Variants of the orexin2/hcrt2 receptor gene identified in patients with excessive daytime sleepiness and patients with Tourette's syndrome comorbidity.

The orexin-2/hypocretin-2 (OX2R) receptor gene is mutated in canine narcolepsy and disruption of the prepro-orexin/hypocretin ligand gene results in both an animal model of narcolepsy and sporadic cases of the human disease. This evidence suggests that the structure of the OX2R gene, and its homologue, the OX1R gene, both members of the G protein-coupled receptor (GPCR) family, and the gene encoding the peptide ligands, the prepro-orexin/hypocretin gene, may be variables in the etiology of sleep disorders. We report a single stranded conformational polymorphism (SSCP) analysis of the coding regions of these genes in idiopathic sleep disorder patients diagnosed with excessive daytime sleepiness (EDS) (n = 28), narcolepsy (n = 28), Tourette's syndrome/chronic vocal or motor tic disorder (n = 70), and control subjects (n = 110). Two EDS patients showed a Pro11Thr change. One Tourette's syndrome patient was found to have a Pro10Ser alteration. The Pro10Ser and Pro11Thr variants were not found in non-disease populations. Analysis of the ability of the mutant receptors to mobilize calcium compared to the wild-type receptor in response to orexin agonists indicated that they resulted in decreased potency at high (etaM) concentrations of orexin ligands. Further work is warranted to study the variability of the orexin/hypocretin system in a variety of disorders characterized by EDS.     

Sleep-related myoclonus in rheumatic pain modulation disorder (fibrositis syndrome) and in excessive daytime somnolence

We describe a new syndrome, Rheumatic Pain Modulation Disorder (RPMD) ("fibrositis syndrome") with sleep-related myoclonus (involuntary periodic leg movements). Measures of sleepiness, fatigue and pain, before and after sleep, and aspects of sleep of nine subjects (Ss) with RPMD and sleep-related myoclonus were compared to nine subjects with excessive daytime somnolence and sleep-related myoclonus. In eight of the RPMD with sleep-related myoclonus and three of those with daytime sleepiness, an alpha (7.5-11 Hz) EEG Non-Rapid Eye Movement sleep disorder was demonstrated. The RPMD with sleep-related myoclonus group contained a greater number of women, more pain, morning fatigue, and disturbances in sleep (more stage changes and alpha EEG sleep prior to leg myoclonus); but in comparison to the sleep-related myoclonus, daytime somnolent group, there were no differences in evening and morning sleepiness, number of limb movements, movement arousals, awakenings after sleep onset, sleep duration, and percent sleep stages.     

Narcolepsy and the ability to resist sleep

We describe five patients who presented with irresistible daytime sleepiness and who have the clinical and laboratory features of narcolepsy but differ from most patients with narcolepsy in their ability to resist falling asleep during the daytime. All of the patients described partial or complete remission of their symptoms. Using an HLA marker, the expected haplotypes for narcolepsy were found, but no specific genetic features were found associated with chromosome 6p that differentiated this group from patients with typical narcolepsy. Problems are discussed in the laboratory assessment of such patients using both the multiple sleep latency test and the maintenance of wakefulness test.     

The significance of the sleeping-waking brain for the understanding of widespread musculoskeletal pain and fatigue in fibromyalgia syndrome and allied syndromes

The clinical focus of rheumatologists on the widespread pain and numerous tender points in specific anatomic regions in their patients who show no evidence for disease pathology has lead to the characterization of such peripheral symptoms as a specific disorder of the musculoskeletal system, now commonly known as fibromyalgia. This rheumatologic diagnostic entity has resulted in relative inattention to an understanding of their patients' common complaints of unrefreshing sleep, chronic fatigue and psychological distress. Experimental evidence from humans and animal studies indicate that there is an inter-relationship of disturbances in the physiology of the sleeping-waking brain with the widespread musculoskeletal pain, chronic fatigue, and psychological distress in patients with hitherto unexplained pain/fatigue illnesses, e.g., fibromyalgia and chronic fatigue syndromes. The emerging knowledge of the dysfunction of the nervous system in such patients has lead to the study of novel medications that affect neurotransmitter functions, e.g., pregabalin, serotonin/noradrenaline compounds and sodium oxybate that are shown to improve many of the symptoms of such patients.     

