DQ (rather than DR) gene marks susceptibility to narcolepsy.
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Black People↗
Biomedical subjects
C Guilleminault
Publications and source records attributed to C Guilleminault.
Breathing disorders during sleep in myasthenia gravis.
Twenty consecutive patients (16 women and 4 men), with a mean age of 40 years, who were diagnosed and treated for myasthenia gravis were enrolled in a prospective investigation aimed at determining the amount of respiratory disturbance occurring during sleep while they received treatment. Patients were clinically evaluated to determine body mass index, presence of upper airway anatomical abnormalities, level of functional capacity and activity scored from 1 to 5, and presence of sleep-related complaints. They underwent daytime pulmonary function tests, determination of maximal static inspiratory pressure, measurement of transdiaphragmatic pressure, and measurement of arterial blood gas levels. Polygraphic monitoring during sleep, evaluating respiration and oxygen saturation, was also performed. Results indicated that in the studied population, all subjects had evidence of daytime diaphragmatic weakness as demonstrated by transdiaphragmatic pressure measurements, independent of the degree of autonomy and functional capacity and activity level reached. Older patients with moderately increased body mass index, abnormal total lung capacity, and abnormal daytime blood gas concentrations were the primary candidates for development of diaphragmatic sleep apneas and hypopneas, and oxygen desaturation of less than 90% during sleep. However, these clear indicators were not found in all subjects with sleep-related disordered breathing. Rapid-eye-movement sleep was the time of highest breathing vulnerability during sleep. Sleep-related complaints may also help identify subjects at risk for abnormal breathing during sleep, even when daytime functional activity is judged normal.
Adult↗
DQB1-0602 (DQw1) is not present in most nonDR2 Caucasian narcoleptics.
Human narcolepsy is a genetically determined disorder of sleep strongly associated with the human leucocyte antigens (HLA) DR2 and DQw1. In black narcoleptic patients, susceptibility for narcolepsy is more closely related to a specific gene subtype of DQw1, DQB1-0602, than to DR2. About 30% of black narcoleptic patients are nonDR2, but all carry the HLA DQB1-0602 gene. In the present study, we have tested caucasian nonDR2 cataplectic patients (6 sporadic cases and 7 familial cases from 3 multiplex families) for the presence of the HLA DQB1-0602 and DQA1-0102 (DQw1) using a specific polymerase chain reaction (PCR)-oligotyping technique. None of the patients was DQB1-0602 or DQA1-0102 positive, thus proving that, in caucasians, DQB1-0602 and DQA1-0102 (DQw1) are not prerequisites for the diagnosis of narcolepsy. Further studies with more patients are warranted to exclude the possibility that a few caucasian patients carry rare haplotypes with DQB1-0602 independently of DR2.
Amino Acid Sequence↗
Polygraphic investigation of respiration during sleep in infants and children.
Controls of respiration have different settings during sleep than during wakefulness. Respiration will also be influenced by sleep state organization and circadian rhythm. Polygraphic monitorings in infants and children must take into account the timing of the longest sleep and longest wakeful periods and the distribution of sleep states. Attention must be given not only to "apneas" and blood gas changes monitored noninvasively but also to breathing frequency, upper airway resistance, and the impact of respiratory changes on the cardiovascular system and sleep continuity. Respiratory efforts and upper airway resistance are responsible for important mechanical intrathoracic changes, which must be evaluated, since they have clinical consequences. For example, infants with an apparent life-threatening event may have an unrecognized increase in upper airway resistance long before having a mixed or obstructive sleep apnea. Muscle disorders in young children require regular sleep monitoring whose results will strongly influence therapeutic approaches. Therapy may change over time, depending on the prominence of the inspiratory muscle weakness or the importance of the mandibular abnormalities induced by the muscle disorder and its impact on upper airway resistance during sleep. At times, it is difficult to avoid sleep disturbances with aggressive investigation of breathing during sleep, and several successive days of monitoring may be needed to determine sleep-related pathology.
Airway Resistance↗
Cardiovascular changes associated with obstructive sleep apnea syndrome.
