Neuropsychological Function in Obstructive Sleep Apnea Syndrome (OSAS) Compared to Chronic Obstructive Pulmonary Disease (COPD)

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1 Sleep 18(5}: '95 American Sleep Disorders Association and Sleep Research Society Neuropsychological Function in Obstructive Sleep Apnea Syndrome (OSAS) Compared to Chronic Obstructive Pulmonary Disease (COPD) Timothy Roehrs, Martha Merrion, Bonita Pedrosi, Edward Stepanski, Frank Zorick and Thomas Roth Henry Ford Hospital, Sleep Disorders and Research Center, Detroit, Michigan, U.S.A. Summary: Forty-nine men, 25 with obstructive sleep apnea syndrome (OSAS) and 24 with chronic obstructive pulmonary disease (COPD), were evaluated with a standard 8-hour nocturnal polysomnogram, multiple sleep latency test the following day and a neuropsychological test battery. The OSAS patients had more respiratory disturbances per hour of sleep, more stage 1 sleep and greater daytime sleepiness than COPD patients. The OSAS patients were as impaired as the COPD patients in neuropsychological test functioning, with the pattern of impairment nonspecific as to hypoxemic-sensitive versus sleepiness-sensitive tasks, with two exceptions. The OSAS patients performed more poorly on a test requiring sustained attention and considered sensitive to sleepiness, whereas the COPD patients performed more poorly on a test requiring motor skills and sensitive to hypoxemia. These deficits in psychomotor and attention appear to be specifically related to patient group (OSAS vs. COPD), but the other deficits found in complex reasoning and memory are nonspecific. Key ords: Sleepiness-Hypoxemia-Neuropsychological testing-obstructive sleep apnea syndrome-chronic obstructive pulmonary disease. There is clear behavioral morbidity associated with the obstructive sleep apnea syndrome (OSAS) (1). In addition to the well-documented excessive daytime sleepiness (EDS) of OS AS there are a number of stu dies documenting cognitive impairments on standard neuropsychological tests (2-11). But the extent, nature and cause of the cognitive impairment of OSAS is as yet not well established. Neuropsychological deficits in other medical conditions with known etiology can serve as a frame of reference for the deficits seen in OSAS. One medical condition clearly associated with cognitive impairment on standard neuropsychological tests is chronic obstructive pulmonary disease (COPD) (12-18). The impairment seen in COPD is global in nature, and the level of impairment is systematically related to the degree of waking hypoxemia (17,18). hereas OSAS patients experience only periodic nocturnal hypoxemia (unlike the continuous daily hypoxemia of COP D), the EDS associated with OSAS is also disruptive of cog- Accepted for publication March Address correspondence and reprint requests to Timothy Roehrs, Ph.D., Henry Ford Hospital, 2921 est Grand Blvd., Detroit, MI 48202, U.S.A. 382 nitive function. Any number of studies have shown that increased sleepiness in healthy normals and EDS patients, whether due to total sleep deprivation, sleep restriction or sleep fragmentation, impairs cognitive function (19-23). In an effort to better understand the nature, extent and causes of the cognitive impairment of OSAS, this study assessed the neuropsychological function of OS AS patients compared to that of COPD patients. The COPD patient group provides a hypoxemia without sleepiness comparison group for OSAS patients. The neuropsychological test battery used in this study was designed to include tests known to be sensitive to hypoxemia-related impairments, as well as tests sensitive to sleepiness-related impairments. Hypoxemia-sensitive tests are those assessing complex and abstract reasoning and perceptual-motor skills (14). On the other hand, sleepiness-sensitive tests involve functions of attention, tracking, memory and learning (18). Subjects METHODS Forty-nine men (25 with OSAS and 24 with COPD) were evaluated with a standard nocturnal polysom-

