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1.  Do asthmatics suffer bronchoconstriction during rapid eye movement sleep? 
Many patients with asthma are troubled by nocturnal wheeze. The cause of this symptom is unknown, but sleep is an important factor. A study was carried out to determine whether nocturnal bronchoconstriction is related to any specific stage of sleep. Eight asthmatics with nocturnal wheeze and eight control subjects performed forced expiratory manoeuvres immediately after being woken from rapid eye movement (REM) or non-REM sleep, wakings being timed to differentiate temporal effects from those related to the stage of sleep. The control subjects showed no significant temporal bronchoconstriction or bronchoconstriction related to the stage of sleep. All patients showed bronchoconstriction overnight, the mean peak expiratory flow rate falling from 410 (SEM 50) 1/min before sleep to 186 (49)1/min after sleep. After the patients had been woken from REM sleep the forced expiratory volume in one second was on average 300 ml lower (p less than 0.02) and peak expiratory flow rate 45 1/min lower (p less than 0.03) than after they had been woken from non-REM sleep. As wakenings from REM sleep were 21(8) minutes later in the night than those from non-REM sleep multivariate analysis was performed to differentiate temporal effects from those related to the stage of sleep. This showed that the overnight decreases in forced expiratory volume in one second and peak expiratory flow rate were significantly related both to time and to REM sleep. This study suggests that asthmatics may suffer bronchoconstriction during REM sleep.
PMCID: PMC1340176  PMID: 3085766
2.  Association of Obstructive Sleep Apnea Risk or Diagnosis with Daytime Asthma in Adults 
Obstructive sleep apnea (OSA) worsens nocturnal asthma, but its potential impact on daytime asthma remains largely unassessed. We investigated whether the sleep disorder is associated with daytime, in addition to nighttime asthma symptoms.
Asthma patients at tertiary-care centers completed the Sleep Apnea scale of the Sleep Disorders Questionnaire (SA-SDQ), and an asthma control questionnaire. SA-SDQ scores ≥36 for men and ≥32 for females defined high OSA risk. Medical records were reviewed for established diagnosis of OSA and continuous positive airway pressure (CPAP) use.
Among 752 asthma patients, high OSA risk was associated similarly with persistent daytime and nighttime asthma symptoms (p<0.0001 for each). A diagnosis of OSA was robustly associated with persistent daytime (p<0.0001), in addition to nighttime (p=0.0008) asthma symptoms. In regression models that included obesity and other known asthma aggravators, high OSA risk retained associations with persistent daytime (odds ratio =1.96 [95% confidence interval 1.31–2.94]) and nighttime asthma symptoms (1.97 [1.32–2.94]). Diagnosed OSA retained an association with persistent daytime (2.08 [1.13–3.82]) but not with nighttime (1.48 [0.82–2.69]) asthma symptoms. CPAP use was associated with lower likelihood of persistent daytime symptoms (0.46 [0.23–0.94]).
Questionnaire-defined OSA risk and historical diagnosis were each associated with persistent daytime asthma symptoms, to an extent that matched or exceeded associations with nighttime asthma symptoms. Unrecognized OSA may be a reason for persistent asthma symptoms during the day as well as the night.
PMCID: PMC3626099  PMID: 22742082
asthma; asthma control; sleep; obstructive sleep apnea; obstructive sleep apnea risk
3.  Sleep and allergic disease: A summary of the literature and future directions for research 
Atopic diseases, such as asthma and allergic rhinitis, are common conditions that can influence sleep and subsequent daytime functioning. Children and patients with allergic conditions from ethnic minority groups might be particularly vulnerable to poor sleep and compromised daytime functioning because of the prevalence of these illnesses in these groups and the high level of morbidity. Research over the past 10 years has shed light on the pathophysiologic mechanisms (eg, inflammatory mediators) involved in many atopic diseases that can underlie sleep disruptions as a consequence of the presence of nocturnal symptoms. Associations between nocturnal symptoms and sleep and poorer quality of life as a result of missed sleep have been demonstrated across studies. Patients with severe illness and poor control appear to bear the most burden in terms of sleep impairment. Sleep-disordered breathing is also more common in patients with allergic diseases. Upper and lower airway resistance can increase the risk for sleep-disordered breathing events. In patients with allergic rhinitis, nasal congestion is a risk factor for apnea and snoring. Finally, consistent and appropriate use of medications can minimize nocturnal asthma or allergic symptoms that might disrupt sleep. Despite these advances, there is much room for improvement in this area. A summary of the sleep and allergic disease literature is reviewed, with methodological, conceptual, and clinical suggestions presented for future research.