Five men free of lung or cardiovascular diseases and with severe obstructive sleep apnea participated in a study on the impact of sleep states on cardiovascular variables during sleep apneas. A total of 128 obstructive apneas [72 from stage 2 non-rapid-eye-movement (NREM) sleep and 56 from rapid-eye-movement (REM) sleep] were analyzed. Each apnea was comprised of an obstructive period (OP) followed by a hyperventilation period, which was normally associated with an arousal. Heart rate (HR), stroke volume (SV), cardiac output (CO) (determined with an electrical impedance system), radial artery blood pressures (BP), esophageal pressure nadir, and arterial O2 saturation during each OP and hyperventilation period were calculated for NREM and REM sleep. During stage 2 NREM sleep, the lowest HR always occurred during the first third of the OP, and the highest was always seen during the last third. In contrast, during REM sleep the lowest HR was always noted during the last third of the OP. There was an inverse correlation when the percentage of change in HR over the percentage of change in SV during an OP was considered. The HR and SV changes during NREM sleep allowed maintenance of a near-stable CO during OPs. During REM sleep, absence of a compensatory change in SV led to a significant drop in CO. Systolic, diastolic, and mean BP always increased during the studied OPs.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
MESAM 4: an ambulatory device for the detection of patients at risk for obstructive sleep apnea syndrome (OSAS).
A validation study was performed on the MESAM 4, a digital recording device developed to monitor oxygen saturation, heart rate (HR), snoring, and body position in order to screen subjects for obstructive sleep apnea syndrome (OSAS). MESAM 4 recordings were scored with the computer-based automatic scoring system provided with the equipment. Nocturnal polysomnography (PSG) and MESAM 4 recordings were run simultaneously on 56 subjects presenting with any type of sleep complaint, including those secondary to OSAS. Patients were assigned to one room by hospital administration and were monitored consecutively. The polygraphic equipment and MESAM 4 equipment were placed on the subjects by separate teams. Records of PSG and MESAM 4 were analyzed in double-blind fashion. With the MESAM 4 computerized analysis, three indices based on SaO2 (ODI), on heart rate (HVI), and on snoring (ISI) were obtained, and the number of abnormal respiratory events occurring during the time selected for analysis (TAT) were determined. Polysomnographic records were scored by 30-s epochs following the American Sleep Disorders Association standards for sleep states and stages and for sleep-related events, including sleep apneas, hypopneas, and periodic leg movements. Following independent scoring, 26 subjects were identified with OSAS by PSG, while MESAM 4 identified 25 subjects with OSAS using oxygen algorithm; all had a respiratory disturbance index greater than or equal to 10 with PSG. Results of each polysomnogram and each MESAM 4 analysis were compared. With the polysomnogram used as a standard, the degree of error for each variable with the MESAM 4 was calculated. Specificity and sensitivity of the most accurate index of the MESAM 4, the ODI, were 97 percent and 92 percent, respectively. The other two indices, HVI and ISI, were less accurate: specificity and sensitivity were 32 percent and 58 percent for HVI and 27 percent and 96 percent for ISI. Nevertheless, a combination of all three indices (ODI, HVI, ISI) would have prevented the two false-positive cases we observed. The results of this validation study show that MESAM 4 can be helpful to general practitioners, clinicians, and epidemiologists as a low-cost screening device for subjects with OSAS and habitual snoring.
Female↗
From apnea of infancy to obstructive sleep apnea syndrome in the young child.
Obstructive sleep apnea syndrome (OSAS) and heavy snoring during sleep, without sleep apnea, has been well described in children and adults. We report a case series of 25 full-term infants, prospectively obtained from a database of nearly 700 "apparent life-threatening event" (ALTE) cases, who presented between 3 weeks and 4 1/2 months of age an ALTE and who progressively developed more florid symptomatology and polygraphic findings. All of them were classified as OSAS patients by five years of age. These index cases are compared with two other ALTE infant groups followed in parallel during the first year of life but whose symptoms were short-lived. The index cases presented more frequently a positive family history of OSAS and an early report of snoring or noisy breathing during sleep. Usage of an esophageal balloon to monitor esophageal pressure (Pes) and usage of nasal continuous positive airway pressure (CPAP) as a test may help in the early recognition of these infants, who appear to make more effort to breathe during sleep, based on the indirect evidence of Pes measurements. It is suggested that anatomic features, including a small posterior airway space leading to an abnormal degree of upper airway resistance, may be the cause of the symptoms presented by these infants. Considering the parental anxiety generated by persistence of symptoms after the first year of life in ALTE infants, recognition of this subgroup is important.
Apnea↗
From obstructive sleep apnea syndrome to upper airway resistance syndrome: consistency of daytime sleepiness.
Some patients with excessive daytime sleepiness who do not present the features of obstructive sleep apnea syndrome (OSAS) present a sleep fragmentation due to transient alpha EEG arousals lasting between three and 14 seconds. These transient EEG arousals are related to an abnormal amount of breathing effort, indicated by peak inspiratory esophageal pressure (Pes) nadir. In the studied population, these increased efforts were associated with snoring. Usage of nasal CPAP, titrated on Pes nadir values, for several weeks eliminated subjective daytime sleepiness and improved Multiple Sleep Latency Test scores from baseline evaluations. Patients suspected of CNS hypersomnia should be asked about continuous snoring, and their clinical evaluation should include a good review of maxillo-mandibular and upper airway anatomy.