2 COGNITIVE FUNCTION, HYPOXEMIA AND SLEEPINESS 383 TABLE 1. The demographic characteristics of the patient groups OSAS COPD Forx' Number Age (years) ** (8.73) (6.15) Education (years) "' (2.21) (3.24) eight (pounds) ** (53.2) (59.5) Race a 14B II 6B * 56% 44% 25% 75% Data are means and standard deviations (SO). Means with the same symbol do not differ significantly; * p < 0.05, ** p < ns indicates not significant. a Chi-square analysis conducted. nogram and multiple sleep latency test (MSLT) the following day (as described below). On the following day each patient completed an extensive neuropsychological test battery (as described below). Tables I and 2 present the group demographic and diagnostic characteristics. Excluded from the patient samples were persons with known alcohol or drug abuse, use ofcns depressant drugs, history ofleaming disability and head injury and current psychiatric disorder or neurological disease. The protocol was reviewed and approved by the Institutional Human Rights Board. Each patient signed an informed consent and was paid for his participation. Procedures The COPD patients were recruited from a data base of patients within the Division of Pulmonary Medicine who had received their diagnosis within the past year. The appropriate medical treatment for the COPD patients had been initiated prior to the time of the sleep TABLE 2. The diagnostic characteristics of the patient groups OSAS COPD F POMS fatigue ** (7.38) (6.95) Number of apneas ** (218.9) (34.7) REI *** (28.1) (8.61) Number of times SaO, * <85% (241.1) (38.2) Minutes SaO, * <85% (241.1) (38.2) Lowest SaO, * (241.1) (38.2) % Stage I sleep *** (28.1) (8.61) FEVI *** (7.71) (13.9) Data are means and SO. Means with the same symbol do not differ significantly; * p < 0.05, ** p < 0.0 I, *** P < 0.00 I. TABLE 3. Medication usage Bronchodilators Analgesics Antihypertensives Diuretics Anti-anginal agents Antidepressants Glucose-lowering drugs Anti-arrhythmia agents OSAS 4% 8% 44% 32% 32% 4% 4% 0% COPD 75% 17% 46% 54% 29% 8% 13% 33% disorders and neuropsychological evaluation. After agreeing to participate, the COPD patients were scheduled for a standard sleep disorders evaluation. The OSAS patients were recruited from the population of all incoming patients at the Sleep Disorders Center who were undergoing their evaluation. For the sleep disorders evaluation all patients completed a sleep disorders questionnaire before their first clinic visit that detailed the symptoms and history of any sleep complaints. During the clinical interview, the sleep questionnaire was reviewed, a medical, psychiatric and medication history was taken and a physical examination was given. Seven or more days before undergoing a clinical polysomnogram, all sedative and stimulant medications were discontinued. If clinically indicated, other medications were allowed at the time of the polysomnogram; usually they were diuretics, bronchodialators, antihypertensives and digitalis (Table 3 lists the medications used in the groups). Although many of the patients were medicated at the time of the sleep disorders and neuropsychological testing, the medications allowed were judged to have a minimal potential to adversely affect testing. The fact that the COPD patients had undergone treatment whereas OSAS patients had not potentially underestimates the extent of impairment in COPD patients. But treated COPD patients can serve as a comparison group because the neuropsychological impairment is well established and it is known to only gradually reverse with treatment (16). One standard all-night polysomnogram was obtained from each patient with an MSLT the following day. The polysomnogram included a central (C3 or C4) and occipital (Oz) electroencephalogram (EEG), a right and left electrooculogram (EOG), each referenced to Al or A2; a submental electromyogram (EMG) and an electrocardiogram recorded with a V5 lead. In addition, respiratory effort was measured with a mercuryfilled strain gauge stretched over the abdomen, and air flow was monitored with oral and nasal thermistors. Oxygenation was monitored with a Hewlett-Packard (altham, MA) or Biox (Boulder, CO) ear oximeter. Sleep, Vol. 18, No.5, 1995

3 384 T. ROEHRS ET AL. The all-night polysomnograms were made using Grass model 78-D or Nihon Kohden (models 4312 and 4212) polygraphs. The Grass polygraphs were calibrated with a pen deflection of 50 J.N = 7.5 mm for the EEG andeogand 50 j.lv = 10.0 mm for the EMG. The 0.5-amp low frequency filter was set at 0.3 Hz with sensitivity x 5 for the EEG and EOG and at 10 Hz with sensitivity x 1 for the EMG. The 0.5-amp high frequency filter was set at 90 Hz. The Nihon Kohden machines were calibrated at 50 j.l V = 10.0 mm for the EEG and EOG and 50 j.l V = 16.5 mm for the EMG. The 0.5-amp low frequency filters were set at 0.3 Hz with sensitivity x 5 for the EEG and EOG and at Hz with sensitivity x 1 for the EMG. The 