Role of diffuse airway obstruction in the hypercapnia of obstructive sleep apnea

The mechanisms responsible for the development of chronic hypercapnia in patients with obstructive sleep apnea (OSA) are not well defined. Therefore, we tested the hypothesis that diffuse airway obstruction may be involved by studying 50 patients with a well-documented OSA syndrome. Seven patients had daytime hypercapnia with a mean PaCO2 of 51 +/- 2 (SEM) mm Hg, compared to a PaCO2 of 35 +/- 1 in the other 43 patients. There were no differences between the 2 groups in the number or duration of nocturnal obstructive events. In contrast, the hypercapnic patients were significantly heavier than the normocapnic patients (body weight, 189 +/- 11 versus 148 +/- 6% of ideal; p less than 0.005) and had evidence of diffuse airway obstruction, as indicated by an increased residual volume and a reduction in all expiratory flow rates. When the hypercapnic patients were compared with a weight-matched group of 9 normocapnic patients (body weight, 196 +/- 8% of ideal), there were still no differences in nocturnal obstructive events, but the differences in tests of airway mechanics persisted. Multiple regression analysis of PaCO2 against several anthropometric, respiratory physiologic, and polysomnographic variables revealed that only 2 variables (expiratory reserve volume and FEV1/FVC), both of which are influenced by airway mechanics, were significantly correlated with PaCO2 (multiple r = 0.78; p = 0.0001). The findings suggest that OSA alone does not produce daytime hypercapnia even in obese patients, and that the presence of diffuse airway obstruction is an important predisposing factor to the development of chronic CO2 retention in such patients.     

The probability of recovery and return to work from work disability as a function of time

This paper describes a prospective longitudinal cohort study of musculoskeletal soft tissue pain impairment following a work related injury. It focuses on specific, univariate prognostic factors indicated in previous research studies that might affect the likelihood that injured workers will return to work or remain on work disability at any point in time. These factors include gender, age, return to work attempts and site of injury. Life table analysis was used to model the probability of work disability. The results showed that different disability and return to work patterns emerged for males and females. Males were more likely to return to work; however, females had a higher probability than males of remaining at work once they returned to work. Older workers had the highest probability of being off work any given number of days after injury; were less likely to return to work, and if they did, had a higher probability of becoming disabled again. Efforts to return early to work contributed to a decrease in overall work disability. Workers with low back injuries had a greater likelihood of recurrence compared to injuries at other body sites.Project supported by the Workers' Compensation Board of Ontario and the Institute of Work and Health. Actuary Consultant: Nicolas P. Crook. F.S.A.     

Comparison of clinical and computed tomographic staging of head and neck tumors

The extent of tumor was staged independently using conventional clinical methods and high-resolution computed tomography (CT) in 100 patients with tumors at the base of the skull, nasopharynx, oropharynx, hypopharynx, larynx, nose, and paranasal sinuses. Conventional clinical methods used for staging included physical examination, routine biopsy, routine radiography, tomography, and sonography when appropriate. In 10 patients, CT identified tumors that had not been apparent clinically; eight of these were in the nasopharynx and two in the hypopharynx. In another 26 patients, CT showed the tumor to be more locally extensive than had been evident clinically; 12 of these tumors were in the oropharynx. A new technique of CT-guided biopsy of head and neck tumors was used in 20 patients to attain histologic information or to confirm the extent of the tumor. Thus, information obtained by CT scanning or CT-guided biopsy significantly altered treatment planning in 36 of the 100 patients.