Sleep Medicine

Published by Elsevier
Print ISSN: 1389-9457
Narcolepsy is a sleep disorder with a genetic association with the haplotype DRB1*1501, DQA1*0102, DQB1*0602. This haplotype has been described in different ethnic groups suffering from narcolepsy (Japanese, Caucasian, African Americans, Jews). In a recent study we have found the haplotype DRB1*1502, DQB1*0601, DQA1*0103 in three patients with hypersomnolence. The similarity of this haplotype to the narcoleptic haplotype DRB1*1501, DQB1*0602 and DQA1*0102 has raised the question of whether this haplotype is a marker for sleepiness, or rather indicates a variant of non-cataplectic narcolepsy. This study was conducted to further investigate this question. HLA-DNA analysis was carried out in 20 healthy Jewish patients (age 23.9+/-6.3 years; 13 Ashkenazi, seven non-Ashkenazi) who had objective measures of hypersomnolence. All underwent whole-night polysomnography, multiple sleep latency test and tissue typing. HLA-DNA analysis revealed HLA-DR2 in eight patients of whom five (25%) carried the haplotype DRB1*1502, DQB1*0601, DQA1*0103 (vs. 1.4% in the Israeli population, P<0.0001). Six patients were diagnosed as non-cataplectic narcoleptics. Five of them carried the haplotype DRB1*1502, DQB1*0601, DQA1*0103. Forty percent of the patients carried the haplotype DRB1*04, DQB1*0302, which was not statistically different from its prevalence in the healthy Israeli population (25%). This is the first report describing the haplotype DRB1*1502, DQB1*0601, DQA1*0103 in narcoleptic patients (non-cataplectic). This haplotype is close but different from the already known narcoleptic haplotype DRB1*1501, DQA1*0102, DQB1*0602. We assume that this haplotype represents a variant of non-cataplectic narcolepsy rather than association with hypersomnolence. However, in order to conclude whether this haplotype is a marker for the lack of cataplexy, or represents a variant of non-cataplectic narcolepsy, a larger group of patients should be investigated.
We aimed to evaluate the efficacy of the selective H3 receptor inverse agonist MK-0249 to treat excessive daytime sleepiness (EDS). In this three-period, double-blind, crossover study, 125 patients (100 men, 25 women; mean age, 48.6years) with obstructive sleep apnea receiving nasal continuous positive airway pressure therapy who had refractory EDS were randomized to 2weeks each of daily MK-0249 (5, 8, 10, or 12mg, adaptively assigned), modafinil 200mg, and placebo. At baseline and after each treatment period, six maintenance of wakefulness tests (MWT) and Psychomotor Vigilance Tasks (PVT) were conducted at 2-h intervals, beginning 1h postdose (∼09:00). The Epworth sleepiness scale (ESS), Clinical Global Impression of Severity (CGIS) and Digit Symbol Substitution Test (DSST) also were assessed. The primary end point was MWT sleep latency averaged over the first four time points (MWT-early). MWT-early mean change from baseline sleep latency at week 2 was 1.2min for placebo, 2.1min for MK-0249 (top two doses pooled; P>.05 vs placebo), and 5.9min for modafinil (P⩽.001 vs placebo). MK-0249 showed improvements vs placebo on secondary and exploratory end points of ESS, CGIS, PVT, and DSST. Insomnia adverse events (AEs) were greater for MK-0249 (combined doses, 17.5%) than for placebo (0.9%) or modafinil (1.8%). MK-0249 did not significantly affect MWT sleep latency. However, the pattern of improvement on subjective ratings and psychomotor performance end points suggested that MK-0249 was associated with changes in aspects of cognition and performance not captured by the MWT.
Background: Narcolepsy, a neurological disorder characterized by excessive daytime sleepiness and abnormal REM sleep, is known to be tightly associated with the human leukocyte antigen (HLA) DQB1*0602.Methods: In this study, baseline data collected for a large clinical trial involving 504 narcolepsy patients were used to compare clinical and polysomnographic features of narcolepsy patients with and without HLA-DQB1*0602. Comparisons were adjusted for possible confounding factors and linear regression modeling was used to extract the best predictors for DQB1*0602 positivity.Results: As previously reported, cataplexy was the best clinical predictor for DQB1*0602 positivity. At the polysomnographic level, subjects with DQB1*0602 were found to have a significantly more disrupted nocturnal sleep, a much shorter nocturnal rapid eye movement (REM) sleep latency and more multiple sleep latency test abnormalities (increased number of sleep onset REM periods and decreased mean sleep latency). We also found that subjects with DQB1*0602 had a much higher incidence of periodic limb movements during sleep, confirming the notion that this symptom is genuinely associated with the narcolepsy phenotype.Conclusions: These results support the notion that HLA-DQB1*0602-positive narcolepsy patients are more etiologically homogenous than HLA-DQB1*0602-negative narcoleptic patients.
The aim of the present study was to assess sleep patterns in the adult population of the city of Campinas (Brazil) according to socioeconomic/demographic variables, chronic diseases, and symptoms. A population-based cross-sectional study was conducted using data from the Campinas Health Survey (ISACAMP) carried out in 2008 and 2009. A total of 2637 individuals aged 18 years or older (obtained from a probabilistic sample) were analyzed. Associations between sleep pattern and the independent variables were determined using the chi-square test. Multinomial logistic regression models were used to adjust for confounders. The prevalence of six or fewer hours of sleep was greater among individuals aged 40 years or older and among divorced or single individuals. The sleep pattern of nine or more hours was more prevalent among those with less than 40 years of age, among those who were divorced, or single, among those with a lower level of schooling, those who did not work and housewives. Both short and long sleep patterns were more prevalent among individuals with heart disease, vascular problems, rheumatism/arthritis/arthrosis, osteoporosis, or emotional problems. The prevalence of the short sleep duration was greater among individuals with back problems and those with three or more health conditions. A strong association was found between sleep duration and sleep quality. Socio-demographic factors and health diseases were associated to sleep duration. This issue should be considered in health promotion strategies.