PMCID: PMC3576835  PMID: 22867694
Sleep; allergic disease; asthma; allergic rhinitis; atopic dermatitis
4.  Nocturnal Asthma Symptoms and Poor Sleep Quality among Urban School Children with Asthma 
Academic pediatrics  2011;11(6):493-499.
To describe nocturnal asthma symptoms among urban children with asthma and assess the burden of sleep difficulties between children with varying levels of nocturnal symptoms.
We analyzed baseline data from 287 urban children with persistent asthma (ages 4–10) enrolled in the School-Based Asthma Therapy trial; Rochester, NY. Caregivers reported on nocturnal asthma symptoms (# nights/2 weeks with wheezing or coughing), parent quality of life (Juniper’s PACQLQ), and sleep quality using the validated Children’s Sleep Habits Questionnaire. We used bivariate and multivariate statistics to compare nocturnal asthma symptoms with sleep quality/quantity and quality of life.
Most children (mean age 7.5yrs) were Black (62%); 74% had Medicaid. Forty-one percent of children had intermittent nocturnal asthma symptoms, 23% mild persistent, and 36% moderate to severe. Children’s average total sleep quality score was 51 (range 33–99) which is above the clinically significant cut-off of 41, indicating pervasive sleep disturbances among this population. Sleep scores were worse for children with more nocturnal asthma symptoms compared to those with milder symptoms on total score, as well as several subscales including night wakings, parasomnias, and sleep disordered breathing (all p<.03). Parents of children with more nocturnal asthma symptoms reported their child having fewer nights with enough sleep in the past week (p=.018) and worse parent quality of life (p<.001).
Nocturnal asthma symptoms are prevalent in this population, and are associated with poor sleep quality and worse parent quality of life. These findings have potential implications for understanding the disease burden of pediatric asthma.
PMCID: PMC3481184  PMID: 21816697
asthma; childhood; symptoms; sleep; quality of life; smoke
5.  Morbidity in nocturnal asthma: sleep quality and daytime cognitive performance. 
Thorax  1991;46(8):569-573.
Most patients with asthma waken with nocturnal asthma from time to time. To assess morbidity in patients with nocturnal asthma nocturnal sleep quality, daytime sleepiness, and daytime cognitive performance were measured prospectively in 12 patients with nocturnal asthma (median age 43 years) and 12 age and intellect matched normal subjects. The median (range) percentage overnight fall in peak expiratory flow rate (PEF) was 22 (15 to 50) in the patients with nocturnal asthma and 4 (-4 to 7) in the normal subjects. The patients with asthma had poorer average scores for subjective sleep quality than the normal subjects (median paired difference 1.1 (95% confidence limits 0.1, 2.3)). Objective overnight sleep quality was also worse in the asthmatic patients, who spent more time awake at night (median difference 51 (95% CL 8.1, 74) minutes), had a longer sleep onset latency (12 (10, 30) minutes), and tended to have less stage 4 (deep) sleep (-33 (-58, 4) minutes). Daytime cognitive performance was worse in the patients with nocturnal asthma, who took a longer time to complete the trail making tests (median difference 62 (22, 75) seconds) and achieved a lower score on the paced serial addition tests (-10 (-24, -3)). Mean daytime sleep latency did not differ significantly between the two groups (2 (-3, 7) minutes). It is concluded that hospital outpatients with stable nocturnal asthma have impaired sleep quality and daytime cognitive performance even when having their usual maintenance asthma treatment.
PMCID: PMC463276  PMID: 1926025
6.  Sleep and psychological disturbance in nocturnal asthma 
Archives of Disease in Childhood  1998;78(5):413-419.
Subjective and objective sleep disturbance was studied in children with nocturnal asthma. Relations between such disturbance and daytime psychological function were also explored, including possible changes in learning and behaviour associated with improvements in nocturnal asthma and sleep. Assessments included home polysomnography, parental questionnaires concerning sleep disturbance, behaviour, and mood and cognitive testing. Compared with matched controls, children with asthma had significantly more disturbed sleep, tended to have more psychological problems, and they performed less well on some tests of memory and concentration. In general, improvement of nocturnal asthma symptoms by changes in treatment was followed by improvement in sleep and psychological function in subsequent weeks. The effects of asthma on sleep and the possible psychological consequences are important aspects of overall care.

