Sleep, 15(6):514-518 © 1992 American Sleep Disorders Association and Sleep Research Society

Sleep Architecture and Sleep Apnea in Patients with C~ushing's Disease James E. Shipley, David E. Schteingart, Rajiv Tandon and Monica N. Starkman Department of Psychiatry. University of Michigan. Ann Arbor. Michigan. U.S.A.

Summary: Patients with Cushing's syndrome (CS) frequently have sleep complaints. We evaluated sleep polysomnographically in 22 patients, including 17 with pituitaly-ACTH-dependent Cushing's disease (CD) and five with CS from an adrenal tumor. Data were compared to healthy controls of comparable age. Seven patients (32%) demonstrated at least mild sleep apnea (~9.4 events/hour), and four of 22 (18%) had ~17.5 events/hour. The apneic CD and CS patients had a trend for a greater complaint of excessive daytime sleepiness. Both apneic and nonapneic groups had considerable snoring and obesity. The electroencephalographic (EEG) sleep of nonapneic patients was compared to that of normal subjects. Nonapneic CD patients differed strikingly from healthy volunteers in sleep continuity and architecture, demonstrating lighter, fragmented sleep. Rapid eye movement (REM) sleep in CD patients bore many similarities to the sleep of patients with major depression, with REM latency being significantly shortened and REM density significantly increased. Continued examination of EEG sleep in CD patients may shed light on similarities in pathophysiology between CD and major depression, disorders which are characterized by both a dysfunction of the hypothalamic-pituitary-adrenal axis and alterations in mood. Key Words: Sleep architecture-Sleep apnea-Cushing's disease.

Cushing's syndrome (CS) is characterized by spon .. taneous hypersecretion of cortisol. It can result from excessive adrenocorticotropic hormone (ACT H) se .. cretion by a pituitary tumor (Cushing's disease) or from ACTH-independent primary adrenal disease (AICS), in which ACTH levels are suppressed. As part of th{: clinical manifestations of CS, a psychiatric syndrome has been described, which includes depressed mooel and irritability, cognitive dysfunction and vegetative symptoms (1-3). Disordered sleep with middle-night and early morning awakenings are reported by over 50% of patients with CS (l,2). Electroencephalographic (EEG) sleep in patients with CS was investigated by Krieger and Glick (4) and Krie·ger (5). They observed in five patients with Cushing's disease (CD) poor sleep continuity with increased awake time and a lower percentage of slow wave (delta) sleep than seen in normal control subjects. At that time, however, sleep apnea was not well recognized as an entity that may confound sleep EEG parameters and was not investigated. CS patients may, in fact, be at increased risk for apnea due to their obesity.

Accepted for publication July 1992. Address correspondence and reprint requests to James E. Shipley, M.A., M.D., Department of Psychiatry, University of Michigan, Med Inn Box 0840, 1500 East Medical Center Dr., Ann Arbor, Michigan 48109-0840, U.S.A.

The purpose of this study was to further evaluate objective sleep measures in CS using curr~nt polysomnographic techniques and to compare these findings with those of an age-matched group of healthy control subjects. METHODS Subjects Patients with suspected CD or AICS were electively admitted to the Clinical Research Center (CRC) of the University of Michigan Hospital for evaluation. This facility is a low-density, low-acuity research unit. The diagnosis of CS was established by standard clinical criteria, e.g. moon facies, truncal obesity, skin and muscle atrophy and most, if not all, of the following biochemical findings: lack of normal cortisol circadian rhythm, excessive cortisol secretion as measured by high urinary free cortisol, cortisol secretion rates and plasma cortisol values. Patients with CD had normal or elevated ACTH levels, failed to suppress cortisol normally after 2 mg of dexamethasone, but showed > 50% suppression after 8 mg. The diagnosis was further confirmed through microscopic pathology following pituitary surgery. Patients with AICS had low ACTH levels and failed to suppress on 8 mg of dexamethasone. The adrenal pathology was confirmed after sur-

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EEG SLEEP IN CUSHING'S DISEASE gery. Patients were excluded from sleep studies if they had taken medication in the prior two weeks which would invalidate sleep measures (one with a hypnotic and one with an antidepressant) or if they had intermittent rather than chronic CS. Seventeen patients were found to have CD (3 male, 14 female). Of these, 11 patients (2 male, 9 female) under the age of 70 (mean ± SD age = 37.1 ± 11.9 years; range = 16-66 years) and without significant sleep apnea were utilized for analysis of sleep architecture on night 2. Plasma levels of cortisol on the second baseline day at 8:00 a.m., 4:00 p.m., and 10:00 p.m. were high (mean ± SD value of 28.1 ± 22.9 Ilgldl); the elevated 10:00 p.m. value (25.6 ± 20.8 Ilgldl) indicated loss of circadian rhythm. Five additional patients with AICS due to adrenal adenoma (1 male, 3 female) or carcinoma (1 female) were identified and evaluated for apnea on night 1. In order to achieve a uniform sample, these patients with AICS were not included in the analysis of sleep architecture on night 2. Fourteen healthy control subjects (8 male and 6 female; mean ± SD age = 35.0 ± 13.4 years; range = 21-64 years) were recruited from advertisements and screened for medical and psychiatric illness or significant obesity by history or physical exam. None took medication that would affect sleep measures and each was asked to abstain from alcohol for the two weeks preceding the recordings. Study protocol