Increasing evidence suggests an association between short sleep with adverse health outcomes: obesity, type 2 diabetes and hypertension. But there are few or no data on "who these short sleepers are" in the general population. To describe short sleepers and the associated sleep disorders in young adults. Cross-sectional telephone survey in a representative sample of 1004 French young adults (25-45 years old). Total sleep time (TST), insomnia, snoring, sleepiness and daytime consequences were assessed using subjective validated tools. Short sleepers were defined as sleeping <6h a weekday (sleep+nap+pauses). Sleep debt was defined as those who "sleep 90 min less than the sleep they need to be in good shape." Prevalence of short sleep was 18%, insomnia 12%, and sleep debt 20% in the total group. Among short sleepers, 16% had insomnia, 45% sleep debt, and 39% neither. Short sleepers were significantly mostly males, blue collar workers and more overweight and obese compared to nonshort sleepers. Working >10h per day, smoking and drinking coffee after 5p.m. were also significantly associated with short sleep. Short sleepers had higher Epworth sleepiness scale ESS scores (7.8 vs 6.7; p = 0.0058) and more sleepiness while driving (11.5% vs 2.9%; p < 0.0001). Short sleep is highly prevalent in young adults but is not an homogeneous group, including both insomniacs and subjects with or without sleep debt. Short sleep has to be defined more precisely in order to better understand its impact on public health.
Health expenses, income from employment, and public transfer income by age and gender.
Despite the fact that narcolepsy is a chronic disorder affecting younger people, there is insufficient information about its societal burden, time course, and familiar effect. We aimed to estimate the factual direct and indirect costs of narcolepsy patients and their families in a national sample using a controlled study design. Using records from the Danish National Patient Registry (1997-2009), all 816 narcolepsy patients and their partners were identified and compared with 3254 randomly chosen controls matched for age, gender, geographic area, and civil status. Direct and indirect costs, including frequencies of primary and secondary sector contacts' and procedures, medication, labor supply, and social transfer payments were extracted from the national databases. Fewer patients (46.7%) than controls (51.4%) were married or cohabiting. Patients with narcolepsy had significantly higher rates of health-related contact, medication use, and a higher socioeconomic cost. Furthermore, they had lower employment rates, and those in employment had a lower income level than control subjects. Partners presented higher public health insurance and public transfers and lower income from employment. In all, the annual mean excess health-related cost, including social transfers, was €9572 for patients with narcolepsy and €3606 for their partners (both p<0.001). Patient consequences could be identified up to 11 years before first diagnosis and became more pronounced as the disease advanced. Narcolepsy causes socioeconomic consequences, not only for patients, but also for their partners, which is present years prior to disease diagnosis, confirming a diagnostic delay.
Since its original description, idiopathic RBD has become a well-established risk factor for neurodegenerative disease. Studies from sleep centers have found that at least 40-65% of patients with idiopathic RBD will develop a defined neurodegenerative phenotype over 10years. This elevated risk of neurodegeneration has been recently confirmed in a population-based study of probable RBD. When a defined syndrome develops, it is almost always a 'synucleinopathy' (Parkinson's disease, Dementia with Lewy Bodies or multiple system atrophy). Often, manifestations of parkinsonism and cognitive impairment overlap. The ability of RBD to predict disease has major implications for development of neuroprotective therapy. First, RBD is a prodromal marker with a disease risk sufficiently high for design of neuroprotective trials. Second, study of idiopathic RBD allows prospective testing of other predictive markers of neurodegeneration. Third, it allows an unprecedented direct examination of the evolution of prodromal disease into defined neurodegenerative syndromes. This review summarizes what is known about the risk of neurodegeneration in idiopathic RBD, the utility of prodromal/predictive markers in synuclein-mediated neurodegeneration, and the evolution of motor and non-motor markers in prodromal stages.
To obtain normative sleep architecture data from unattended home polysomnography in Caucasian and Hispanic children aged 6-11 years. Unattended home polysomnography was performed on a single night in Caucasian and Hispanic children aged 6-11 years as part of the Tucson Children's Assessment of Sleep Apnea Study (TuCASA), a cohort study designed to examine the prevalence and correlates of sleep disordered breathing. A subset of 42 children enrolled in TuCASA who had no symptoms of any sleep disorder and had polysomnograms without technical recording problems. Sleep architecture in preadolescent Caucasian and Hispanic children was not different between boys and girls. However, total sleep time (TST), sleep efficiency (SLE) and time spent in REM sleep declined with increasing age. In addition, the number of sleep to wake stage shifts was slightly higher in younger children. Hispanic children had less Stage 3/4 sleep (18+/-1 vs. 22+/-1%, P</=0.02) and correspondingly more Stage 2 sleep (55+/-2 vs. 50.0+/-1%, P</=0.02) than their Caucasian counterparts. Using unattended home polysomnography, indices of sleep duration and architecture are not different between preadolescent boys and girls. However, with increasing age, TST and SLE decreased. In addition, there are differences in sleep architecture between Caucasians and Hispanics, which may be an important consideration in the evaluation of children with sleep disorders.
An 11-year-old girl was referred for an irresistible urge to move her legs associated with uncomfortable sensations. She was diagnosed with definite Restless Legs Syndrome (RLS) according to 2003 NIH criteria. The IRLSSG severity scale score was 31 (very severe). The girl also presented with dysthymic disorder according to DSM-IV criteria, as confirmed by the semi-structured interview Kiddie-SADS-PL. The score on the Children Depression Inventory (CDI) was in the clinical range (21). The total score on the Sleep Disturbance Scale for Children (SDSC) was 100. A standard PSG revealed a periodic limb movement index of 16.5, indicating that the child also presented with Periodic Limb Movements Disorder. The girl was treated with ropinirole (a D2/D3 dopamine agonist). After 3 months of treatment (0.50mg/day at 8.00 PM), RLS, as well as depressive symptoms, remarkably improved, as suggested by the improvement in the IRLSSG severity and CDI scores (14 and 4, respectively). No side effects were reported. The total score on the SDSC also improved (73). The PLM index did not remarkably change. We strongly recommend double blind, randomized, controlled studies to gain insight into the effective treatment strategies for RLS and depression when they coexist in children.