0.5-amp frequency high filters were set at 70 Hz. All electrode impedances were < 10,000 ohms and paper speed was 10 mm/second. The MSL T was done the following day by asking patients to lie down on a bed in a quiet, darkened room and try to sleep, as specified in the published guidelines (24). The MSLT was conducted at 1000, 1200, 1400 and 1600 hours, with each test being terminated after 15 minutes of sleep or 20 minutes of wakefulness as determined by the Rechtschaffen and Kales standard criteria (25). Latency to sleep on the MSLT was scored by scorers unaware of the patient diagnosis and was defined as time to the first epoch of sleep (24). All nocturnal po1ysomnograms were scored for sleep stages according to the standard criteria ofrechtschaffen and Kales (25). The respiratory tracings were scored for the presence of apneas (a "2: la-second cessation of oronasal air flow) or hypopneas (a "2: 10-second or greater reduction of oronasal air flow of "2: 50%). The oximetry data recorded included the level of waking oxygen saturation immediately before sleep, the lowest level of saturated oxygen (Sa0 2 ) for the recording, the number of times and total minutes ofsa0 2 < 85% and the number of oximeter events (3% reductions in Sa0 2 ). The number of apneas and hypopneas was summed and then expressed as an index, that is, the sum of respiratory events divided by the hours of total sleep time (TST). For the waking pulmonary function evaluation, patients were evaluated with spirometry within the Department of Pulmonary Medicine according to standard clinical procedures. Pulmonary function testing was done prior to the neuropsychological testing, except for the COPD patients, in which case it had been done at the time of diagnosis. Spirometry was conducted by experienced technicians with three tests, appropriate rest periods between tests being administered and the best effort accepted for analysis. Two measures were derived: forced expiratory volume at 1 second (FEV 1) and FEV 1 expressed as a percentage of the total forced vital capacity (FEV!). The diagnosis for subjects TABLE 4. Test Category test Trailmaking, part B Digit symbol Finger tapping test Block design Judgment of line orientation Facial recognition Mental control Digit span Continuous performance test Digit vigilance test Logical memory test Visual reproduction Neuropsychological battery Control Age Age Area of sensitivity Abstract thinking, mental flexibility Complex, conceptual visuomotor tracking Complex, perceptual, motor accuracy, speed Subtest: immediate memory Motor dexterity Visual perception, organization Visuoperceptive organization, parietal lobe Visuoperceptive organization, temporal lobe Automatisms, simple tracking, attention, memory Immediate memory Attention, memory Attention, memory Verbal memory, both immediate, delayed Visual memory, both immediate, delayed with COPD was made according to standard clinical practice. Patients underwent neuropsychological testing using a battery of tests with well-established validity, reliability and for most tests standardized norms. The component tests ofthe battery including the standardization controls and areas of sensitivity of each test are listed in Table 4. The battery was administered on the day following the MSLT, commencing at 4:00 p.m. and lasting about 2 hours. The battery was administered by a single examiner experienced in the procedures and blind to the diagnosis of the patients. Briefly, the battery included the Category test, which requires selection of odd members within sets of stimulus figures and the completion of incompletely depicted figures. The Trails B requires the visuomotor tracking, with a pencil, of a series of alternating numbered and lettered circles on a worksheet. Finger Tapping is merely the rapid depression of a tapping key. The Digit Symbol test requires pairing numbers to nonsense symbols. In the Block Design test subjects reproduce colored designs created with blocks. The Line Orientation Judgment test requires estimation of the orientation of lines by matching angled line pairs. On the Facial Recognition test, faces at differing orientations are matched. The Mental Control, Verbal, and Visual Memory tests are all subtests ofthe echsler Memory test. In Mental Control, alphabet recita-