PMCID: PMC1717552  PMID: 9659086
7.  Role of respiratory sleep disorders in the pathogenesis of nocturnal angina and arrhythmias. 
Postgraduate Medical Journal  1994;70(822):275-280.
This report documents how respiratory sleep disorders can adversely effect ischaemic heart disease. Three male patients (aged 60-67 years) with proven ischaemic heart disease are described. They illustrate a spectrum of nocturnal cardiac dysfunction, two with nocturnal angina and one with nocturnal arrhythmias. Full sleep studies were performed in a dedicated sleep laboratory on all patients, and one patient had 48 hours of continuous Holter monitoring. Two patients were found to have obstructive sleep apnoea with apnoea/hypopnoea indices of 57 and 36 per hour, respectively, the former with nocturnal arrhythmias and the latter with nocturnal angina. In both cases, nasal continuous positive airways pressure successfully treated the sleep apnoea, with an associated improvement in nocturnal arrhythmias and angina. The third patient who presented with nocturnal angina, did not demonstrate obstructive sleep apnoea (apnoea/hypopnoea index = 7.2) but had significant oxygen desaturation during rapid eye movement (REM) sleep. This patient responded to a combination of nocturnal oxygen and protriptyline, an agent known to suppress REM sleep, and had no further nocturnal angina. All patients were considered to be an optimum cardiac medication and successful symptom resolution only occurred with the addition of specific therapy aimed at their sleep-related respiratory problem. We conclude that all patients with nocturnal angina or arrhythmias should have respiratory sleep abnormalities considered in their assessment.
PMCID: PMC2397870  PMID: 8183772
8.  Sleep disordered breathing is associated with asthma severity in children 
The Journal of pediatrics  2011;160(5):736-742.
To examine the relationship between obesity, sleep disordered breathing (SDB), and asthma severity in children. We hypothesized that obesity and SDB (intermittent nocturnal hypoxia and habitual snoring) are associated with severe asthma at one year of follow-up.
Study design
Children (4 to 18 years) were recruited sequentially from a specialty asthma clinic, and underwent physiological, anthropometric, and biochemical assessments at enrollment. Asthma severity was determined after one year of follow-up and guidelines-based treatment, using a composite measure of level of controller medication, symptom burden, and health care utilization. Multivariable logistic regression was used to examine adjusted associations of SDB and obesity with asthma severity at 12-month follow-up.
Among 108 participants (mean age 9.1 ± 3.4 years, 45.4% African-American, 67.6% male), obesity and SDB were common, affecting 42.6% and 29.6% of participants respectively. After adjusting for obesity, race, and sex, children with SDB had a 3.62-fold increased odds of having severe asthma at follow up (95% CI: 1.26, 10.40). Obesity was not associated with asthma severity.
We identify SDB as a modifiable risk factor for severe asthma after one year of specialty asthma care. Future studies are needed to determine if treating SDB improves asthma morbidity.
PMCID: PMC3975834  PMID: 22133422
sleep disordered breathing; obesity; asthma
9.  The Effect of Breathing Exercises on the Nocturnal Enuresis in the Children with the Sleep-Disordered Breathing 
The nocturnal enuresis is one of the most common complaints of childhood. Upper airway obstruction and nocturnal snoring affect the nocturnal enuresis in children.
The aim of this study was to investigate the effects of breathing exercises on the nocturnal enuresis in the children with the sleep-disordered breathing.
Patients and Methods
This study was conducted in year of 2011 by a semi-experimental design with the control group among 40 children, aged 6 - 12 years, who had the nocturnal enuresis. Participants were examined based on the criteria of nocturnal enuresis, oral breathing, and nocturnal snoring. Subsequently, they were randomly assigned to the case and control groups. In the case group, the breathing exercises were performed for 45 minutes, and were pursued for four weeks in the morning following and prior to sleeping, and subsequently the arterial blood gases were measured and the frequency of enuresis and the respiratory rates (RR) were recorded.
After intervention the means of PaCO2 and RR in the control group were significantly higher than the case group (P < 0.0001). Likewise, O2sat, PaO2 in the case group were higher than the control group (P < 0.0001). The nocturnal enuresis decreased significantly in the case group, compared to the control group (P < 0.0001).
