia were instructed to hold the device in each hand for 8 mins for 6 cycles on a nightly basis for 2 weeks. Outcomes tested included standardized subjective sleep measures assessing sleep quality, insomnia symptoms, and daytime sleepiness. Sleep was objectively quantified using electroencephalogram (EEG) before and after 2 weeks of treatment with BioBoosti, and wrist actigraphy throughout the study. RESULTS: Twenty adults (mean age: 45.6±17.1 y/o; range 18-74 y/o) were enrolled in the study. No significant side effects were noted by any of the subjects. After 2 weeks of BioBoosti use, subjects reported improved sleep quality (Pittsburgh Sleep Quality Index: 12.6±3.3 versus 8.5±3.7, p=0.001) and reduced insomnia symptoms (Insomnia Severity Index: 18.2±5.2 versus 12.8±7.0, p<0.001). Sleepiness, as assessed by a visual analog scale, was significantly reduced after treatment (5.7±2.8 versus 4.0±3.3, p=0.03). CONCLUSION: BioBoosti use yielded an improvement in insomnia symptoms. Larger placebo-controlled studies are needed to fully assess efficacy.

Lack of change in glucose metabolism in eszopiclone-treated primary insomnia patients.

STUDY OBJECTIVES: Primary insomnia (PI) may increase diabetes risk. We tested the hypothesis that the effects of PI on glucose metabolism could be improved by 2 months of pharmacological treatment. METHODS: Adult men and women meeting clinical criteria for PI were studied (n=20, body mass index 25.1±2.7 kg/m2, age 39.7±7.9) in a randomized, double-blind, placebo-controlled clinical trial. The study consisted of two 1-day inpatient admissions to a General Clinical Research Center separated by 2 months of at-home treatment with 3 mg eszopiclone or placebo. During inpatient admissions, each subject underwent two intravenous glucose tolerance tests (IVGTTs) pre- and post-treatment. Diet was controlled for micro- and macro-nutrient content and calories on the day prior to pre- and post-treatment IVGTTs. Subjects were randomized following completion of the initial IVGTT to take either placebo or eszopiclone 30 min prior to bedtime at home for 2 months. RESULTS: Two-month eszopiclone treatment did not change insulin sensitivity, glucose tolerance, or any of the sleep measures significantly, compared with placebo. Changes in glycated hemoglobin (HbA1c, clinical measure of glycemic control) were correlated with changes in diary-reported total sleep time in the eszopiclone group (r=0.66, p=0.0360), and in the combined groups' data (r=0.55, p=0.0125). Changes in polysomnography-measured wake after sleep onset, a hallmark of PI, were positively related to changes in IVGTT-derived glucose effectiveness, or non-insulin-mediated glucose uptake. CONCLUSION: Treatment with 3 mg eszopiclone for 2 months, compared with placebo, did not significantly influence either sleep or measures of diabetes risk in this preliminary study.

Sleep-dependent memory consolidation in the epilepsy monitoring unit: A pilot study.

OBJECTIVE: We sought to examine whether patients with focal epilepsy exhibit sleep dependent memory consolidation, whether memory retention rates correlated with particular aspects of sleep physiology, and how the process was affected by seizures. METHODS: We prospectively recruited patients with focal epilepsy and assessed declarative memory using a task consisting of 15 pairs of colored pictures on a 5×6 grid. Patients were tested 12h after training, once after 12h of wakefulness and once after 12h that included sleep. EMG chin electrodes were placed to enable sleep scoring. The number and density of sleep spindles were assessed using a wavelet-based algorithm. RESULTS: Eleven patients were analyzed age 21-56years. The percentage memory retention over 12h of wakefulness was 62.7% and over 12h which included sleep 83.6% (p=0.04). Performance on overnight testing correlated with the duration of slow wave sleep (SWS) (r=+0.63, p<0.05). Three patients had seizures during the day, and 3 had nocturnal seizures. Day-time seizures did not affect retention rates, while those patients who had night time seizures had a drop in retention from an average of 92% to 60.5%. CONCLUSIONS: There is evidence of sleep dependent memory consolidation in patients with epilepsy which mostly correlates with the amount of SWS. Our preliminary findings suggest that nocturnal seizures likely disrupt sleep dependent memory consolidation. SIGNIFICANCE: Findings highlight the importance of SWS in sleep dependent memory consolidation and the adverse impact of nocturnal seizures on this process.

Sleep in psychogenic nonepileptic seizures and related disorders.

Psychogenic nonepileptic seizures (PNES), a form of functional neurological symptom disorder (FNSD), are very rarely seen in genuine, electroencephalography (EEG)-confirmed sleep. However, they are more commonly reported as a nocturnal occurrence, likely from a state that is misidentified as sleep (termed by some as "pseudosleep"). Sleep state can be helpful to distinguish FNSD from other neurological disorders. Pseudo-cataplexy, a form of "psychogenic" narcolepsy, "pseudo-parasomnia" and PNES can have a similar presentation. PNES and posttraumatic stress disorder (PTSD) frequently share previously experienced psychological trauma, and therefore the sleep abnormalities found in PTSD may be similarly present in PNES. Future research should use EEG monitoring to evaluate the sleep physiology of patients with FNSD such as PNES, as insights into sleep abnormalities may enable further understanding of the etiology and manifestations of PNES.