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Sleep Dec 2014Forty-one percent of shift workers report dozing while driving. This study tested whether armodafinil improves driving simulator performance in subjects with shift work... (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY OBJECTIVES
Forty-one percent of shift workers report dozing while driving. This study tested whether armodafinil improves driving simulator performance in subjects with shift work disorder (SWD). A primary outcome was performance late in the shift when workers are typically driving home.
DESIGN
Randomized, double-blind, crossover. During each 12-h test session (21:30-09:30), subjects were kept awake except for multiple sleep latency testing (MSLT: 01:30, 03:30, 05:30, and 07:30). Subjective sleepiness (Karolinska Sleepiness Scale, KSS), driving performance, and cognitive performance (digit symbol substitution test and creativity on the Remote Associates Test, RAT) were evaluated during the night shift and commute home times.
SETTING
Hospital-based sleep research laboratory.
PARTICIPANTS
Twenty night workers (age: 42.7 ± 8.7 y, 17 F) with excessive sleepiness (≥ 10 on the Epworth Sleepiness Scale), meeting International Classification of Sleep Disorders, Second Edition (ICSD-2) criteria for SWD, and having no other medical conditions.
INTERVENTIONS
Armodafinil (150 mg) or placebo at (23:45 h) on counterbalanced nights separated by 7-14 days.
MEASUREMENT AND RESULTS
Primary endpoints were driving simulator performance (standard deviation of lateral position (SDLP) and off-road deviations) with four sessions starting 3.25 h after drug administration, objective sleepiness (MSLT; 1.75 to 7.75 h post-drug), and creativity (5 h post-drug). Significant effects of drug were observed for each driving measure (P < 0.05). Armodafinil significantly improved SDLP for simulator sessions at 05:30, 07:30, and 09:30, and off-road deviations at 7 h, 15 min and 9 h, 15 min post-drug (P < 0.05). Armodafinil also improved objective sleepiness from 3.7 ± 0.6 min to 9.7 ± 5.2 min (P < 0.001) and RAT score from 8.75 ± 4.9 to 11.25 ± 6.0 (P < 0.005).
CONCLUSIONS
Armodafinil 150 mg early in the night shift improves driving simulator performance in SWD. Effects on sleepiness, cognition, and driving were found up to 9.5 h post-ingestion, during the critical time when many night workers are driving home.
Topics: Adult; Attention; Automobile Driving; Benzhydryl Compounds; Cognition; Creativity; Cross-Over Studies; Disorders of Excessive Somnolence; Double-Blind Method; Female; Humans; Male; Middle Aged; Modafinil; Motor Skills; Sleep Disorders, Circadian Rhythm; Sleep Stages; Wakefulness; Wakefulness-Promoting Agents
PubMed: 25325498
DOI: 10.5665/sleep.4256 -
CNS Drugs Apr 2022Sodium oxybate has been recognized as a gold standard for the treatment of disrupted nighttime sleep due to narcolepsy. Its short half-life and immediate-release... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sodium oxybate has been recognized as a gold standard for the treatment of disrupted nighttime sleep due to narcolepsy. Its short half-life and immediate-release formulation require patients to awaken 2.5-4 h after their bedtime dose to take a second dose. A novel extended-release, once-nightly sodium oxybate formulation (ON-SXB; FT218) is under US Food and Drug Administration review for the treatment of adults with narcolepsy.
OBJECTIVE
A phase III trial of ON-SXB in individuals with narcolepsy type 1 (NT1) or 2 (NT2) [the REST-ON trial; NCT02720744] has been conducted and the primary results reported elsewhere. Secondary objectives from REST-ON were to assess the efficacy of ON-SXB on disrupted nighttime sleep; the results of this analysis are reported here.
METHODS
In the double-blind, phase III REST-ON trial, patients aged ≥ 16 years were randomly assigned 1:1 to ON-SXB (1 week, 4.5 g; 2 weeks, 6 g; 5 weeks, 7.5 g; 5 weeks, 9 g) or placebo. Secondary endpoints included polysomnographic measures of sleep stage shifts and nocturnal arousals and patient-reported assessments of sleep quality and refreshing nature of sleep at 6, 7.5, and 9 g; post hoc analyses included changes in time spent in each sleep stage, delta power, and assessments in stimulant-use subgroups for prespecified endpoints.