This study suggests that the breathing exercises may reduce the frequency of nocturnal enuresis in the patients with the oral breathing and nocturnal snore. The clinical implications of these findings should be verified in the future longitudinal studies.
PMCID: PMC3971783  PMID: 24719691
Breathing Exercises; Nocturnal Enuresis; Child
10.  Salmeterol in nocturnal asthma: a double blind, placebo controlled trial of a long acting inhaled beta 2 agonist. 
BMJ : British Medical Journal  1990;301(6765):1365-1368.
OBJECTIVE--To determine whether inhaled salmeterol, a new long acting inhaled beta adrenergic agonist, reduces nocturnal bronchoconstriction and improves sleep quality in patients with nocturnal asthma. DESIGN--Randomised, double blind, placebo controlled crossover study. SETTING--Hospital outpatient clinics in Edinburgh. SUBJECTS--Twenty clinically stable patients (13 women, seven men) with nocturnal asthma, median age 39 (range 18-60) years. INTERVENTIONS--Salmeterol 50 micrograms and 100 micrograms and placebo taken each morning and evening by metered dose inhaler. Rescue salbutamol inhalers were provided throughout the run in and study periods. MAIN OUTCOME MEASURES--Improvement in nocturnal asthma as measured by peak expiratory flow rates and change in sleep quality as measured by electroencephalography. RESULTS--Salmeterol improved the lowest overnight peak flow rate at both 50 micrograms (difference in median values (95% confidence interval for difference in medians) 69 (18 to 88) l/min) and 100 micrograms (72 (23 to 61) l/min) doses twice daily. While taking salmeterol 50 micrograms twice daily patients had an objective improvement in sleep quality, spending less time awake or in light sleep (-9 (-4 to -44) min) and more time in stage 4 sleep (26 (6-34) min). CONCLUSIONS--Salmeterol is an effective long acting inhaled bronchodilator for patients with nocturnal asthma and at a dose of 50 micrograms twice daily improves objective sleep quality.
PMCID: PMC1664533  PMID: 1980220
11.  Effect of sustained release terbutaline on symptoms and sleep quality in patients with nocturnal asthma. 
Thorax  1987;42(10):797-800.
The effect of an oral sustained release beta 2 agonist on symptoms, sleep quality, and peak flow rates has been studied in nine patients with nocturnal asthma. Patients received oral terbutaline 7.5 mg twice daily or placebo for seven days in a double blind crossover study and spent the last two nights of each limb in a sleep laboratory. Oral terbutaline improved morning peak flow (259 v 213 l min-1) and decreased nocturnal inhaler usage (1.3 v 1.9) with no alteration in sleep quality as assessed electroencephalographically. The study shows that oral sustained release terbutaline can be useful in the treatment of nocturnal asthma without impairment of sleep quality.
PMCID: PMC460955  PMID: 3321540
12.  Does sleep cause nocturnal asthma? 
Thorax  1979;34(6):749-754.
The effects of sleep interruption and deprivation were studied in 21 patients with nocturnal asthma. Seven patients were awakened at 0200 on three consecutive night and exercised for 15 minutes. This produced no significant improvement in the overnight fall in peak expiratory flow rate (PEFR) compared with a control night of uninterrupted sleep. In a second study in five patients PEFR was measured at two-hourly intervals to estimate the time of onset of the nocturnal fall in PEFR. On three subsequent nights they were awakened and exercised one hour before this time. This also failed to prevent a fall in PEFR by 0600. Eleven patients, who had followed a similar protocol to the second study, were kept awake until after 0300 or later, and PEFR was observed hourly. Six of them (group A) sustained their usual fall in PEFR while awake, proving that sleep was not responsible for their nocturnal asthma. Five patients (group B) showed little fall in PEFR until they were allowed to sleep, when an appreciable fall was noted on waking at 0600. When sleep deprivation was repeated in two patients in group B, however, they sustained falls in PEFR while still awake. We conclude that the circadian rhythm in PEFR is often in phase with the timing of sleep but sleep does not cause nocturnal asthma. Disruption of sleep therefore has no apparent value in the treatment of nocturnal asthma.
PMCID: PMC471191  PMID: 542914
13.  Exploding Head Syndrome: A Case Report 
Case Reports in Neurology  2013;5(1):14-17.
