Rebound insomnia: a new clinical syndrome.

Rebound insomnia followed the withdrawal of three benzodiazepine hypnotic drugs, each of which had been administered in a single nightly dose for only short-term periods. The intense worsening of sleep is attributed to the short duration of the action of these drugs. A hypothesis involving benzodiazepine receptors in the brain is proposed in which there is a delay or lag in replacement of endogenous benzodiazepine-like molecules after the abrupt withdrawal of exogenous drugs.

Cigarette smoking associated with sleep difficulty.

A group of 50 smokers experienced greater sleep difficulty than a group of 50 nonsmokers matched by age and sex. The two groups did not differ in personality patterns or drug consumption. Also, sleep patterns significantly improved in a group of eight chronic smokers when they abstained from cigarette smoking. These findings are consistent with reports on the stimulant effects of nicotine.

Early morning insomnia with rapidly eliminated benzodiazepines.

Early morning insomnia, a significant increase in wakefulness during the final hours of drug nights, occurred after 1 or 2 weeks of nightly administration of benzodiazepine hypnotics with short elimination half-lives, when tolerance had begun to develop. Early morning insomnia may be a variant of rebound insomnia and therefore specific to benzodiazepines, or it may occur with any rapidly eliminated sedative-hypnotic agent.

Gonadotropin secretion during sleep in normal adult men.

Release of luteinizing hormone and follicle stimulating hormone during sleep in young adult men occurred in unrelated, random, arrhythmic peaks, with no consistency from night to night in the same subject. Release of luteinizing hormone was modestly but significantly larger (14 perecnt) during rapid-eye-movement sleep than it was in non-REM sleep, but release of follicle stimulating hormone was not clearly related to stages of sleep.

Cloning of human lymphocytes reactive with autologous leukemia cells.

The primed lymphocyte typing test has been used to detect leukemia-associated antigens, but interpretation has been difficult because of significant levels of reactivity with normal cells. Elimination of unwanted reactivities could be accomplished by (a) use of the patient's own lymphocytes as responders to the leukemia cells and (b) cloning of the responding cells. Cloning of antigen-activated human lymphocytes can be accomplished through the use of T-lymphocyte growth factor, which permits the long-term growth of antigen-activated lymphocytes. In the study reported here, the remission lymphocytes of a patient with acute myelogenous leukemia were sensitized in culture to the patient's own leukemic myeloblasts and then grown from wells containing one or a few replicating units. Sufficient cells of three clones were growth for further testing of specificity: one responded only to the sensitizing myeloblast but not to normal cells tested; one responded to the sensitizing myeloblasts and one allogeneic myeloblast but not to normal cells; and one responded to none of the cells tested, although it proliferated vigorously with growth factor alone. These results demonstrate the feasibility of cloning human lymphocytes putatively responsive to leukemia-associated antigens in order to improve their discriminatory capacity in the primed lymphocyte typing test. The response pattern observed was that expected of a clone responding to a leukemia-associated antigen.

Excessive daytime sleepiness in a general population sample: the role of sleep apnea, age, obesity, diabetes, and depression.

CONTEXT: Excessive daytime sleepiness (EDS) is commonly considered a cardinal sign of sleep apnea; however, the mechanism underlying the association is unclear. OBJECTIVE: The purpose of this study was to assess the association between the complaint of EDS and sleep apnea, considering a wide range of possible risk factors in a population sample. DESIGN AND SETTING: We examined this question in the Penn State cohort (a random sample of 16,583 men and women from central Pennsylvania, ranging in age from 20 to 100 yr). A random subset of this cohort (n = 1,741) was further evaluated for one night in the sleep laboratory. MAIN OUTCOME MEASURE: The main measure was a complaint of EDS. RESULTS: The final logistic regression model indicated depression was the most significant risk factor for EDS followed by body mass index, age, typical sleep duration, diabetes, smoking, and finally sleep apnea. The strength of the association with EDS decreased with increasing age, whereas the association of depression with EDS was stronger in the young. EDS is more prevalent in the young (<30 yr), suggesting the presence of unmet sleep needs and depression, and in the very old (>75 yr), suggesting increasing medical illness and health problems. EDS was associated with a reduced report of typical sleep duration without any association with objective polysomnographic measures. CONCLUSIONS: It appears that the presence of EDS is more strongly associated with depression and metabolic factors than with sleep-disordered breathing or sleep disruption per se. Our findings suggest that patients with a complaint of EDS should be thoroughly assessed for depression and obesity/diabetes independent of whether sleep-disordered breathing is present.