Although the positive clinical benefits of levodopa have fostered the concept of an abnormality in the dopaminergic system in Restless Legs Syndrome (RLS), research into the nigro-striatal (PET/SPECT studies) or tubero-infundibular (i.e., prolactin secretion) dopaminergic pathways has shown limited positive results. Some research groups have focused on the A11 dopaminergic system in the hypothalamus as this is the primary source of descending dopaminergic input into the spinal cord, an area of the nervous system believed by some investigators to be involved in RLS symptom development. Some investigators have now proposed lesioning or toxin-inhibiting the A11 system as a model of RLS, even though there has been no clear clinical or autopsy data to suggest that RLS is a neurodegenerative disorder. In this study, the A11 cell bodies were identified in 6 RLS and 6 aged-matched control autopsy cases. Cells were stained for tyrosine hydroxylase (TH), and stereological measure of the individual TH (+) cell volume was made. Regional assessment of gliosis as assessed by immunostaining for glial fibrillary acidic protein (GFAP) was made in the surrounding tissue. General histological staining was also performed on the tissue. This study found no significant difference between RLS or control cases on any measure used: TH (+) cell volume, fractional GFAP staining, or general histological examination. Nor was there histological indication of any significant inflammation or concurrent ongoing pathology in these RLS cases. The findings do not support the concept of dramatic cell loss or of a neurodegenerative process in the A11 hypothalamic region of patients with RLS. However, that does not exclude the possibility that the A11 system is involved in RLS symptoms. Changes at the cellular level in dopaminergic metabolism or at the distal synapse with changes in receptors or transporters were not evaluated in this study.
Obstructive sleep apnea (OSA) is a prevalent disorder with multiple consequences including negative effects on neurocognitive function. Several domains of cognitive function are impaired in OSA patients, but the mechanisms through which this sleep disorder results in impairment are not clear. Given the well-known effects of cortisol on cognitive function, in particular memory, the dysregulating effects of OSA on cortisol levels are hypothesized as a potential pathway leading to cognitive impairment. Fifty-five participants with OSA (mean apnea-hypopnea index [AHI], 30.3) were assessed over 2days. Over a 24-h period, blood samples were collected every 2h to examine cortisol levels. The following night, sleep was monitored with polysomnography (PSG). Participants were given a battery of neurocognitive tests, which assessed seven cognitive domains. OSA severity assessed by oxygen desaturation index (ODI) was associated with 24-h cortisol levels. AHI, ODI, and nighttime cortisol levels were associated with global deficit scores (GDS) in cognitive functioning, particularly in domains of learning, memory, and working memory (P<.05 for all). Hierarchical linear regression analysis revealed that nighttime cortisol accounted for 9-16% of variance in learning (P=.018), memory (P=.003), and working memory (P=.016) domains, though apnea severity did not significantly predict any additional variance. In our sample of patients with OSA, nocturnal cortisol levels were associated with neuropsychologic functioning above and beyond the influence of covariates and apnea severity. These findings suggest that OSA-related alterations in cortisol activity may partially explain the pathophysiology of neuropsychologic impairments in sleep apnea.
We investigated cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphic assessment as a supportive diagnostic indicator for idiopathic REM sleep behavior disorder (RBD) complicated by moderate to severe obstructive sleep apnea (OSA). (123)I-MIBG was intravenously injected in 23 idiopathic RBD patients with AHI < 5/h, 9 idiopathic RBD patients with 5 <or= AHI < 15/h, 15 idiopathic RBD patients complicated with moderate to severe OSA with AHI >or= 15/h, and 16 moderate to severe obstructive sleep apnea syndrome (OSAS) patients without RBD by polysomnography. Cardiac MIBG uptake based on H/M was significantly decreased in RBD patients with or without OSA compared with patients with moderate to severe OSAS without RBD. ROC analysis revealed that a delayed H/M cut-off value of 1.97 was useful for differentiating idiopathic RBD complicated by moderate to severe OSA from moderate to severe OSAS without RBD. (123)I-MIBG cardiac scintigraphy has the potential to distinguish true RBD from pseudo-RBD associated with OSA. These results are noteworthy because treatment options and follow-up protocols are determined based on evaluation of moderate to severe OSA complicated with RBD, such as overlapping primary sleep disorders.
Although decrease in myocardial iodine-123 metaiodobenzylguanidine ((123)I-MIBG) radioactivity has been reported in patients with rapid eye movement (REM) sleep behavior disorder (RBD), its pathophysiology has not been thoroughly disclosed. We report two RBD patients with differing clinical progression, in whom myocardial (123)I-MIBG scintigraphy was performed. One 69-year-old patient had more than a 20-year history of idiopathic RBD and showed a decrease in myocardial (123)I-MIBG radioactivity. The other 69-year-old patient started to manifest nocturnal behaviors at age 62, then mild parkinsonism at age 68, and showed a similar decrease in myocardial (123)I-MIBG radioactivity both before and after the onset of parkinsonism. These cases suggest that RBD could develop in diverse patterns of clinical progression even if signs of underlying Lewy body pathology are uniformly indicated.
The purpose of this study was to detect the eventual presence of a minor voluntary motor involvement in restless legs syndrome (RLS), not detectable clinically, which might be observed by means of a sophisticated instrumental analysis of movement, such as gait analysis. Gait analysis was performed and surface EMG activity was recorded in 13 RLS patients and 8 normal controls from 8 muscles: tibialis anterior, gastrocnemius lateralis, gastrocnemius medialis, and soleus in both legs. Ten out of the 13 RLS patients and none of the normal control group showed a mild abnormality of the EMG activation of the gastrocnemius muscles during gait which, however, had no detectable effects on its kinematics. These preliminary results might be interpreted as the effect of an impaired supraspinal dopaminergic control with possible action on spinal structures involved in the control of gait. If confirmed in future studies, this mild EMG abnormality might constitute an additional supportive feature for the diagnosis of RLS in difficult cases.