Airway Obstruction↗
Sleep-related hemodynamics and hypertension with partial or complete upper airway obstruction during sleep.
Many different hemodynamic changes can be observed during obstructive apneas in the nocturnal sleep period. The most significant changes are observed whenever apneas occur in rapid succession. Systemic, pulmonary, and wedge pressure are modified. Many of these changes are mediated through cholinergic mechanisms. The mechanical effort of breathing against a partially or completely obstructed airway may also have an impact on hemodynamics. This impact must be dissociated from the impact of hypoxemia and blood gas changes. It has been questioned whether obstructive sleep apnea syndrome (OSAS) has any significant role in the development of 24-hour hypertension. In support of this theory, we found that tracheostomy does eliminate hypertension in obstructive sleep apneic children. In adults the issue is more complicated. Hypertension was eliminated in a subgroup of our patients treated with tracheostomy or nasal continuous positive airway pressure (CPAP), although the total group had no statistically significant blood pressure differences. Many variables that might dissociate treatment responders from nonresponders are not available. Hypertensive patients whose blood pressure normalized with OSAS treatment were significantly less overweight than the nonresponders in our series. Patients who remained hypertensive after treatment did, however, develop a normal circadian blood pressure trough during nocturnal sleep.
Adult↗
Sleep-related obstructive and nonobstructive apneas and neurologic disorders.
Daytime breathing problems caused by neurologic lesions always worsen during sleep, and in certain cases abnormal breathing patterns are only seen during sleep or specific sleep states. The first clinical manifestation of maltase deficiency, myopathy, or myotonic dystrophy is often a sleep-related complaint, such as unexplained waking from sleep (insomnia) or daytime somnolence. Thus, systematic investigation during sleep of disorders impairing the loop involved in breathing is strongly encouraged. Lesions may involve sensory receptors, sensory pathways, brainstem-controlling neurons, upper motor neurons, descending motor pathways, lower motor neurons, motor nerves, neuromuscular junctions, or respiratory muscles. Most of these lesions lead to a decrease in or absence of inspiratory efforts (diaphragmatic apnea or hypopnea) during sleep. These events differ from the classic obstructive sleep apnea syndrome and the recently described upper airway resistance syndrome, which usually involve mild or significant anatomic abnormalities of the upper airway and craniofacial region. The treatment of abnormal breathing during sleep has been improved by the development of nasal ventilation methods: continuous positive airway pressure, intermittent positive pressure, and volume ventilation. These therapeutic approaches can prevent tracheostomy and diaphragmatic pacing and are more efficacious than drug treatments. Long-term compliance is generally much better in breathing disorders secondary to neurologic impairments than in cases of mild to moderate obstructive sleep apnea.
Humans↗
Effects of SDZ NVI-085, a putative subtype-selective alpha 1-agonist, on canine cataplexy, a disorder of rapid eye movement sleep.
Canine narcolepsy is an animal model of the human rapid eye movement sleep disorder. Dogs exhibit bouts of sleep attacks and muscle atonia (cataplexy) that are induced by emotions and thought to be abnormal rapid eye movement sleep episodes. We have previously demonstrated that cataplexy is strongly inhibited by increases in noradrenergic activity. This effect is mediated through central alpha 1-adrenoceptors, presumably of the alpha 1B subtype. In this study, we demonstrate with the canine model that SDZ NVI-085, a new compound with alerting effects, is a potent anticataplectic agent that may act through stimulation of an alpha 1-adrenoceptor subtype.
Adrenergic alpha-Agonists↗
Genetic linkage of autosomal recessive canine narcolepsy with a mu immunoglobulin heavy-chain switch-like segment.
Identification of genes determining narcolepsy susceptibility is important not only for understanding that disorder but also for possible clues to general sleep-control mechanisms. Studies in humans reveal at least one such gene related to the major histocompatibility complex and in dog an as-yet-unmapped single, autosomal recessive gene canarc-1. Gene markers for canarc-1 were therefore sought by DNA restriction fragment length polymorphisms in our colony of narcoleptic dogs. A human mu-switch immunoglobulin probe and the enzyme Hae III identified a gene cosegregating with canarc-1 in backcrossed animals (logarithm of odds scores: m = 24, Z max = 7.2 at theta = 0%). canarc-1 was also shown not to be tightly linked with the dog major histocompatibility complex (m = 40, Z less than -2 at theta less than 4.8%). These results represent the mapping of a non-major histocompatibility complex narcolepsy gene and strongly suggest involvement of the immune system in the pathophysiology of that disease.