RESULTS
In total, 190 participants (n = 97, ON-SXB; n = 93, placebo) were included in the efficacy analyses. All three ON-SXB doses demonstrated a clinically meaningful, statistically significant decrease vs placebo in the number of transitions to wake/N1 from N1, N2, and rapid eye movement (REM) stages (all doses p < 0.001) and the number of nocturnal arousals (p < 0.05 ON-SXB 6 g; p < 0.001 7.5 and 9 g). Sleep quality and refreshing nature of sleep were significantly improved with all three ON-SXB doses vs placebo (p < 0.001). Post hoc analyses revealed a significant reduction in time spent in N1 (p < 0.05 ON-SXB 6 g; p < 0.001 7.5 and 9 g) and REM (all p < 0.001) and increased time spent in N3 with ON-SXB vs placebo (all p < 0.001), with a significant increase in delta power (p < 0.01 ON-SXB 6 g; p < 0.05 7.5 g; p < 0.001 9 g) and increased REM latency (ON-SXB 7.5 g vs placebo; p < 0.05). Significant improvements in disrupted nighttime sleep were observed regardless of concomitant stimulant use.
CONCLUSIONS
The clinically beneficial, single nighttime dose of ON-SXB significantly improved disrupted nighttime sleep in patients with narcolepsy.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov NCT02720744.
Topics: Adult; Humans; Narcolepsy; Polysomnography; Sleep; Sleep Stages; Sodium Oxybate
PubMed: 35380374
DOI: 10.1007/s40263-022-00904-6 -
Irish Journal of Medical Science Aug 2022Patients with adrenal insufficiency (AI) are treated with glucocorticoid replacement therapy (GRT). Although current glucocorticoid regimens aim to mimic the...
BACKGROUND
Patients with adrenal insufficiency (AI) are treated with glucocorticoid replacement therapy (GRT). Although current glucocorticoid regimens aim to mimic the physiological circadian rhythm of cortisol secretion, temporary phases of hypo- and hypercortisolism are common undesired effects which lead to a variety of consequences like increased cardiovascular risk and premature mortality. Additionally, poor quality of life (QoL) and impaired sleep have been reported. However, little is known about these topics regarding the effects of daily dosage, duration of therapy, and patients with different forms of AI (primary, PAI, and secondary, SAI).
METHODS
In this study, 40 adults with AI substituted with hydrocortisone (HC) and 20 matched healthy controls completed questionnaires evaluating depressive symptoms, subjective health status, quality of sleep and daytime sleepiness. Furthermore, demographic data, dosage of HC, duration of therapy and co-medication were evaluated. Patients were compared in different groups.
RESULTS
Patients assessed general health significantly worse than controls; likewise, daytime sleepiness was reported significantly more often. Depressive symptoms differed significantly in the two groups but did not reach clinically relevant scores. There was no difference between patients with PAI and SAI. High dosage of hydrocortisone had negative impact on mental health but not on sleep quality or daytime sleepiness.
CONCLUSIONS
The present data highlight that poor QoL and impaired sleep are still severe and underrated issues in current GRT and might be additional factors for premature mortality in patients with AI. Some AI patients reach normal or near-normal self-assessed QoL and sleep, even despite unphysiological replacement.
Topics: Adrenal Insufficiency; Adult; Disorders of Excessive Somnolence; Glucocorticoids; Humans; Hydrocortisone; Quality of Life; Sleep
PubMed: 34389925
DOI: 10.1007/s11845-021-02731-y -
Journal of Thoracic Disease Jan 2018Excessive daytime sleepiness (EDS) is a complaint common to many aspects of medicine. There are primary and secondary causes for EDS, with secondary causes including a...
BACKGROUND
Excessive daytime sleepiness (EDS) is a complaint common to many aspects of medicine. There are primary and secondary causes for EDS, with secondary causes including a large number of common conditions. Primary causes, such as narcolepsy, are much rarer. When assessing for primary hypersomnia, restricted or fragmented sleep must be ruled out. This process involves assessment of sleeping habits using a sleep diary and/or actigraphy. Clinicians are suspicious of the accuracy with which patients use the former. This review aims to evaluate the accuracy of a sleep diary study against the 'objective gold standard' actigraphy report.
METHODS
Data from 35 patients at a Sleep Disorder Centre who underwent both a sleep diary and actigraphy study for suspected primary hypersomnia in 2016 was collected. Mean values of four variables were calculated: 'time of lights out', 'time to fall asleep', 'time of waking' and 'sleep time'. The 'similarity' was assessed. This was a term defined in three different ways: if sleep diary values are accurate to within 20, 30 and 60 min respectively. Percentage 'similarity', mean time differences and standard deviations (SDs) were calculated for each variable. A paired -test was also performed to assess the significance of the time differences between the two modalities.