4 COGNITIVE FUNCTION, HYPOXEMIA AND SLEEPINESS 385,...,. c E '--"" I- «---l a.. ---l (J) 5 Z «~ 0 OSAS COPO FIG. 1. Mean sleep latency (mins) on the MSLT for each patient group. OSAS = Obstructive Sleep Apnea Syndrome. COPD = Chronic Obstructive Pulmonary Disease. tion and counting by threes is required, whereas as their names imply the two memory subtests involve visual and verbal recall of stimuli. Digit Span requires recall of random number sequences, and the Digit Vigilance test requires marking with a pencil a target numeral embedded in rows of digits. The Continuous Performance test similarly requires identification of a target stimulus (i.e. "A") when occurring in the continuous presentation of single letters on a CRT display. X Cl Z I- Z 1.5 ~ 0::: «1.0 a.. ~ OSAS COPO FIG. 2. Impairment index for the patient groups. Scores> 1.5 are considered to be clinically impaired. TABLE 5. Neuropsychological performance as raw scores OSAS COPD F Category test "' (33.8) (29.3) Trials B "' (84.6) (78.8) Digit symbol (corr) "' ( 11.5) (11.3) Digit symbol (mem) "' (1. 7) (2.0) Finger tapping test ** (5.4) (4.9) Block design "' (11.3) (10.6) Line orientation judgment "' (3.9) (5.1) Facial recognition "' (4.8) (4.8) Mental control "' (1.8) (2.1) Digit span "' (4.7) (4.5) Continuous performance * (12.7) (10.4) Digit vigilance test "' (50.6) (56.3) Verbal memory "' (6.9) (6.7) Visual memory "' (2.5) (3.3) Data are means and SD. Means with same symbol do not differ significantly; * p < 0.05, ** p < 0.01, *** P < ns, not significant. As noted above, hypoxemia-sensitive tests involve complex and abstract reasoning and perceptual-motor skills, whereas sleepiness-sensitive tests involve functions of attention, tracking, memory and learning (14,18). Because of the large number of dependent variables, the between-group differences were analyzed with MANOV As (SAS Institute, Cary, NC). The dependent variables were grouped into three sets of variablesneuropsychological, demographic and diagnostic-with each of the three sets submitted to a MANOV A. To reduce the number of neuropsychological variables, on those tests yielding two dependent measures, means of the two measures were used. One exception was the digit symbol test, in which the two measures reflected two different areas of function. Regression analyses were also conducted using the maximum R procedure, in which a best single predictor, a set of two predictors and a set of "n" predictors are determined for the dependent measure (SAS Institute). In this method variables are switched to maximize the R2. The dependent measure was a neuropsychological impairment index (as described below and illustrated in Fig. 2), and the seven predictor variables included the respiratory events index, mean sleep latency on the MSLT, percent stage 1 sleep, minutes Sa0 2 was < 85%, number of times Sa0 2 was <85%, lowest Sa0 2 and

5 386 T. ROEHRS ET AL. forced expiratory volume in 1 second/forced vital capacity. RESULTS The group demographic characteristics are presented in Table 1. The multivariate group effect was significant (F = 11.33, P < 0.001), and the univariate F values are included in Table 1. The groups differed in age, with the COPD patients being older, but the OSAS and COPD patients did not differ in education. The age difference was controlled for by using normalized scaled scores on those neuropsychological tests where such were available (Table 5). There also were differences in the racial composition of the groups, and an Fmax analysis was conducted on the neuropsychological variables, with only the visual memory (delayed) variable showing a significant racial effect. Finally, as would be predicted, the OSAS patients were heavier than the COPD patients. The diagnostic characteristics of the groups, as outlined in Table 2, also yielded a significant overall MANOVA (F = 10.08, p < 0.001). The univariate F values are included in Table 2. The differences were in the anticipated direction, with OSAS patients significantly more sleepy than COPD patients on both subjective and objective measures. They differed on the Profile of Mood States (fatigue scale), but not on any ofthe other POMS scales. The mean sleep latency on the MSLT for each group is illustrated in Fig. 1. The groups differed significantly in mean sleep latency on the MSLT (F = 12.73, p < 0.001). The OSAS patients had significantly greater nocturnal respiratory disturbance than the COPD group, as indicated by both the number of apneas and the respiratory events index (REI). The respiratory disturbance of OSAS was associated with fragmented sleep as reflected in the significantly