Phase II study of fluorouracil, leucovorin, and interferon alfa-2a in metastatic colorectal carcinoma.

PURPOSE: To test the activity of a regimen of interferon alfa-2a (IFN alpha-2a) 5 x 10(6) U/m2 subcutaneously (SC) days 1 through 7 combined with leucovorin 500 mg/m2/d intravenously (IV) over 30 minutes and fluorouracil (5-FU) 370 mg/m2/d through IV push 1 hour after leucovorin days 2 through 6 in a phase II study. PATIENTS AND METHODS: Forty-six patients with a good performance status (PS) with measurable colorectal cancer and no prior therapy for metastatic disease were entered. Cycles were repeated at 3-week intervals if toxicity had resolved. The 5-FU dose was increased by 15% if toxicity was mild, and decreased by 15% for grade 3 to 4 nonhematologic or grade 4 hematologic toxicity. RESULTS: Three complete responses (CRs) and 21 partial responses (PRs) were seen among 44 assessable patients (54%; 95% confidence interval, 39% to 70%). A moderately strong association was noted between PS and response: PS O (n = 26), two CRs and 15 PRs (65%); PS 1 (n = 13), one CR and six PRs (54%); PS 2 (n = 5), zero CRs and zero PRs (0%; two-tailed P = .026). With a median follow-up duration of 18.8 months, the median time to treatment failure (TTF) and survival were 7.8 months and 16.3 months, respectively. Doses were escalated to 425 mg/m2/d 5-FU in 10 patients, but only four tolerated the higher dose. When expressed as the most severe degree of toxicity experienced by each patient across all cycles, grade 3 to 4 toxicity of the following types was observed; mucositis, 37%; diarrhea, 40%; rash, 7%; fatigue, 14%; granulocytopenia, 13%. Dose-limiting toxicity at 370 mg/m2/d 5-FU eventually occurred in 28 patients (61%). Twelve patients (26%) required an IFN alpha-2a dose reduction for constitutional toxicity. CONCLUSION: This regimen has promising activity in advanced colorectal cancer, particularly in patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1.

Night terrors. Clinical characteristics and personality patterns.

The development and clinical course of night terrors and the personality patterns of patients with this disorder were evaluated in 40 adults who had a current complaint of night terrors. Compared with a group of adult sleepwalkers, the patients with night terrors had a later age of onset for their disorder, a higher frequency of events, and an earlier time of night for the occurrence of episodes. Both groups had high levels of psychopathology, with higher values for the night terror group. This sleepwalkers showed active, outwardly directed behavioral patterns, whereas the night terror patients showed an inhibition of outward expressions of aggression and a predominance of anxiety, depression, tendencies obsessive-compulsive/, and phobicness. Although night terrors and sleepwalking in childhood seem to be related primarily to genetic and developmental factors, their persistence and especially their onset in adulthood are found to be related more to psychological factors.

Personality patterns in insomnia. Theoretical implications.

Subjects with a primary complaint of insomnia (N = 124) were evaluated with Minnesota Multiphasic Personality Inventories (MMPIs). A high percentage of subjects (85%) had one or more MMPI scales elevated to a pathological degree. The scales most elevated were, in order. 2 (depression), 7 (psychasthenia), and 3 (conversion hysteria). A striking finding was the preponderance of depression. This was indicated by the frequency in which scale 2 was elevated above 70, the frequency in which this this scale had the highest elevation, and the frequency of MMPI code types that included scale 2. Four common MMPI code types representing various types of depression were noted, indicating considerable homogeneity for code types in this sample. The predominant personality styles in this sample were characterized by the internalization of psychological distrubances rather than by acting out or aggression. We propose that this internalization produces a state of constant emotional arousal and resultant physiological activation and that this process is a psychophysiological mechansim underlyling insomnia.