CSF hypocretin-1 measurements were performed during a period of hypersomnia and during an asymptomatic interval in a 14-year-old girl affected with severe Kleine-Levin syndrome. A twofold decrease in hypocretin-1 was evidenced during the period of hypersomnia in comparison with the asymptomatic interval. Together with previous data, this result is in favour of recurrent dysfunction at the hypothalamic level in Kleine-Levin syndrome.
Demographic and clinical data in 14 patients treated with melatonin for REM sleep behavior disorder
Adverse effects in 14 patients treated with melatonin for REM sleep behavior disorder
To describe the treatment response with melatonin for rapid eye movement (REM) sleep behavior disorder (RBD) associated with other neurologic disorders. Clonazepam has been considered the treatment of choice for RBD. However, an alternative treatment is desirable for those with RBD refractory to clonazepam, for those who experience intolerable side-effects with clonazepam, and for those in whom clonazepam precipitates or aggravates obstructive sleep apnea (OSA). To date, there is minimal published data and limited follow-up regarding the use of melatonin for patients with RBD associated with other neurologic syndromes and disorders. The response to melatonin treatment for RBD was reviewed on consecutive patients the investigators treated with this agent at Mayo Clinic Rochester from January 2000 to June 2001. The coexisting neurologic disorders, reasons for using melatonin, effective doses, side-effects, and duration of follow-up were also reviewed on all patients. Fourteen patients were commenced on melatonin over the specified time period (13 male, median RBD onset age 56 years, range 20-77 years). The coexisting neurologic findings/disorders were dementia with Lewy bodies (n=7), mild cognitive impairment with mild parkinsonism (n=2), multiple system atrophy (n=2), narcolepsy (n=2), and Parkinson's disease (n=1). The reasons for using melatonin in these cases were incomplete response of RBD to clonazepam in six patients, existing cognitive impairment in five, intolerable side-effects with clonazepam in two, and presence of severe obstructive sleep apnea and narcolepsy in one. With seven patients continuing to use clonazepam at 0.5-1.0 mg/night, RBD was controlled in six patients, significantly improved in four, and initially improved but subsequently returned in two; no improvement occurred in one patient and increased RBD frequency/severity occurred in one patient. The effective melatonin doses were 3 mg in two cases, 6 mg in seven cases, 9 mg in one case, and 12 mg in two cases. Five patients reported side-effects, which included morning headaches (2), morning sleepiness (2), and delusions/hallucinations (1); these symptoms resolved with decreased dosage. The mean duration of follow-up was 14 months (range 9-25 months), with eight patients experiencing continued benefit with melatonin beyond 12 months of therapy. In this series, persistent benefit with melatonin beyond 1 year of therapy occurred in most but not all patients. Melatonin can be considered as a possible sole or add-on therapy in select patients with RBD. Prospective, long-term, controlled trials with melatonin are warranted in a larger number of patients with RBD associated with a variety of neurologic symptoms and disorders.
HD-16 among the three groups.
Results of the different dimensions in the specific HD-16 scale
To design a new quality of life (QoL) instrument specifically for insomnia. Based on severe insomniacs' interviews, we have built a new quality of life scale that has been tested in one group of 240 severe insomniacs, in one group of 422 mild insomniacs and in one group of 391 good sleepers. Ten steps led to the construction of a specific QoL scale. Five dimensions have been validated as both relevant and independent from each other. Sixteen items out of the 43 initially tested were retained and significantly different within the groups in each dimension. Based on the 16 items selected, we called the scale Hotel Dieu 16 (HD-16). We have therefore verified the score's specificity (correlation score of +0.36) and the reliability of the scale (Cronbach coefficient alpha=0.78). HD-16 may be used as a focused instrument to better assess an insomniac's quality of life.
Sleep disturbance is a common symptom of tobacco withdrawal and might contribute to early relapse vulnerability in abstinent smokers. This study was designed to compare the effects on sleep of nicotine patches applied either for 24 h (Nicopatch) or 16 h (Nicorette). During a short smoking cessation period (48 h), this open-label, randomised, two-period crossover study compared the effects on sleep of the two nicotine patches in 20 heavy smokers (9 women, 11 men). During each period, polysomnographic recordings were performed from 12 pm to 7 am for two consecutive nights (baseline and treatment nights). Smoking cessation started from 8 pm the day of the baseline sleep recordings, and treatments were applied around 8 am the following morning. Compared to the 16-h nicotine patch, smokers who received the 24-h nicotine patch experienced significantly less microarousals, a greater proportion of slow wave sleep, a higher REM density and higher rapid eye movement (REM) beta activities. The results of this study suggest that a 24-h nicotine patch is more efficient than a 16-h nicotine patch to alleviate tobacco withdrawal-induced sleep disturbances.
Objective: To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder. Methods: The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria. Results: 172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinson's disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimer's disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features. Conclusions: In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.
Boissier de Sauvages de La Croix and Gilles de la Tourette, French neurologists, noticed that patients with "anxiety in the lower limbs, shooting pain, tingling legs" may have an insomnia "at the time of wake-sleep transition [and] experience sudden jerks in the lower limbs." Their descriptions confirm that the clinical features of RLS were previously described in French literature in the 18th century.
A multitude of studies used external sensory stimuli to experimentally induce electroencephalographic, vegetative or behavioral reactions in the sleeping subject, either to gather information on the nature of sleep or to induce sleep fragmentation. But Ernst Otto Heinrich Kohlschütter was the first to systematically investigate the change of awakening thresholds across the night, generating a sleep depth curve for his 1862 dissertation "Measurements on the Firmness of Sleep" ("Messungen der Festigkeit des Schlafes"). For the time, his concepts of sleep and the design of his experiments were impressive. A re-analysis of his data with modern regression techniques and a comparison with a polysomnographic laboratory study on the effects of traffic noise on sleep shows that he correctly captured the typical evolution of awakening thresholds across the night, with only 74 measurements in a single subject. Nevertheless, Kohlschütter's analyses were hypothesis driven, as he discarded almost 50% of the data points to derive what he called an "idealized curve of sleep". This does not belittle his achievement of being the first to systematically investigate arousal thresholds across the night without the help of electrophysiologic measurement techniques.