Exploding head syndrome (EHS) is a rare parasomnia in which affected individuals awaken from sleep with the sensation of a loud bang. The etiology is unknown, but other conditions including primary and secondary headache disorders and nocturnal seizures need to be excluded.
Case Presentation
A 57-year-old Indian male presented with four separate episodes of awakening from sleep at night after hearing a flashing sound on the right side of his head over the last 2 years. These events were described ‘as if there are explosions in my head’. A neurologic examination, imaging studies, and a polysomnogram ensued, and the results led to the diagnosis of EHS.
EHS is a benign, uncommon, predominately nocturnal disorder that is self-limited. No treatment is generally required. Reassurance to the patient is often all that is needed.
PMCID: PMC3573786  PMID: 23467433
Exploding head syndrome; Parasomnia; Headache disorder
14.  Breathing patterns during sleep in patients with nocturnal asthma. 
Thorax  1987;42(8):600-603.
Breathing patterns early and late in the night, at the same sleep stage, were compared in six healthy subjects and 15 adults with nocturnal asthma, to try to identify changes of overnight bronchoconstriction, and breathing patterns at different sleep stages, to see whether there were changes related to sleep stages that were indicative of bronchoconstriction. Despite an average 31% fall in FEV1 overnight in the patients with asthma, neither breathing frequency nor expiratory time, which might be expected to change during bronchoconstriction, was different early in the night from late in the night, nor did they differ between sleep stages. There was no evidence of asynchronous movement of the chest and abdomen in any patient. This study did not identify any abnormality of breathing pattern that would indicate the development of nocturnal asthma without the need to awaken the patient.
PMCID: PMC460860  PMID: 3509951
15.  Sleep symptoms and polysomnographic architecture in advanced Parkinson's disease after chronic bilateral subthalamic stimulation 
Methods: Sleep was studied in 11 patients (six women and five men; mean (SD) age 63.6 (7.8) years) who underwent STN-DBS. Subjective sleep evaluation was assessed by clinical sleep interview and the Pittsburgh sleep quality index (PSQI) questionnaire, and sleep architecture by polysomnography with audiovisual recording. Nocturnal mobility was evaluated.
Results: Before surgery, eight patients rated their sleep quality as unsatisfactory; seven of these had a marked improvement after surgery, and the PSQI questionnaire showed significantly improved sleep quality. After surgery, polysomnography showed an increase in the longest period of uninterrupted sleep and a decrease in the arousal index. There was an increase in nocturnal mobility after surgery, but no change in REM sleep behaviour disorder.
Conclusions: In advanced Parkinson's disease, chronic STN-DBS is associated with subjective improvement in sleep quality, probably through increased nocturnal mobility and reduction of sleep fragmentation.
PMCID: PMC1737853  PMID: 11971059
16.  Using difficulty resuming sleep to define nocturnal awakenings 
Sleep medicine  2010;11(3):236-241.
Nocturnal awakenings are one of the most prevalent sleep disturbances in the general population. Little is known, however, about the frequency of these episodes and how difficulty resuming sleep once awakened affects subjective sleep quality and quantity. Method: This is a cross-sectional telephone study with a representative sample consisting of 8,937 non-institutionalized individuals aged 18 or over living in Texas, New York and California. The interviews included questions on sleeping habits, health, sleep and mental disorders. Nocturnal awakenings were evaluated according to their frequency per week and per night, as well as their duration.
A total of 35.5% of the sample reported awakening at least 3 nights per week. Of this 35.5%, 43% (15.2% of the total sample) reported difficulty resuming sleep once awakened. More than 80% of subjects with insomnia symptoms (difficulty initiating or maintaining sleep or non-restorative sleep) also had nocturnal awakenings. Difficulty resuming sleep was associated with subjective shorter sleep duration, poorer sleep quality, greater daytime impairment, greater consultations for sleep disturbances and greater likelihood of receiving a sleep medication.
Nocturnal awakenings disrupt the sleep of about one-third of the general population. Using difficulty resuming sleep identifies individuals with significant daytime impairment who are most likely to seek medical help for their sleep disturbances. In the absence of other insomnia symptoms, nocturnal awakenings alone are unlikely to be associated with daytime impairments.