Somnambulism. Clinical characteristics and personality patterns.

Fifty adults with either a present or past complaint of somnambulism were evaluated to determine the development and clinical course of their disorder as well as their personality patterns. Generally, when sleepwalking was outgrown, its onset was before age 10 years and its termination before age 15 years. Current sleepwalkers, compared with past sleepwalkers, started sleepwalking at a later age, had a higher frequency of events, and had episodes earlier in the night. Their episodes were also characterized by more intense clinical manifestations. Furthermore, current sleepwalkers demonstrated high levels of psychopathology, whereas past sleepwalkers had essentially normal psychological patterns. Specifically, the current sleepwalkers showed active, outwardly directed behavioral patterns, suggestive of difficulties in handling aggression. The clinical application of these findings is discussed and practical recommendations are given for the evaluation and management of sleepwalking.

Obesity without sleep apnea is associated with daytime sleepiness.

BACKGROUND: Daytime sleepiness and fatigue is a frequent complaint of obese patients even among those who do not demonstrate sleep apnea. OBJECTIVE: To assess in the sleep laboratory whether obese patients without sleep apnea are sleepier during the day compared with healthy controls with normal weight. METHODS: Our sample consisted of 73 obese patients without sleep apnea, upper airway resistance syndrome, or hypoventilation syndrome who were consecutively referred for treatment of their obesity and 45 controls matched for age. All patients and healthy controls were monitored in the sleep laboratory for 8 hours at night and at 2 daytime naps, each for 1 hour the following day. RESULTS: Obese patients compared with controls were sleepier during the day and their nighttime sleep was disturbed. During both naps, sleep latency, wake time after onset of sleep, and total wake time were significantly lower, whereas the percentage of sleep time was significantly higher in obese patients compared with controls. In contrast, during the nighttime testing, obese patients compared with controls demonstrated significantly higher wake time after onset of sleep, total wake time, and lower percentage of sleep time. An analysis of the relation between nighttime and daytime sleep suggested that daytime sleepiness in obese patients is a result of a circadian abnormality rather than just being secondary to nighttime sleep disturbance. CONCLUSIONS: Daytime sleepiness is a morbid characteristic of obese patients with a potentially significant impact on their lives and public safety. Daytime sleepiness in individuals with obesity appears to be related to a metabolic and/or circadian abnormality of the disorder.

Sleep apnea and sleep disruption in obese patients.

OBJECTIVES: To describe the frequency and severity of sleep apnea in obese patients without a primary sleep complaint and to assess the sleep patterns of obese patients without apnea and compare them with the sleep patterns of nonobese controls. DESIGN AND SETTING: Prospective case series with historical controls in an obesity and sleep disorders clinic. SUBJECTS: Two hundred obese women and 50 obese men (mean body mass index, 45.3) consecutively referred for treatment of their obesity and 128 controls matched for age and sex. MAIN OUTCOME MEASURES: Eight-hour sleep laboratory recording, including electroencephalogram, electro-oculogram, electromyogram, and respirations. Subjectively reported sleep-related symptoms and signs were also recorded. RESULTS: Twenty men (40%) and six women (3%) demonstrated sleep apnea warranting therapeutic intervention. Another four men (8%) and 11 women (5.5%) showed sleep apneic activity that warranted recommendation for evaluation in the sleep laboratory. In contrast, none of the 128 controls demonstrated sleep apneic activity severe enough for therapeutic intervention. The best clinical predictors of sleep apnea in the obese population were severity of snoring, subjectively reported nocturnal breath cessation, and sleep attacks. Obese patients, both men and women, without any sleep-disordered breathing demonstrated a significant degree of sleep disturbance compared with nonobese controls. Wake time after sleep onset, number of awakenings, and percentage of stage 1 sleep were significantly higher in obese patients than in controls, while rapid eye movement sleep was significantly lower. CONCLUSION: Severely or morbidly obese men are at extremely high risk for sleep apnea and should be routinely evaluated in the sleep laboratory for this condition, while for severely or morbidly obese women the physician should include a thorough sleep history in the clinical assessment.