In 1888, Eduard Robert Michelson (1861-1944), a student of the German psychiatrist Emil Kraepelin at the university clinic of Dorpat (Tartu, Estonia), established a sleep laboratory in which he conducted a fundamental and innovative study about the physiology of sleep regulation. Based on the then current theoretical concepts and methodological techniques of Wundtian experimental psychology, and Kraepelin's research strategy, Michelson, for the first time, was able to describe a "very strange phenomenon" of human sleep - a "remarkable periodicity" of the "sleep depth curve." Furthermore, Michelson postulated that this within sleep periodicity should not be explained as an effect of external stimuli but rather of "antagonistic" physiological processes. Unfortunately, Michelson's publication of 1891 fell almost into oblivion as contemporary theories of sleep could not offer an explanation for his findings. Nevertheless, Michelson's "Untersuchungen über die Tiefe des Schlafes" should be considered as one of the key studies in the development of sleep research in the 19th century and a pioneer description of within sleep periodicity.
To assess the prevalence of insomnia symptoms, their associated factors and daytime symptoms in the general population of Sweden. This is a cross-sectional postal survey performed in the general population of Sweden aged between 19 and 75 years (6 million inhabitants). A total of 1209 out of 1705 randomly selected participants from the National Register of the Total Population completed the questionnaire. The participation rate was 71.3%. Participants filled out a paper-pencil questionnaire composed of 157 items covering sociodemographic characteristics, sleeping habits and environment, sleep quality and sleep symptoms, and health status. We found 32.1% (95% confidence interval: 29.5-34.8%) of the sample reported having difficulty initiating (DIS) or maintaining sleep (DMS) or non-restorative sleep accompanied with sufficient sleep (NRS) at least 4 nights per week: 6.3% of the sample had DIS, 14.5% had DMS and 18.0% had NRS. Results from logistic regressions showed that restless legs symptoms, breathing pauses during sleep and depressive or anxious mood were associated with DIS and DMS but not NRS. Living in an urban area (OR:2.0) and drinking alcohol daily (OR:4.6) were associated only with NRS. Daytime symptoms were reported by over 75% of subjects with insomnia symptoms. DIS, DMS and NRS were associated with daytime fatigue but not excessive sleepiness as measured by the Epworth scale. DIS was associated with the use of sleeping pills or natural sleeping aid compounds in multivariate models. Insomnia symptoms occurring at least 4 nights per week are frequent in Sweden, affecting about a third of the population. Subjects with NRS have a distinctly different profile than those with DIS or DMS, which suggests different etiological causes for this symptom.
Idiopathic (primary) insomnia can be difficult to treat; only two prior cases responsive to opiate therapy have been reported. A case is now presented of severe, idiopathic, childhood-onset, familial insomnia, with increased libido, absence of psychopathology, tardive emergence of restless legs syndrome (RLS), and selective response to opiate therapy. A 39-year-old woman was referred in 1981 by her physician who had discovered 3 years earlier that propoxyphene treatment of migraines also controlled her chronic insomnia. She had experienced severe insomnia since childhood, and during early adulthood the insomnia intensified, as she would sleep 0-3 h nightly and never napped. Daily generalized motor restlessness resulted in her frequently walking around the house while feeling exhausted. The quality of her life was considerably compromised by her insomnia, motor restlessness, and by an increased libido that was present since puberty and that was only partially relieved by having sex repeatedly with her husband. Nightly opiate therapy for 19 years has controlled the insomnia, motor restlessness, and excessive libido without affecting her normal libido. The insomnia had not responded to treatment with >25 agents covering >10 pharmacologic categories. During her first (unmedicated) polysomnographic (PSG) study in 1981, she slept 0 min while spending 436 min in bed. In 1984, four consecutive PSG studies were conducted in a design that confirmed the efficacy of propoxyphene therapy of her insomnia. In 1990, an ambulatory PSG revealed two runs of EEG rhythmic paroxysmal activity arising from sleep and wakefulness, without clinical correlate. Neurologic history was negative for seizures, but positive for complete right carotid artery occlusion and three transient ischemic attacks. At age 55 years, typical RLS emerged that was controlled with levodopa therapy, and a concurrent relapse of insomnia was controlled with oxycodone replacing propoxyphene. Nightly opiate therapy of severe idiopathic (primary) insomnia can remain effective during very long-term clinical follow-up. Guidelines are provided for when to consider such an unusual treatment in other cases of severe, chronic insomnia.
The association between sleep habits and hemoglobin A1c (HbA1c) level has not been sufficiently examined. In the present study of residents in a local community, the associations between sleep duration and HbA1c level were examined. Self-administered questionnaires were mailed to 1062 residents in a rural community in Japan, and completed questionnaires were collected. At the time of collection, the fasting plasma glucose and Hb(1c levels were measured using peripheral blood samples. For the analyses, values that were considered to represent high levels were a fasting plasma glucose level of 126mg/dl and a HbA1c level of 6.5%. Logistic regression analyses were performed to examine the associations between sleep duration and high fasting plasma glucose or high HbA1c levels. The prevalence of high fasting plasma glucose and high HbA1c levels was significantly high (p<0.01) in subjects with a short or a long sleep duration. Logistic regression analyses demonstrated a significant association between high HbA1c level and sleep duration. The adjusted odds ratios for a high HbA1c level showed high values with regard to both short and long sleep durations. HbA1c level showed a U-shaped association with sleep duration. These results suggest that there may be an appropriate range of sleep duration in individuals with glucose tolerance disorders. It is expected that the present findings will contribute to the treatment and prevention of diabetes mellitus.