PMCID: PMC2830306  PMID: 20075004
17.  Effect of sleep deprivation on overnight bronchoconstriction in nocturnal asthma. 
Thorax  1986;41(9):676-680.
Nocturnal cough and wheeze are common in asthma. The cause of nocturnal asthma is unknown and there is conflicting evidence on whether sleep is a factor. Twelve adult asthmatic subjects with nocturnal wheeze were studied on two occasions: on one night subjects were allowed to sleep and on the other they were kept awake all night, wakefulness being confirmed by electroencephalogram. Every patient developed bronchoconstriction overnight both on the asleep night, when peak expiratory flow (PEF) fell from a mean (SE) of 418 (40) 1 min-1 at 10 pm to 270 (46) 1 min-1 in the morning, and on the awake night (PEF 10 pm 465 (43), morning 371 (43) 1 min-1). The morning values of PEF were, however, higher (p less than 0.1) after the awake night and both the absolute and the percentage overnight falls in PEF were greater when the patients slept (asleep night 38% (6%), awake night 20% (4%); p less than 0.01). This study suggests that sleep is an important factor in determining overnight bronchoconstriction in patients with nocturnal asthma.
PMCID: PMC460429  PMID: 3787554
18.  Parasomnias: An Updated Review 
Neurotherapeutics  2012;9(4):753-775.
Parasomnias are abnormal behaviors emanating from or associated with sleep. Sleepwalking and related disorders result from an incomplete dissociation of wakefulness from nonrapid eye movement (NREM) sleep. Conditions that provoke repeated cortical arousals, or promote sleep inertia lead to NREM parasomnias by impairing normal arousal mechanisms. Changes in the cyclic alternating pattern, a biomarker of arousal instability in NREM sleep, are noted in sleepwalking disorders. Sleep-related eating disorder (SRED) is characterized by a disruption of the nocturnal fast with episodes of feeding after an arousal from sleep. SRED is often associated with the use of sedative-hypnotic medications; in particular, the widely prescribed benzodiazepine receptor agonists. Recently, compelling evidence suggests that nocturnal eating may in some cases be a nonmotor manifestation of Restless Legs Syndrome (RLS). rapid eye movement (REM) Sleep Behavior Disorder (RBD) is characterized by a loss of REM paralysis leading to potentially injurious dream enactment. The loss of atonia in RBD often predates the development of Parkinson’s disease and other disorders of synuclein pathology. Parasomnia behaviors are related to an activation (in NREM parasomnias) or a disinhibition (in RBD) of central pattern generators (CPGs). Initial management should focus on decreasing the potential for sleep-related injury followed by treating comorbid sleep disorders. Clonazepam and melatonin appear to be effective therapies in RBD, whereas paroxetine has been reported effective in some cases of sleep terrors. At this point, pharmacotherapy for other parasomnias is less certain, and further investigations are necessary.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0143-8) contains supplementary material, which is available to authorized users.
PMCID: PMC3480572  PMID: 22965264
Parasomnia; Sleepwalking; Sleep terrors; REM sleep behavior disorder; Restless legs syndrome
19.  The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease 
Brain  2013;136(7):2120-2129.
In Parkinson’s disease, rapid eye movement sleep behaviour disorder is an early non-dopaminergic syndrome with nocturnal violence and increased muscle tone during rapid eye movement sleep that can precede Parkinsonism by several years. The neuronal origin of rapid eye movement sleep behaviour disorder in Parkinson’s disease is not precisely known; however, the locus subcoeruleus in the brainstem has been implicated as this structure blocks muscle tone during normal rapid eye movement sleep in animal models and can be damaged in Parkinson’s disease. Here, we studied the integrity of the locus coeruleus/subcoeruleus complex in patients with Parkinson’s disease using combined neuromelanin-sensitive, structural and diffusion magnetic resonance imaging approaches. We compared 24 patients with Parkinson’s disease and rapid eye movement sleep behaviour disorder, 12 patients without rapid eye movement sleep behaviour disorder and 19 age- and gender-matched healthy volunteers. All subjects underwent clinical examination and characterization of rapid eye movement sleep using video-polysomnography and multimodal imaging at 3 T. Using neuromelanin-sensitive imaging, reduced signal intensity was evident in the locus coeruleus/subcoeruleus area in patients with Parkinson’s disease that was more marked in patients with than those without rapid eye movement sleep behaviour disorder. Reduced signal intensity correlated with the percentage of abnormally increased muscle tone during rapid eye movement sleep. The results confirmed that this complex is affected in Parkinson’s disease and showed a gradual relationship between damage to this structure, presumably the locus subcoeruleus, and abnormal muscle tone during rapid eye movement sleep, which is the cardinal marker of rapid eye movement sleep behaviour disorder. In longitudinal studies, the technique may also provide early markers of non-dopaminergic Parkinson’s disease pathology to predict the occurrence of Parkinson’s disease.