Association of hypertension and sleep-disordered breathing.

BACKGROUND: To our knowledge, the association between sleep-disordered breathing (SDB) and hypertension has not been evaluated in subjects from the general population with a wide age range while adjusting for the possible confounding factors of age, body mass index, sex, menopause and use of hormone replacement therapy, race, alcohol use, and smoking. METHODS: In the first phase of this study, we interviewed 4364 men and 12,219 women, aged 20 to 100 years. In the second phase of this study, 741 men and 1000 women, previously interviewed, were selected based on the presence of risk factors for SDB (snoring, daytime sleepiness, obesity, hypertension, and, for women, menopause). Each subject selected for the second phase of the study provided a comprehensive history, underwent a physical examination, and was evaluated for 1 night in the sleep laboratory. In terms of severity of SDB, 4 groups were identified: moderate or severe (obstructive apnea/hypopnea index > or =15.0), mild (snoring and an obstructive apnea/hypopnea index of 0.1-14.9), snoring, and no SDB, the control group. RESULTS: Sleep-disordered breathing was independently associated with hypertension when potential confounders were controlled for in the logistic regression analysis. The strength of this association decreased with age and was proportional to the severity of SDB. In the best-fitted model, neither sex nor menopause changed the relationship between hypertension and SDB. CONCLUSIONS: In the results of this study, SDB, even snoring, was independently associated with hypertension in both men and women. This relationship was strongest in young subjects, especially those of normal weight, a finding that is consistent with previous findings that SDB is more severe in young individuals.

Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity.

Excessive daytime sleepiness (EDS) and fatigue are frequent symptoms in the general population and the chief complaint of the majority of patients at Sleep Disorders Centers. There is evidence that the inflammatory cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), and IL-6 are involved in physiological sleep regulation and that their administration to humans is associated with sleepiness and fatigue. To explore whether plasma levels of TNF alpha, IL-1beta, and IL-6 are elevated in patients with EDS, we measured morning plasma levels of TNF alpha, IL-1beta, and IL-6 in 12 sleep apneics, 11 narcoleptics, 8 idiopathic hypersomniacs, and 10 normal controls. TNF alpha was significantly elevated in sleep apneics and narcoleptics compared to that in normal controls (P < 0.001 and P = 0.001, respectively). Plasma IL-1beta concentrations were not different between sleep disorder patients and controls, whereas IL-6 was markedly and significantly elevated in sleep apneics compared to that in normal controls (P = 0.028). The primary factor influencing TNF alpha values was the degree of nocturnal sleep disturbance, whereas the primary determinant for IL-6 levels was the body mass index. Our findings suggest that TNF alpha and IL-6 might play a significant role in mediating sleepiness and fatigue in disorders of EDS in humans.

Endoscopic findings in sleep apnea associated with acromegaly.

Two acromegalic patients presented with the additional complaint of excessive daytime sleepiness. Subsequent sleep laboratory evaluation revealed that each patient had concurrent obstructive sleep apnea. In each patient, endoscopic examination of the upper airway revealed that on inspiration, the soft tissue of the posterior and lateral hypopharynx invaginated into the laryngeal vestibule before any posterior movement of the tongue. Neither enlargement of the tongue nor in movement in relation to respiration appeared to be the primary factors in the etiology of the upper airway obstruction. After tracheostomy, both the obstructive sleep apnea and excessive daytime sleepiness were eliminated. Our case reports indicate that the treatment and prognosis of patients with acromegaly are affected when sleep apnea is concurrently diagnosed. When a patient is suspected of being acromegalic and also complains of excessive daytime sleepiness, obtaining a through sleep history from the patient as well as from the bed partner is essential. If sleep apnea is then diagnosed, a tracheostomy should be considered an initial and continuing part of the overall treatment plan.

Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of premenopausal women, characterized by chronic hyperandrogenism, oligoanovulation, and insulin resistance. Obstructive sleep apnea (OSA) and excessive daytime sleepiness (EDS) are strongly associated with insulin resistance and hypercytokinemia, independently of obesity. We hypothesized that women with PCOS are at risk for OSA and EDS. Fifty-three women with PCOS (age range, 16-45 yr) and 452 control premenopausal women (age range, 20-42), from a general randomized sample for the assessment of prevalence of OSA, were evaluated in the sleep laboratory for 1 night. In addition, women with PCOS were tested for plasma free and weakly bound testosterone, total testosterone, and fasting blood glucose and insulin concentrations. In this study, PCOS patients were 30 times more likely to suffer from sleep disordered breathing (SDB) than the controls [odds ratio = 30.6, 95% confidence interval (7.2-139.4)]. Nine of the PCOS patients (17.0%) were recommended treatment for SDB, in contrast with only 3 (0.6%) of the control group (P < 0.001). In addition, PCOS patients reported more frequent daytime sleepiness than the controls (80.4% vs. 27.0%, respectively; P < 0.001). PCOS patients who were recommended treatment for SDB, compared with those who were not, had significantly higher fasting plasma insulin levels (306.48 +/- 52.39 vs. 176.71 +/- 18.13 pmol/L, P < 0.01) and a lower glucose-to-insulin ratio (0.02 +/- 0.00 vs. 0.04 +/- 0.00, P < 0.05). Plasma free and total testosterone and fasting blood glucose concentrations were not different between the two groups of PCOS women. Our data indicate that SDB and EDS are markedly and significantly more frequent in PCOS women than in premenopausal controls. Also, insulin resistance is a stronger risk factor than is body mass index or testosterone for SDB in PCOS women. These data support our proposal that, independently of gender, sleep apnea might be a manifestation of an endocrine/metabolic abnormality in which insulin resistance plays a principal role.

Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia.

Sleep apnea and associated daytime sleepiness and fatigue are common manifestations of mainly obese middle-aged men. The onset of sleep apnea peaks in middle age, and its morbid and mortal sequelae include complications from accidents and cardiovascular events. The pathophysiology of sleep apnea remains obscure. The purpose of this study was to test three separate, albeit closely related, hypotheses. 1) Does sleep apnea contribute to the previously reported changes of plasma cytokine (tumor necrosis factor-alpha and interleukin-6) and leptin levels independently of obesity? 2) Among obese patients, is it generalized or visceral obesity that predisposes to sleep apnea? 3) Is apnea a factor independent from obesity in the development of insulin resistance? Obese middle-aged men with sleep apnea were first compared with nonapneic age- and body mass index (BMI)-matched obese and age-matched lean men. All subjects were monitored in the sleep laboratory for 4 consecutive nights. We obtained simultaneous indexes of sleep, sleep stages, and sleep apnea, including apnea/hypopnea index and percent minimum oxygen saturation. The sleep apneic men had higher plasma concentrations of the adipose tissue-derived hormone, leptin, and of the inflammatory, fatigue-causing, and insulin resistance-producing cytokines tumor necrosis factor-alpha and interleukin-6 than nonapneic obese men, who had intermediate values, or lean men, who had the lowest values. Because these findings suggested that sleep apneics might have a higher degree of insulin resistance than the BMI-matched controls, we studied groups of sleep-apneic obese and age- and BMI-matched nonapneic controls in whom we obtained computed tomographic scan measures of total, sc, and visceral abdominal fat, and additional biochemical indexes of insulin resistance, including fasting plasma glucose and insulin. The sleep apnea patients had a significantly greater amount of visceral fat compared to obese controls (<0.05) and indexes of sleep disordered breathing were positively correlated with visceral fat, but not with BMI or total or sc fat. Furthermore, the biochemical data confirmed a higher degree of insulin resistance in the group of apneics than in BMI-matched nonapneic controls. We conclude that there is a strong independent association among sleep apnea, visceral obesity, insulin resistance and hypercytokinemia, which may contribute to the pathological manifestations and somatic sequelae of this condition.

Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines.