Animals↗
Platelet alpha 2 adrenoceptors in human and canine narcolepsy.
We have recently established that canine narcolepsy (an autosomal recessive genetic model of the human disorder) is dramatically improved by treatment with alpha 2 antagonists such as yohimbine (Nishino et al: J Pharmacol Exp Ther 253:1145-1152, 1990). To further investigate the role of alpha 2 adrenoceptors in narcolepsy, receptors labeled with [3H] yohimbine were examined on platelets from human and canine narcoleptic subjects. Twenty-eight Doberman pinschers were studied, 7 controls (C), 7 heterozygous (Hz), and 14 narcoleptics (N) (age and sex matched), including eight animals born in a backcross setting (narcoleptic x heterozygous; 5 narcoleptics and 3 heterozygous). The Kd and Bmax of each group respectively, were as follows: C, Kd = 2.86 +/- 0.76 nmol/L, Bmax = 295.78 +/- 31.89 fmol/mg protein; Hz, Kd = 2.06 +/- 0.23 nmol/L, Bmax = 307.02 +/- 22.21 fmol/mg protein; and N, Kd = 2.72 +/- 0.45 nmol/L, Bmax = 267.52 +/- 19.47 fmol/mg protein. No statistical differences were found between groups using nonparametric (Kruskall-Wallis) statistical procedures, and there were no correlations between any binding parameter and symptom severity within the narcoleptic group. Platelet alpha 2 receptor affinity and density also did not differ between narcoleptic and heterozygous dogs in the backcross litter (N [n = 5], Kd = 1.94 +/- 0.59 nmol/L, Bmax = 290.6 +/- 64.7 fmol/mg protein; Hz [n = 3], Kd = 2.83 +/- 0.47 nmol/L, Bmax = 294.2 +/- 42.9 fmol/mg protein). Fourteen human subjects, seven control and seven narcoleptic patients (age and sex matched), were included in the study.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Snoring during NREM sleep: respiratory timing, esophageal pressure and EEG arousal.
Eight men who were regular heavy snorers were monitored while awake and during nocturnal sleep. All subjects were known to be free of lung disease, obstructive sleep apnea syndrome, and oxygen drops during sleep. For each subject, two snoring periods of 3-31 min with a mean of 12.7 min were randomly selected for comparison with periods of normal, non-snoring NREM sleep breathing. A mean of 150 respiratory cycles per period were analyzed. For each respiratory cycle, respiratory inductive plethysmography and measurements of peak flow, laryngeal sounds, and esophageal pressure (Pes) were used to calculate breathing frequency (bf), inspiratory time (Ti), expiratory time (Te), total respiratory cycle length (Ttot), and Pes at its nadir. During NREM sleep silent breathing, the Ti/Te ratio was analogous to that already measured in normal subjects. With the onset of snoring, an immediate increase in Ti, Te, and Pes nadir were noted. Mean peak Pes nadir increased 120 +/- 37%, and mean Ttot increased by 18%. Through the duration of the snoring period, a further increase in Ti (mean = 10.4 +/- 3.4%) and a decrease in Te were noted, with a mean change in Ti/Ttot of 12 +/- 3.1%. The shape of the esophageal pressure wave during expiration shifted from its normal dynamics. The percentage of Te decreased by a mean of -9.8 +/- 2.3% (P less than 0.0001), and the rise time in Pes increased a mean of 37%. When Pes nadir was the most negative, a mean peak flow decrease of 43 +/- 13.6% from baseline was observed. Tidal volume had decreased by a mean of 22% and minute ventilation by a mean of 21% at the end of the snoring period. Separate investigation of each subject indicates that the evolutions of Ti, Te and Pes during snoring were not the same for all subjects. At least two different groups of snorers exist; these groups may be differentiated by the evolution of Pes over time during snoring. Modifications in the 'braking' role of inspiratory muscles during expiration may explain the changes in the Pes wave dynamics snoring which lead to repetitive EEG arousals, termination of snoring periods, and some sleep fragmentation.
Adult↗
Changes in the QT interval during obstructive sleep apnea.