PMCID: PMC3692035  PMID: 23801736
MRI; RBD; diffusion imaging; neuromelanin-sensitive imaging; VBM
20.  Early-life trauma is associated with rapid eye movement sleep fragmentation among military veterans 
Biological Psychology  2012;89(3):570-579.
The role of sleep in the relations between early-life trauma and the development of adverse psychological trajectories is relatively unknown and was the primary aim of the present study. Military veterans were evaluated for Posttraumatic Stress Disorder, combat exposure, trauma history, sleep quality, disruptive nocturnal behaviors, and a subsample completed overnight polysomnography that yielded objectively measured sleep parameters. When relevant variables were controlled, increased earlier-life traumatic event exposure was associated with increased rapid-eye-movement sleep (REMs) fragmentation, and increased REMs fragmentation was associated with increased later-life disruptive nocturnal behaviors. REMs fragmentation carried an indirect relation between earlier-life trauma and later-life disruptive nocturnal behaviors. Objectively measured sleep parameters were used to describe REMs fragmentation physiology. The current findings elucidate the important role that earlier-life trauma exposure may have in the development of REM sleep physiology, and how this altered sleep physiology may have dynamic influences on subsequent posttraumatic stress symptoms in adulthood.
PMCID: PMC3299844  PMID: 22266135
Sleep; Development; Translational; Trauma; Fear; PTSD; Combat
21.  Sleep disorders and the prevalence of asymptomatic nocturnal acid and non-acid reflux 
Nocturnal acid reflux is associated with symptomatic and asymptomatic sleep arousals, leading to fragmented sleep. The frequency and influence of acid reflux in patients with various forms of insomnia has not been reported. The aim of this study was to quantify nocturnal acid and nonacid reflux in patients with primary sleep disorders as previously diagnosed by polysomnography.
Thirty one subjects were studied: (A) 9 subjects with a polysomnographically diagnosed sleep disorder (1 with restless legs syndrome, 4 with narcolepsy, 4 with periodic limb movement disorder); (B) 12 subjects with primary insomnia (PI) and unrevealing polysomnography; and (C) 10 controls without disturbed sleep. All subjects underwent a physical examination and 24 h transnasal pH and impedance monitoring to detect acid and non-acid reflux.
The 21 subjects with fragmented sleep due to a primary sleep disorder had significantly more recumbent acid exposure (>1.2% of time) as compared with control subjects (33% versus 0%). When fragmented sleep subjects were divided into two groups, 17% of PI subjects and 55% of subjects with a diagnosed sleep disorder had significant recumbent acid exposure (P=0.009). Likewise, the median recumbent nonacid events were increased in the sleep disordered group (P=0.011).
This study indicates that patients with primary sleep disorders have prominent nocturnal acid reflux without symptoms of daytime acid reflux. Acid reflux is most prominent in patients with polysomnographic findings of disturbed sleep as compared to patients with PI; while non acid reflux is increased minimally in these patients.
PMCID: PMC3959439
Gastro-esophageal reflux; nocturnal acid reflux; non-acid reflux; sleep disorders; insomnia
22.  Sleep Disturbances Associated with Parkinson's Disease 
Parkinson's Disease  2011;2011:219056.
Sleep disturbances are common problems affecting the quality life of Parkinson's disease (PD) patients and are often underestimated. The causes of sleep disturbances are multifactorial and include nocturnal motor disturbances, nocturia, depressive symptoms, and medication use. Comorbidity of PD with sleep apnea syndrome, restless legs syndrome, rapid eye movement sleep behavior disorder, or circadian cycle disruption also results in impaired sleep. In addition, the involvement of serotoninergic, noradrenergic, and cholinergic neurons in the brainstem as a disease-related change contributes to impaired sleep structures. Excessive daytime sleepiness is not only secondary to nocturnal disturbances or dopaminergic medication but may also be due to independent mechanisms related to impairments in ascending arousal system and the orexin system. Notably, several recent lines of evidence suggest a strong link between rapid eye movement sleep behavior disorder and the risk of neurodegenerative diseases such as PD. In the present paper, we review the current literature concerning sleep disorders in PD.