The mandibular advancement appliance (MAA) is now recognized as a first-line therapy option for mild to moderate obstructive sleep apnea syndrome (OSAS). The aim of this follow-up study was to re-assess the long-term efficacy of MAAs provided to patients in a previous comparative study. Sixteen subjects had participated in a previous comparative study in which the efficacy and compliance of two MAAs (Klearway - K and Silencer - S) were compared in a randomized cross-over design. At the end of the previous comparative study, subjects selected the MAA they preferred. Nine chose the K and seven the S. Fifteen subjects were available for a follow-up interview and 14 (4 women and 10 men; mean ± SEM: 51.9 ± 1.7 y.o.) agreed to participate in an overnight sleep recording at a hospital sleep laboratory from January to February 2009. The mean time lag between the end of the previous comparative study and the follow-up was 40.9 ± 2.1 months (range of 2.5-4.5 years). Comparisons were made across the three polysomnographic evaluations (PSGE): baseline, the night with the appliance of their choice at the end of the previous comparative study, and the follow-up night. Subjects completed the Epworth sleepiness scale (ESS), the fatigue severity scale (FSS), and a quality of life questionnaire (FOSQ). At the follow-up, the respiratory disturbance index (RDI) remained significantly lower than baseline (p<0.001). Questionnaire responses revealed that ESS, FSS, and FOSQ remained improved at follow-up (p<0.02). Body mass index (BMI) increased slightly from baseline to follow-up (p<0.05). Diastolic and systolic blood pressure and cardiac rhythm decreased significantly from baseline to follow-up. The MAAs remained effective in improving RDI, sleepiness, blood pressure, cardiac rhythm, fatigue, sleep quality, and quality of life over a period of 2.5-4.5 years. The rise in BMI is a concern that merits further examination.
To examine the associations between sleep hygiene and sleep patterns in children ages newborn to 10 years. The relationships between key features of good sleep hygiene in childhood and recognizable outcomes have not been studied in large, nationally representative samples. A national poll of 1473 parents/caregivers of children ages newborn to 10 years was conducted in 2004. The poll included questions on sleep hygiene (poor sleep hygiene operationally defined as not having a consistent bedtime routine, bedtime after 9:00 PM, having a parent present when falling asleep at bedtime, having a television in the bedroom, and consuming caffeinated beverages daily) and sleep patterns (sleep onset latency, frequency of night wakings, and total sleep time). Across all ages, a late bedtime and having a parent present when the child falls asleep had the strongest negative association with reported sleep patterns. A late bedtime was associated with longer sleep onset latency and shorter total sleep time, whereas parental presence was associated with more night wakings. Those children (ages 3+) without a consistent bedtime routine also were reported to obtain less sleep. Furthermore, a television in the bedroom (ages 3+) and regular caffeine consumption (ages 5+) were associated with shorter total sleep time. Overall, this study found that good sleep hygiene practices are associated with better sleep across several age ranges. These findings support the importance of common US based recommendations that children of all ages should fall asleep independently, go to bed before 9:00 PM, have an established bedtime routine, include reading as part of their bedtime routine, refrain from caffeine, and sleep in bedrooms without televisions.
Previous studies have shown an inconsistent association between sleep duration and hypercholesterolaemia. This study examined the association between sleep duration and hypercholesterolaemia in a nationally representative sample of US adults. A cross-sectional study of 16,652 participants in the 2008 National Health Interview Survey (aged ⩾18years, 52.5% women) was conducted. Sleep duration was categorized as ⩽5, 6, 7, 8, or ⩾9h. Hypercholesterolaemia (n=5578) was assessed by questionnaire. A significant gender difference was found in the association between sleep duration and hypercholesterolaemia (P interaction=0.003). Among women, sleep duration ⩽5h was positively associated with hypercholesterolaemia after adjusting for potential confounders and mediators including physical activity, psychological distress, body mass index, diabetes mellitus, and hypertension. Compared with a sleep duration of 7h (referent), the multivariate odds ratio (OR) of hypercholesterolaemia was 1.27 (95% confidence interval [CI] 1.04-1.54) for sleep duration ⩽5h. In contrast, among men, sleep duration ⩾8h was inversely associated with hypercholesterolaemia. Compared with a sleep duration of 7h (referent), the multivariate OR of hypercholesterolaemia was 0.80 (95% CI 0.69-0.94) and 0.78 (95% CI 0.60-1.00) for sleep durations of 8 and ⩾9h, respectively. In subgroup analyses, the positive association between sleep duration ⩽5h and hypercholesterolaemia in women, and the inverse association between sleep duration ⩾8h and hypercholesterolaemia in men, were more pronounced among those aged <60 years and race/ethnic groups other than non-Hispanic Whites. Sleep duration ⩽5h was positively associated with hypercholesterolaemia in women, whereas sleep duration ⩾8h was inversely associated with hypercholesterolaemia in men.
To evaluate polysomnographic (PSG) and self-reported measures of the efficacy and safety of EVT 201 in patients with primary insomnia. Following clinical and PSG screening, 75 patients (mean age: 45.1+/-11.2 y; 50 f, 25 m) meeting DSM-IV criteria for primary insomnia entered this crossover study and were randomly assigned to double-blind treatment sequences of 1.5 mg or 2.5 mg EVT 201, or placebo using a balanced Latin square design. For each study condition study medication was administered on two consecutive nights and PSG and self-reported data were collected. Safety assessments included physical examination, clinical laboratory measures, electrocardiogram, documentation of adverse events, and the digit symbol substitution test (DSST) and self-reported sleepiness/alertness ratings to detect residual sedation. Data were collected at five US sleep laboratories. Efficacy analyses were performed for the 67 patients completing the study. Safety analyses included all 75 randomized patients. On PSG measures compared to placebo, EVT 201 1.5 mg and 2.5 mg increased total sleep time (TST; 33.1, 45.0 min; both p<0.0001), reduced wake after sleep onset (WASO; -16.7, -25.7 min; both p<0.0001), reduced latency to persistent sleep (LPS; -17.0, -20.7 min; both p<0.0001), and reduced the number of awakenings (-1.2, -2.6; both p<0.0001). Significant reduction of wake time was seen with 1.5 mg during each of the first three quarters of the night (p<0.0001-0.002), and with 2.5 mg in all four quarters (p<0.0001-0.0005). Both doses also improved all key self-reported measures of sleep including total sleep time (rTST; 51.9, 51.1 min; both p<0.0001), wake after sleep onset (rWASO; -29.3, -29.6 min; both p<0.0001), sleep latency (rSL; -24.0 min, p<0.004; -25.1 min, p<0.0002), and number of awakenings (rNAW; -1.1, -1.2; both p<0.0001). Sleep quality was also improved by both doses. Self-rated sleepiness in the morning did not differ from placebo for either dose; however, there was a small negative effect on the DSST for both doses. Both doses had similar effects on sleep architecture including an increase in Stage 2 sleep and REM latency and a small, but significant decrease in REM (REM -5.7, -8.3 min; p=0.0175, p=0.0006). No effect on other sleep architecture parameters, including SWS, was seen. EVT 201 was well tolerated. No serious or unexpected adverse events were reported. This first study of EVT 201 in adult patients with primary insomnia demonstrated improved measures of sleep onset and sleep maintenance, including during the third and fourth quarters of the night. Adverse events were infrequent and all were mild to moderate in severity.