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For patients with suspected CS, polysomnography was done on two consecutive nights on the first two days of hospitalization. Patients were not acutely ill and were free to ambulate within the hospital grounds. Nighttime blood draws were not done in order to avoid disturbing the subjects' sleep. Recordings for control subjects were performed during the first and second nights in the hospital, as for the patients. Controls were included in the analysis if the first recording night did not demonstrate sleep apnea (2: 5 apnea plus hypopnea events/hour) or nocturnal myoclonus (2: 5 events/ hour).

in which information required for sleep staging was obtained [EEG, electroculogram (EOG) and chin electromyogram (EMG)]. Healthy controls slept in clinical study rooms in the sleep laboratory, as previously described (6). All polygraph records were scored visually using a 60-second epoch, according to modified Rechtshaffen-Kales criteria (6,7). Briefly, sleep latency was defined in several ways: as the latency to the first epoch of stage 1 sleep, the latency to the first epoch of stage 2 sleep and the latency to persistent sleep, defined as the time from the beginning of the recording until the onset of Stage 2 sleep for at least 10 minutes interrupted by no more than 2 minutes of stage 1, or 1 minute of stage 1 plus 1 minute of wakefulness. REM sleep latency was the time between sleep onset and the first REM period, minus intermittent wakefulness. A REM period was defined as a minimum 00 minutes of REM sleep within 30 minutes of each other. Factors related to sleep apnea Weight, height, body mass index [weight in kg -;(height in m)2], and responses on a self-rated sleep disorders questionnaire (8) were assessed in the CD and AICS patients. Statistical analysis Due to the non-normal distribution of some sleep variables, such as stage 3, stage 4 and delta sleep, the nonparametric Mann-Whitney U-test was used to assess differences between control and patient means for individual variables. RESULTS Sleep apnea

Of 17 patients with CD, five (29%) manifested at least mild sleep apnea. In addition, two of the five patients with AICS (1 with adrenal carcinoma and 1 with adrenal adenoma) manifested apnea. Of these seven patients, three had mild apnea [respiratory distress index (RDI) = 9.4-12.0 desaturations/hour], three had moderate apnea (RDI = 17.5-20.4 desaturations/hour) Polysomnography and one had severe apnea (RDI = 50.8 de saturations/ Sleep recordings for CS patients were carried out in hour). In the majority of these seven patients, more their rooms in the CRe. Data were transmitted from than 90% of the events were characterized as mixed the patient's bedside to the sleep laboratory using a or obstructive apneas or hypopneas, rather than being TeleDiagnostics S 1O/R 10 telephone telemetry system, central in nature. Thus, although 32% of the combined and sleep tracings were recorded using a Grass Model sample of CD and AICS patients had at least mild 78D polygraph, yielding a nominal EEG band pass of sleep apnea (2:9.4 events/hour), only four of22 (18%) 0.3-30 Hz. On the first night, a full montage polysom- had clinically significant apnea (2: 17.5 events/hour). nogram was recorded to assess primary sleep disorders. Minimum oxygen saturation for these four ranged from Most patients underwent a recording the next night, 65-76%. Review of sleep disorders questionnaire data Sleep. Vol. 15. No, 6.1992

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TABLE 1. EEG sleep measures in Cushing's disease (n Variables Age Total recording period Sleep Continuity Latency to stage I Latency to stage 2 Latency to persistent sleep Number of awakenings Awake during sleep time Total sleep time Entries to stage I Sleep efficiency (%) Sleep maintenance (%) Sleep Architecture Stage 1% Stage 2% Stage 3% Stage 4% Delta % REM % REM Measures REM latency minus awake REM periods REM activity (units) REM density REM 1 time REM 1 activity REM 1 density a NS = not significant.

=

11) vs. healthy controls (n

=

14)

CD Mean ± SD

Controls Mean ± SD

p

37.1 ± 11.7 409.2 ±32.5

35.0 ± 13.4 406.4 ± 44.6

NSa NS

29.6 45.6 50.7 5.7 43.5 306.0 18.6 74.7 87.7

± ± ± ± ± ± ± ± ±

29.3 26.2 25.8 3.2 34.8 45.8 5.1 7.9 9.5

8.5 ± 5.2 16.3 ± 14.8 16.1 ± 15.0 2.7 ± 2.4 10.4 ± 14.3 373.2 ± 52.0 19.0±7.9 91.9 ± 8.2 97.2 ± 3.7

Sleep architecture and sleep apnea in patients with Cushing's disease.

Patients with Cushing's syndrome (CS) frequently have sleep complaints. We evaluated sleep polysomnographically in 22 patients, including 17 with pitu...
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