PMCID: PMC3159123  PMID: 21876839
23.  Oximetry Signal Processing Identifies REM Sleep-Related Vulnerability Trait in Asthmatic Children 
Sleep Disorders  2013;2013:406157.
Rationale. The sleep-related factors that modulate the nocturnal worsening of asthma in children are poorly understood. This study addressed the hypothesis that asthmatic children have a REM sleep-related vulnerability trait that is independent of OSA. Methods. We conducted a retrospective cross-sectional analysis of pulse-oximetry signals obtained during REM and NREM sleep in control and asthmatic children (n = 134). Asthma classification was based on preestablished clinical criteria. Multivariate linear regression model was built to control for potential confounders (significance level P ≤ 0.05). Results. Our data demonstrated that (1) baseline nocturnal respiratory parameters were not significantly different in asthmatic versus control children, (2) the maximal % of SaO2 desaturation during REM, but not during NREM, was significantly higher in asthmatic children, and (3) multivariate analysis revealed that the association between asthma and REM-related maximal % SaO2 desaturation was independent of demographic variables. Conclusion. These results demonstrate that children with asthma have a REM-related vulnerability trait that impacts oxygenation independently of OSA. Further research is needed to delineate the REM sleep neurobiological mechanisms that modulate the phenotypical expression of nocturnal asthma in children.
PMCID: PMC3832976  PMID: 24288619
24.  Sustained release choline theophyllinate in nocturnal asthma. 
Nocturnal wheeze is common in patients with asthma, and slow release theophyllines may reduce symptoms. As theophyllines are stimulants of the central nervous system the effect of 10 days' twice daily treatment with sustained release choline theophyllinate or placebo on symptoms, overnight bronchoconstriction, nocturnal oxygen saturation, and quality of sleep were studied in a double blind crossover study in nine stable patients with nocturnal asthma (five men, four women, age range 23-64 years; forced expiratory volume in one second (FEV1) 0.85-3.8 1; vital capacity 1.95-6.1 1). When treated with the active drug all patients had plasma theophylline concentrations of at least 28 mmol/l (5 micrograms/ml) (peak plasma theophylline concentrations 50-144 mmol/l (9-26 micrograms/ml]. Morning FEV1 was higher when treated with sustained release choline theophyllinate (2.7 (SEM 0.3) 1) than placebo (2.1 (0.3) 1) (p less than 0.01). Both daytime and nocturnal symptoms were reduced when the patients were treated with sustained release choline theophyllinate and subjective quality of sleep was improved (p less than 0.002). When treated with the active drug, however, quality of sleep determined by electroencephalography deteriorated with an increase in wakefulness and drowsiness (p less than 0.05) and a reduction in non-rapid eye movement sleep (p less than 0.005). Treatment with choline theophyllinate had no effect on either the occurrence or the severity of transient nocturnal hypoxaemic episodes or apnoeas or hypopnoeas. In conclusion, sustained release choline theophyllinate prevents overnight bronchoconstriction, but impairs quality of sleep defined by electroencephalography.
PMCID: PMC1418455  PMID: 3935204
25.  Nocturnal Frontal Lobe Epilepsy Presenting as Excessive Daytime Sleepiness 
Excessive daytime sleepiness (EDS) is common in the general population. Etiologies include insufficient sleep and primary sleep disorders. Due to its high prevalence, physicians often overlook EDS as a significant problem. However, EDS may also be the presenting symptom of seizures, in particular Nocturnal Frontal Lobe Epilepsy (NFLE). Due to the clinical similarity between the nocturnal behaviors of NFLE and parasomnias, and poor patient-related history, NFLE remains a challenging diagnosis. We report the case of a patient with NFLE who presented with a primary complaint of EDS, and discuss the differential diagnosis and evaluation of patients with EDS associated with nocturnal behaviors. In the context of a patient presenting with EDS and stereotyped nocturnal events, clinical suspicion should be high for NFLE.
PMCID: PMC3894023  PMID: 24479058
Epilepsy; excessive daytime sleepiness; hypersomnia; parasomnia; seizures

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