Two doses of EVT 201, a partial positive allosteric modulator of the GABA(A) system, were evaluated in elderly primary insomnia patients with daytime sleepiness. Participants were 149 elderly patients with DSM-IV primary insomnia including evidence of daytime sleepiness (53 males, 96 females; mean age 71.3yrs, range 65-86yrs). A randomized, multicentre, double-blind, placebo-controlled, parallel-group design was used to assess the hypnotic efficacy of EVT 201 1.5 and 2.5mg during seven consecutive nights. Polysomnography (PSG) was performed on nights 1, 6 and 7 of treatment. Daytime assessments on Day 8 included the multiple sleep latency test (MSLT), Rey Auditory Verbal Learning Test (RAVLT), Psychomotor Vigilance Task (PVT) and the Karolinska Sleepiness Scale (KSS). The primary endpoint was total sleep time (TST) and the key secondary endpoint was mean MSLT latency. Compared to placebo, EVT 201 1.5 and 2.5mg increased TST (30.9, 56.4min, respectively; p=0.0001, p<0.0001); reduced wake after sleep onset (WASO; -15.2, -36.1min, respectively; p=0.014, p<0.0001); reduced latency to persistent sleep (LPS; -15.9, -19.9min, respectively; p=0.009, p=0.001). The 2.5mg dose also reduced WASO in hours 5-8 (-16.3min, p=0.001). Both doses also improved subjective sleep quality and usual subjective efficacy measures. A significantly longer mean MSLT latency was observed on Day 8 with both doses, compared to placebo (2min increase; p=0.03, both doses). The PVT, RAVLT, and POMS did not differ among treatment groups. No serious or unexpected treatment emergent adverse events were noted. EVT 201 improved PSG measures of sleep onset and sleep maintenance and significantly reduced daytime physiological sleep tendency. These findings suggest that treatment of primary insomnia in older patients has the potential to improve daytime sleepiness as well as sleep.
The aim of this study was to examine the effects of extended work hours (10 h on, 14 h off for 21 days) on sleep and sleepiness in an extreme and isolated environment in the far north (Spitsbergen, 78 degrees north). We wanted to examine whether sleep duration, sleepiness and other parameters changed over the 3-week working period and whether the parameters differed between day and night shifts. The work consisted of tunnel construction in Svea, Spitsbergen. The participants worked alternate fixed day shift (06:00-16:00) or fixed night shift (18:00-04:00) for a 21-day work period in a counterbalanced, crossover design. The participants were 25 male workers (age 24-60 years). We used subjective and objective measures of sleep (diary and actigraphy) and a subjective daytime sleepiness and function questionnaire. The workers had a high sleep efficiency measured both subjectively and objectively. This did not change across days or between day and night shifts. Total sleep time was significantly shorter (about (1/2) to 1h) during the day shift period than during the night shift period, as measured both subjectively and objectively, but did not differ across days. Subjective ratings of sleepiness did not differ between shifts. There were few differences between the day and night shift periods and across the 21-day working period, as measured both subjectively and objectively. The subjects experienced few problems and seemed to adapt easily to their work schedule. This contrasts with what is usually the case in more conventional shift work situations, where workers do not adapt well, as measured by sleepiness and various sleep parameters.
Background: Restless legs syndrome (RLS) is a disorder characterized by disagreeable sensations in the legs that occur at rest and are relieved by movement. These symptoms, which are worse at night, may result in sleep onset or sleep maintenance insomnia. Most patients are found on polysomnography (PSG) to have periodic limb movements in sleep (PLMS). The disorder, idiopathic in most cases, may be sometimes associated with specific disorders.Methods: Using the Province of Manitoba Health database, we compared the diagnoses made in the 5 years prior to sleep laboratory evaluation of 218 patients (103 men and 115 women) with RLS and 872 matched control subjects from the general population.Results: We found that 43.7% of male RLS patients vs. 10.4% of male controls and 46.1% of female RLS patients vs. 22.8% of female controls had been diagnosed as having psychological/psychiatric (most often depression) disorders (P<0.05). Extrapyramidal disease or movement disorders were previously diagnosed in 17.5% of male RLS patients vs. 0.2% of male controls and in 23.5% of female patients vs. 0.2% of female controls (P<0.05). Many patients had been previously diagnosed with disorders of the musculoskeletal system: 35.9% of male patients vs. 22.8% of male controls and 49.6% of female RLS patients vs. 23.3% of female controls had been diagnosed as having diseases of joints (male; P=ns, female; P<0.05). Disorders of the back were also more frequently diagnosed in RLS patients: 21.4% of male patients vs. 13.1% of male controls and 38.3% of female patients vs. 15.0% of female controls (male; P=ns, female; P<0.05).Conclusions: We conclude that RLS patients are much more likely to have previously been diagnosed with extrapyramidal disorders, musculoskeletal disorders, depression, and painful conditions such as joint and back disorders.
To investigate the sleep-wake behavior and performance of a random sample of European truck drivers. The drivers completed a questionnaire concerning sleep-wake habits and disorders experienced during the previous 3 months. In addition, they were asked to complete a sleep and travel log that included their usual work and rest periods during the previous two days. They answered questions concerning working conditions and reported their caffeine and nicotine intake during their trips. A total of 227 drivers, mean age 37.7+/- 8.4 years (96.2% acceptance rate), participated in the study. The drivers were found to have a fairly consistent total nocturnal sleep time during their work week, but on the last night at home prior to the new work week there was an abrupt earlier wake-up time associated with a decrease in nocturnal sleep time. Of the drivers, 12.3% had slept less than 6 h in the 24 h previous to the interview and 17.1% had been awake more than 16 h. Shifting sleep schedules between work and rest periods can generate long episodes of wakefulness. This type of sleep deprivation is rarely investigated. Its is usually not taken into consideration when creating work schedules, but affects the performance of drivers. Unsuspected shifts occur at the onset of a new workweek. Sleep hygiene education for professional drivers is still far from perfect.