Total sleep restriction in humans is associated with increased daytime sleepiness, decreased performance, and hormonal/metabolic disturbances. The effects of mild chronic sleep restriction that mimic real life are not known. To assess the effects of modest sleep restriction from 8 to 6 h/night for 1 wk, 25 young, healthy, normal sleepers (12 men and 13 women) were studied for 12 consecutive nights in the sleep laboratory. After 1 wk of sleep restriction, although subjects' nighttime sleep was deeper, subjects were significantly sleepier (multiple sleep latency test) and performed worse in four primary variables of psychomotor vigilance test (both P < 0.01). Furthermore, 24-h secretion of IL-6 was increased by 0.8 +/- 0.3 pg/ml (P < 0.05) in both sexes, whereas TNFalpha was increased only in men. Also, the peak cortisol secretion was lower after sleep restriction than at baseline, and this difference was stronger in men (55.18 +/- 24.83 nmol/liter; P < 0.05) than in women (35.87 +/- 24.83 nmol/liter; P < 0.16). We conclude that in young men and women, modest sleep loss is associated with significant sleepiness, impairment of psychomotor performance, and increased secretion of proinflammatory cytokines. Given the potential association of these behavioral and physical alterations with health, well-being, and public safety, the idea that sleep or parts of it are optional should be regarded with caution.

Rapid eye movement sleep correlates with the overall activities of the hypothalamic-pituitary-adrenal axis and sympathetic system in healthy humans.

To assess the association of the overall amount of rapid eye movement (REM) sleep and the activities of the hypothalamic-pituitary-adrenal axis and sympathetic system, we performed polysomnography and measured 24-h urinary free cortisol and catecholamine excretion in 21 healthy adults. After an adaptation night, each subject was recorded in the sleep laboratory for 3 consecutive nights while 24-h urine specimens were collected. Urinary free cortisol, epinephrine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid levels were significantly and positively correlated with the average values of percent REM sleep (P < 0.05). There were no correlations between hormone values and REM latency, other variables of REM distribution, or REM density, an index of phasic activity during REM sleep. The positive correlations between stress system activity and REM sleep are consistent with hormonal and sleep alterations in melancholic depression, a state characterized by increased cortisol and catecholamine secretion.

Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications.

Although insomnia is, by far, the most commonly encountered sleep disorder in medical practice, our knowledge in regard to its neurobiology and medical significance is limited. Activation of the hypothalamic-pituitary-adrenal axis leads to arousal and sleeplessness in animals and humans; however, there is a paucity of data regarding the activity of the hypothalamic-pituitary-adrenal axis in insomniacs. We hypothesized that chronic insomnia is associated with increased plasma levels of ACTH and cortisol. Eleven young insomniacs (6 men and 5 women) and 13 healthy controls (9 men and 4 women) without sleep disturbances, matched for age and body mass index, were monitored in the sleep laboratory for 4 consecutive nights, whereas serial 24-h plasma measures of ACTH and cortisol were obtained during the fourth day. Insomniacs, compared with controls, slept poorly (significantly higher sleep latency and wake during baseline nights). The 24-h ACTH and cortisol secretions were significantly higher in insomniacs, compared with normal controls (4.2 +/- 0.3 vs. 3.3 +/- 0.3 pM, P = 0.04; and 218.0 +/- 11.0 vs. 190.4 +/- 8.3 nM, P = 0.07). Within the 24-h period, the greatest elevations were observed in the evening and first half of the night. Also, insomniacs with a high degree of objective sleep disturbance (% sleep time < 70), compared with those with a low degree of sleep disturbance, secreted a higher amount of cortisol. Pulsatile analysis revealed a significantly higher number of peaks per 24 h in insomniacs than in controls (P < 0.05), whereas cosinor analysis showed no differences in the temporal pattern of ACTH or cortisol secretion between insomniacs and controls. We conclude that insomnia is associated with an overall increase of ACTH and cortisol secretion, which, however, retains a normal circadian pattern. These findings are consistent with a disorder of central nervous system hyperarousal rather than one of sleep loss, which is usually associated with no change or decrease in cortisol secretion or a circadian disturbance. Chronic activation of the hypothalamic-pituitary-adrenal axis in insomnia suggests that insomniacs are at risk not only for mental disorders, i.e. chronic anxiety and depression, but also for significant medical morbidity associated with such activation. The therapeutic goal in insomnia should be to decrease the overall level of physiologic and emotional arousal, and not just to improve the nighttime sleep.