RESULTS
Least accurate was 'sleep time', with 14.7%, 23.5% and 58.8% of patients within 20, 30 and 60 min of the actigraphy respectively. Mean time difference for this variable was 66 min (versus 33, 15 and 22). 'Time to fall asleep' was most accurate, with 76.5%, 82.4% and 100% 'similarity' respectively.
CONCLUSIONS
The clinically acceptable accuracy has no universal definition, so clinicians must use experience and reasoning to determine this level to interpret this data. The review suggests that some variables are entered with high accuracy, and the diary is low cost and adds subjective information that cannot be gathered from actigraphy. Therefore, use is recommended to continue alongside actigraphy.
PubMed: 29445542
DOI: 10.21037/jtd.2017.12.127 -
Frontiers in Psychiatry 2023Hypersomnia poses major challenges to treatment providers given the limitations of available treatment options. In this context, the application of non-invasive brain...
Single sessions of transcranial direct current stimulation and transcranial random noise stimulation exert no effect on sleepiness in patients with narcolepsy and idiopathic hypersomnia.
BACKGROUND
Hypersomnia poses major challenges to treatment providers given the limitations of available treatment options. In this context, the application of non-invasive brain stimulation techniques such as transcranial electrical stimulation (tES) may open up new avenues to effective treatment. Preliminary evidence suggests both acute and longer-lasting positive effects of transcranial direct current stimulation (tDCS) on vigilance and sleepiness in hypersomniac patients. Based on these findings, the present study sought to investigate short-term effects of single sessions of tDCS and transcranial random noise stimulation (tRNS) on sleepiness in persons suffering from hypersomnia.
METHODS
A sample of 29 patients suffering from narcolepsy or idiopathic hypersomnia (IH) was recruited from the Regensburg Sleep Disorder Center and underwent single sessions of tES (anodal tDCS, tRNS, sham) over the left and right dorsolateral prefrontal cortex on three consecutive days in a double-blind, sham-controlled, pseudorandomized crossover trial. The primary study endpoint was the mean reaction time measured by the Psychomotor Vigilance Task (PVT) before and directly after the daily tES sessions. Secondary endpoints were additional PVT outcome metrics as well as subjective outcome parameters (e.g., Karolinska Sleepiness Scale; KSS).
RESULTS
There were no significant treatment effects neither on objective (i.e., PVT) nor on subjective indicators of sleepiness.
CONCLUSION
We could not demonstrate any clinically relevant effects of single sessions of tDCS or tRNS on objective or subjective measures of sleepiness in patients with hypersomnia. However, we cannot exclude that repeated sessions of tES may affect vigilance or sleepiness in hypersomniac patients.
PubMed: 38146280
DOI: 10.3389/fpsyt.2023.1288976 -
Sleep Medicine Sep 2023Psychiatric symptoms and cognitive deficits add significantly to impairment in academic achievement and quality of life in patients with narcolepsy. The primary aim of...
OBJECTIVE/BACKGROUND
Psychiatric symptoms and cognitive deficits add significantly to impairment in academic achievement and quality of life in patients with narcolepsy. The primary aim of this study was to evaluate the prevalence of psychiatric disorders and executive dysfunctions, secondly to explore the association between psychiatric comorbidity, executive dysfunctions, subjective and objective sleep measures, and severity of cerebrospinal fluid (CSF) hypocretin-1 deficiency in pediatric narcolepsy type 1 (PNT1).
PATIENTS/METHODS
Cross-sectional study of 59 consecutively included PNT1 patients (age: 6-20 years; 34:25 girls: boys; 54/59 H1N1 (Pandemrix®)-vaccinated). Core narcolepsy symptoms including subjective sleepiness, polysomnography and multiple sleep latency test results, CSF hypocretin-1 levels, psychiatric disorders (by semistructured diagnostic interview Kaufmann Schedule for Affective Disorders and Schizophrenia Present and Lifetime version (KSADS)), and executive dysfunction (by Behavior Rating of Executive Function (BRIEF)) were assessed.
RESULTS
52.5% of the patients had one or more psychiatric comorbid disorder, and 64.7% had executive dysfunction in a clinically relevant range, with no sex difference in prevalence, while older age was associated with poorer executive function (p=0.013). Having any psychiatric comorbid disorder was associated with poorer executive functions (p=0.001). CSF hypocretin-1 deficiency severity was significantly associated with presence of psychiatric comorbidity (p=0.022) and poorer executive functions (p=0.030), and poorer executive functions was associated with subjective sleepiness (p=0.009).
CONCLUSIONS
The high occurrence of, and association between, psychiatric comorbidity and executive dysfunction underlines the importance of close attention to both these comorbidities in clinical care of NT1.