Abnormalities of ventricular repolarization are associated with life-threatening ventricular arrhythmias. The effects of obstructive sleep apnea on the QT interval were evaluated in 12 male patients with obstructive sleep apnea syndrome (OSAS) who had no evidence of underlying cardiac, pulmonary or central nervous system disease. Seventy episodes of OSAS during nonrapid eye movement (NREM) sleep were randomly selected for analysis of RR and QT intervals. Differences in the QT interval, corrected QT interval (QTc) and RR interval just before the onset of apnea, at the end of apnea and during the postapnea hyperventilation period were compared. As expected, the RR interval prolonged considerably during OSAS (1,499 +/- 128 msec) compared to quiet sleep (1,019 +/- 131 msec, p less than 0.002) and decreased during the postapnea hyperventilation period (969 +/- 152 msec, p less than 0.002). The QT interval was prolonged at the onset of apnea (482 +/- 34 msec) compared to the active awake state (421 +/- 10 msec, p less than 0.01). Further prolongation of the QT interval was observed during OSAS (528 +/- 64 msec, p less than 0.002). The QT interval shortened abruptly during the postapnea hyperventilation period (435 +/- 34 msec, p less than 0.002). The QTc was also prolonged during the onset of apnea (482 +/- 34 msec) and shortened significantly during apnea (435 +/- 34 msec, p less than 0.002) and during the postapnea hyperventilation period (423 +/- 39 msec). Significant variations of the RR interval, QT and QTc intervals were not observed during episodes of NREM sleep after initiation of effective therapy in six patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Arousal↗
Evaluation of the upper airway in patients with obstructive sleep apnea.
Multiple methods have been used to study the structure and physiological behavior of the upper airway (UA) in patients with obstructive sleep apnea (OSA). Valuable information may be obtained from the physiologic measurement of pressure and resistance along the UA, as well as from imaging techniques that include: direct or fiberoptic visualization, cephalometric roentgenograms, fluoroscopy, acoustic reflection, computerized tomography, and magnetic resonance imaging. This review summarizes the information that each of these methods has contributed to our understanding of the UA. The results obtained with these different methodologies have generally been complementary with structural narrowing being identified in the majority of patients with OSA. This narrowing is usually focal and located in the velopharyngeal or retropalatal segment of the UA. This is also the predominant site of initial UA collapse. Although obesity with enlargement of soft tissue structures is considered the predominant mechanism leading to UA narrowing, abnormal craniofacial development on a genetic or developmental basis plays an important contributory role.
Airway Obstruction↗
Insomnia and use of hypnotics: study of a French population.
A cross-sectional study of insomnia and hypnotic use was performed in a sample of the French population. The quota method was used to select the sample of 1,003 subjects, with less than 3% substitution. Subjects were 15 years old and older and were representative of the French population based on gender, age, marital status and living environment. Subjects were asked questions relevant to the complaint of insomnia and hypnotic use and filled out questionnaires measuring anxiety and depression. The complaint of insomnia is common, even in the 15-24-year-old group. Overall, more women than men were afflicted. The largest group of insomniac subjects, and the group who most often used hypnotics "frequently and chronically", were women 45 years and older. Men presented a sharp increase in hypnotic use after 65 years of age. Ten percent of the entire sample used hypnotics, 8% for more than 6 months and 6.17% on a chronic and frequent basis. Retired and unemployed elderly were also chronic and frequent hypnotic users: aging and social isolation correlate with chronic and frequent hypnotic usage. Higher scores on anxiety and depression scales correlate with more frequent complaints of nocturnal sleep disturbances. Young individuals are a significant complainer group but use hypnotics rarely. A rural environment was associated, overall, with fewer insomnia complaints, but environment had much less impact on complaints and hypnotic use in the elderly than in other age groups. One may question whether, in the French population, hypnotic prescription and intake are not responses to a social rather than a medical problem.
Adolescent↗
Radionuclide evaluation of cardiac function during sleep in children with bronchopulmonary dysplasia.
The influence of sleep on cardiac function in severe bronchopulmonary dysplasia was assessed in five children 1.5 to 5 years of age. Left and right ventricular ejection fractions (LVEF and RVEF) were investigated by equilibrium radionuclide ventriculography in five children undergoing polygraphic monitoring during the different states of alertness: wakefulness, nonrapid eye movement sleep, and rapid eye movement sleep. Intraobserver and interobserver LVEF and RVEF measurement reproducibility was high. During quiet, supine wakefulness, LVEF was normal, but RVEF was low. During sleep, a decrease in both LVEF and RVEF, expressed as a percentage of the awake value, was marked in the two children with the most nocturnal desaturation and longest duration of paradoxic rib cage motion during inspiration. It is concluded that radionuclide ventriculography can be easily performed during sleep in children and can provide useful information regarding right ventricular function during sleep in children with severe bronchopulmonary dysplasia.
Bronchopulmonary Dysplasia↗