Few studies have examined the impact of continuous positive airway pressure (CPAP) therapy on short-term memory (STM) over sustained wakefulness in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). We have investigated if impaired STM can be reversed by CPAP treatment in a 24-h sustained wakefulness paradigm. Our follow-up study was conducted with repeated-memory tasks within 12 OSAHS patients and 10 healthy controls who underwent three 32-h sessions, one before CPAP (T0) and the second (T3) and the third (T6), after 3 and 6months of treatment, respectively, for OSAHS patients. Each session included one night of sleep followed by 24h of sustained wakefulness, during which both groups performed STM tasks including both digit span (DS) and Sternberg tasks. Untreated OSAHS patients had no deficit in the forward DS task measuring immediate memory but were impaired in STM, especially working memory assessed by the complex Sternberg task and the backward DS. However, only performance in the latter was improved after 6months of CPAP treatment. Because the high level of memory scanning required high speed in information processing, persistent impairment on the complex Sternberg task may be attributable to working memory slowing, possibly enhanced by sustained wakefulness.
Objective: The investigations regarding the effect of obstructive sleep apnoea syndrome (OSAS) on hypothalamo-pituitary-adrenal (HPA) axis revealed conflicting results. We aimed to evaluate the effects of OSAS on HPA-axis with dynamic tests. Methods: This study was carried out on 26 patients with OSAS and 15 subjects without OSAS which, were defined according to the International Classification of Sleep Disorders. Patients were enrolled from either Endocrinology outpatient clinic or Neurology Sleep Center. Participants for the control group were included from the patients admitting to Endocrinology Department with the complaint of obesity or volunteers from hospital staff. All the participants were evaluated by polysomnography (PSG) and dynamic tests of HPA axis (dexamethasone suppression test, 1 and 250μg ACTH and glucagon stimulation tests). Results: Serum basal and peak cortisol levels were found to be lower in OSAS patients when compared to the control group during 1μg ACTH and glucagon stimulation tests. When the area under curve (AUC) of cortisol responses to dynamic stimulation tests were calculated according to trapezoid formula, patients with OSAS were found to have lower values compared to control group. AUC responses of all three dynamic stimulation tests were found to be negatively correlated with AHI. Conclusion: OSAS is associated with relative hypocortisolemia in the morning with reduced responses to 1 and 250μg ACTH and glucagon stimulation tests.
To find out if childhood adversities predict poor sleep quality in working age. Survey data from the Health and Social Support (HeSSup) study was used (N=25,605, 59% women). Negative childhood adversities and quality of sleep in adulthood were assessed by the questionnaire in 1998. Multinomial regression models were used. A graded association between childhood adversities and the quality of sleep in adulthood was found. Odds ratio (OR) of poor quality of sleep for those with multiple childhood adversities (3-6) was 3.64 (95% CI 2.94-4.50). The association between childhood adversities and the quality of sleep remained significant after adjustments for work status, use of psychotropic drugs, health behaviours, recent life events and child-parent relationships. Poor quality of sleep was clearly increased among those with both poor child-mother (OR 10.4, 95% CI 6.73-16.07) or poor child-father (OR 5.4, 95% CI 3.89-7.50) relationships and multiple childhood adversities. In the analyses of specific childhood adversities, frequent fear of a family member and serious conflicts in the family showed the strongest associations. The strong association between childhood adversities and the quality of sleep in adulthood highlights the importance of early life circumstances on adult health. Early stage recognition, prevention and supportive measures against childhood adversities and serious family conflicts should be promoted.
The circadian release of the hormone melatonin is regulated by the suprachiasmatic nucleus (SCN), which feeds back into the nucleus to modulate sleep and circadian phase through activation of the MT(1) and/or MT(2) melatonin receptors. Considering the functions of the SCN as a sleep and circadian rhythm regulator, melatonin and melatonin receptor agonists have attracted interest as being possible treatments for sleep and circadian rhythm sleep disorders. Part of this interest has centered on elucidating which melatonin receptors are targets for the regulation of these functions within the SCN. Two G-protein coupled melatonin receptors, the MT(1) and MT(2), inhibit neuronal activity and phase shift circadian firing rhythms in the SCN, respectively. Recent reports have uncovered possible interactions between the two types of receptors in the mammalian SCN, as well as the role of physiological and supraphysiological levels of melatonin on the molecular pharmacology and cellular changes of human and rodent melatonin receptors via desensitization and internalization mechanisms. These data outline the complexity of the interplay between melatonin and its receptors in the SCN and their corresponding roles in sleep and circadian regulation. Although further studies are necessary, a great deal of progress has been made toward understanding how melatonin and its agonists contribute to sleep and circadian phase changes, and how best to develop compounds that can target the functions of the SCN specifically and effectively.
A 35-year-old woman with childhood-onset parasomnia, marked by arm waving with talking and shouting, developed marital discord solely because her parasomnia disrupted her husband's sleep. She became progressively depressed after her husband began to sleep in a separate bedroom, eventually becoming acutely suicidal. There had been no psychiatric history prior to her marriage. An evaluation with a sleep specialist-neurologist and polysomnographic monitoring confirmed the diagnosis of idiopathic REM sleep behavior disorder (RBD). Treatment with clonazepam, 1.0-1.5 mg at bedtime controlled her RBD and she again slept with her husband, which fully resolved their marital discord and her secondary depression.
Top-cited authors
Richard P Allen
  • Johns Hopkins University
Christian Guilleminault
  • Stanford University
Raffaele Ferri
  • Oasi Research Institute - IRCCS
Birgit Högl
  • Medizinische Universität Innsbruck
Sudhansu Chokroverty
  • Seton Hall University