Topics: Male; Female; Humans; Child; Adolescent; Young Adult; Adult; Orexins; Sleepiness; Cross-Sectional Studies; Influenza A Virus, H1N1 Subtype; Quality of Life; Narcolepsy
PubMed: 37442017
DOI: 10.1016/j.sleep.2023.06.021 -
PloS One 2022For the past few years, only a few monovalent EV71 vaccines have been developed, while other enterovirus vaccines are in short supply. We conducted a quantitative... (Meta-Analysis)
Meta-Analysis
BACKGROUND
For the past few years, only a few monovalent EV71 vaccines have been developed, while other enterovirus vaccines are in short supply. We conducted a quantitative meta-analysis to explore the epidemiological characteristics, routine laboratory diagnosis, clinical signs and risk factors for hand, foot and mouth disease (HFMD).
METHODS
PubMed, Embase and the Web of Science were searched for eligible reports published before April 16, 2021, with no publication time or language restrictions. The primary outcome was the odds ratio of the epidemiological characteristics, routine laboratory diagnosis, and clinical signs associated with HFMD severity and death.
RESULTS
After screening 10522 records, we included 32 articles comprising 781903 cases of hand, foot and mouth disease. Patients with severe illness developed some clinical signs (hypersomnia (OR = 21.97, 95% CI: 4.13 to 116.74), convulsion (OR = 16.18, 95% CI: 5.30 to 49.39), limb shaking (OR = 47.96, 95% CI: 15.17 to 151.67), and breathlessness (OR = 7.48, 95% CI: 1.90 to 29.40)) and had some changes in laboratory parameters (interleukin-6 levels standardized mean difference (SMD) = 1.57, 95%CI: 0.55 to 2.60), an increased neutrophils ratio (SMD = 0.55, 95%CI: 0.17 to 0.93), cluster of differentiation 4 (CD4+) (SMD = -1.38, 95%CI: -2.33 to -0.43) and a reduced lymphocytes ratio (SMD = -0.48, 95%CI: -0.93 to -0.33)) compared with patients with mild illness. The risk factors for death included cyanosis (OR = 5.82, 95% CI: 2.29 to 14.81), a fast heart rate (OR = 3.22, 95% CI: 1.65 to 6.30), vomiting (OR = 2.70, 95% CI: 1.33 to 5.49) and an increased WBC count (SMD = 0.60, 95% CI: 0.27 to 0.93).
CONCLUSIONS
China has the highest incidence of HFMD. Our meta-analyses revealed important risk factors that are associated with the severity and mortality of HFMD.
Topics: Blood Coagulation Tests; Enterovirus A, Human; Hand, Foot and Mouth Disease; Humans; Mouth Diseases; Risk Factors
PubMed: 35482791
DOI: 10.1371/journal.pone.0267716 -
BMC Psychiatry Feb 2022The histamine H3 receptor has emerged as one of the most promising targets of novel pharmacotherapy for narcolepsy. Studies now aim to investigate the optimal dose of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The histamine H3 receptor has emerged as one of the most promising targets of novel pharmacotherapy for narcolepsy. Studies now aim to investigate the optimal dose of enerisant, a novel H3 antagonist/inverse agonist, for the treatment of excessive daytime sleepiness in patients with narcolepsy.
METHODS
We conducted two phase 2, fixed-dose, double-blind, randomized, placebo-controlled trials in patients with narcolepsy. The first phase 2 study (Study 1) was conducted to investigate the efficacy and safety of enerisant at dosages of 25, 50, and 100 mg/day administered for 3 weeks based on the results of a phase 1 study conducted on healthy volunteers. The primary endpoint was mean sleep latency in maintenance of wakefulness test (MWT), and the secondary endpoint was the total score on the Epworth Sleepiness Scale (ESS). The dosages of enerisant in the second phase 2 study (Study 2) were set at 5 and 10 mg/day based on the simulation of receptor occupancy results from positron emission tomography study.
RESULTS
Forty-six and fifty-three patients were randomized in Study 1 and Study 2, respectively. The efficacy of enerisant was partially confirmed in Study 1 with ESS; however, the doses were not tolerated, and there were many withdrawals due to adverse events (mainly insomnia, headache, and nausea). The doses in Study 2 were well tolerated, with a lower incidence of adverse events in Study 2 than in Study 1, although the efficacy could not be confirmed with MWT and ESS in Study 2.
CONCLUSIONS
The optimal dose of enerisant could not be determined in these two studies. Although enerisant has a favorable pharmacokinetic profile, it is thought to have large interindividual variabilities in terms of efficacy and safety, suggesting the necessity of tailored dosage adjustments.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT03267303 ; Registered 30 August 2017 (Study 2). Japic identifier: JapicCTI-142529 ; Registered 7 May 2014 (Study 1) and JapicCTI-173689 ; Registered 30 August 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?clinicalTrialId=29277 (Study 2).
Topics: Disorders of Excessive Somnolence; Double-Blind Method; Humans; Narcolepsy; Treatment Outcome; Wakefulness
PubMed: 35193545
DOI: 10.1186/s12888-022-03785-7 -
Neurology Oct 2019While excessive daytime sleepiness (EDS) can predate the clinical diagnosis of Parkinson disease (PD), associations with underlying PD pathogenesis are unknown. Our...
OBJECTIVE
While excessive daytime sleepiness (EDS) can predate the clinical diagnosis of Parkinson disease (PD), associations with underlying PD pathogenesis are unknown. Our objective is to determine if EDS is related to brain Lewy pathology (LP), a marker of PD pathogenesis, using clinical assessments of EDS with postmortem follow-up.
METHODS
Identification of LP was based on staining for α-synuclein in multiple brain regions in a sample of 211 men. Data on EDS were collected at clinical examinations from 1991 to 1999 when participants were aged 72-97 years.
RESULTS
Although EDS was more common in the presence vs absence of LP ( = 0.034), the association became stronger in neocortical regions. When LP was limited to the olfactory bulb, brainstem, and basal forebrain (Braak stages 1-4), frequency of EDS was 10% (4/40) vs 17.5% (20/114) in decedents without LP ( = 0.258). In contrast, compared to the absence of LP, EDS frequency doubled (36.7% [11/30], = 0.023) when LP reached the anterior cingulate gyrus, insula mesocortex, and midfrontal, midtemporal, and inferior parietal neocortex (Braak stage 5). With further infiltration into the primary motor and sensory neocortices (Braak stage 6), EDS frequency increased threefold (51.9% [14/27], < 0.001). Findings were similar across sleep-related features and persisted after adjustment for age and other covariates, including the removal of PD and dementia with Lewy bodies.
CONCLUSIONS
The association between EDS and PD includes relationships with extensive topographic LP expansion. The neocortex could be especially vulnerable to adverse relationships between sleep disorders and aggregation of misfolded α-synuclein and LP formation.
Topics: Aged; Aged, 80 and over; Brain; Dementia; Disorders of Excessive Somnolence; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Parkinson Disease; Sleep Wake Disorders; alpha-Synuclein
PubMed: 31471503
DOI: 10.1212/WNL.0000000000008241 -
Sleep Medicine Sep 2023Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin transmission leading to excessive daytime sleepiness and cataplexy. Opioids have been...
OBJECTIVE
Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin transmission leading to excessive daytime sleepiness and cataplexy. Opioids have been suggested to increase the number of hypocretin-producing neurons. We aimed to assess opioid use and its self-reported effect on narcolepsy type 1 symptom severity through a literature review and questionnaire study.
METHODS
We systematically reviewed literature on opioid use in narcolepsy. We also recruited 100 people with narcolepsy type 1 who completed an online questionnaire on opioid use in the previous three years. The main questionnaire topics were the indication for use, and the possible effects on narcolepsy symptom severity. Structured follow-up interviews were conducted when opioid use was reported.
RESULTS
The systematic literature review mainly showed improvements in narcolepsy symptom severity. Recent opioid use was reported by 16/100 questionnaire respondents, who had used 20 opioids (codeine: 7/20, tramadol: 6/20, oxycodone: 6/20, fentanyl: 1/20). Narcolepsy symptom changes were reported in 11/20. Positive effects on disturbed nocturnal sleep (9/20), excessive daytime sleepiness (4/20), hypnagogic hallucinations (3/17), cataplexy (2/18), and sleep paralysis (1/13) were most pronounced for oxycodone (4/6) and codeine (4/7).
CONCLUSIONS
Opioids were relatively frequently used compared to a similarly young general Dutch sample. Oxycodone and, to a lesser extent, codeine were associated with self-reported narcolepsy symptom severity improvements. Positive changes in disturbed nocturnal sleep and daytime sleepiness were most frequently reported, while cataplexy effects were less pronounced. Randomised controlled trials are now needed to verify the potential of opioids as therapeutic agents for narcolepsy.
Topics: Humans; Cataplexy; Analgesics, Opioid; Orexins; Oxycodone; Narcolepsy; Disorders of Excessive Somnolence; Surveys and Questionnaires
PubMed: 37437491
DOI: 10.1016/j.sleep.2023.06.008