elevated percent stage 1 sleep compared to that of the other group. The COPD patients also showed elevated amounts of stage 1 sleep compared to normal individuals (21 %), as has been previously reported in such a patient sample (26). The OSAS patients differed significantly from the COPD patients on the three parameters of nocturnal hypoxemia (recall that the COPD patients were allowed to continue their treatment for the sleep evaluation). Finally, the COPD patients at the time of diagnosis showed greater waking respiratory impairment than the OSAS patients, as found on the spirometry test results (FEVI). The neuropsychological test results are presented in Table 5 as raw scores for each of the measures. The multivariate group effect was significant (F = 2.66, p < 0.01), and the univariate F values are included in Table 5. Significant group differences were found on two of the 14 measures. On one of the two measures TABLE 6. Neuropsychological performance as scaled scores OSAS COPD F Category test 2.92a 3.70 a 1.22 Digit symbol Trials B 2.34 a 2.57 a 0.29 Verbal memory 2.04a 2.07 a 0.09 Visual memory Finger tapping test * a Scores represent clinical impairment with a cutoff of 2.0 standard scores greater than the mean; * p < the OSAS patients performed more poorly than the COPD patients, and on the other the COPD patients performed more poorly than OSAS patients. The continuous performance test on which the OSAS patients performed more poorly than COPD patients is known for its sensitivity to sleepiness. The tapping test, on which the COPD patients were unique in showing poorer performance, is a test known to be sensitive to hypoxemia. Given the group differences in age and to assess level of impairment relative to norms, the neuropsychological test results are also presented in Table 6 as normalized scaled scores corrected for age and education where those controls were available. The greatest degree and number of tests with impairment was found among the COPD patients (four of six measures). OSAS patients were slightly less impaired than COPD patients both in level of impairment and number of impaired tests on three of six measures. The groups did not differ in impaired memory function, with both exhibiting verbal memory impairment. The six scaled scores of Table 6 were averaged to form an overall index of impairment that is shown in Fig. 2. The OSAS and COPD groups showed overall clinical impairment based on the criteria of a > 1.5 scaled score index. The groups did not differ significantly on the impairment index. The regression analyses results are presented in Table 7 for all subjects and each patient group separately. Among all patients the single best predictor of the impairment index was minutes of Sa0 2 <85%, yielding a significant regression equation of r = The second variable entered was lowest Sa0 2 ith a threepredictor model including the two hypoxemia measures and mean sleep latency, the correlation was r = 0.46 with a significant F. Additional variables did not yield greater prediction. Importantly, the pattern of results within each patient group separately was different for both level of prediction and the specific predictors. Among the OSAS patients the single best predictor was mean sleep latency, with a significant r = The addition of minutes ofsa0 2 < 85% improved this correlation to r = 0.54, and the third variable, number of times Sa0 2 was <85%, increased the cor-

6 COGNITIVE FUNCTION, HYPOXEMIA AND SLEEPINESS 387 TABLE 7. Predictors of neuropsychological impairment OSAS COPD All r F p< r F p< r F p< Ivar MSL FEYI TMOX 2var MSL FEYI TMOX TMOX LOX LOX 3var MSL FEYI TMOX TMOX LOX LOX NTOX PST! MSL Abbreviations: MSL, mean sleep latency on MSLT; PST!, % stage I sleep; TMOX, minutes Sa0 2 <85%; NTOX, number of times Sa0 2 <85%; LOX, lowest Sa0 2 relation to r = 0.58, with both equations being statistically significant. Beyond the three-variable regression equation, statistical significance was lost and improvement in the correlation was minimal. The first variable entered into the equation predicting impairment among COPD patients was FEVI, with r = 0.27, but this equation was not statistically significant. The addition of other variables did not produce a significant correlation among the COPD patients. DISCUSSION These data show that OSAS patients are generally as clinically impaired in neuropsychological function as are COPD patients. But due to the initiation of treatment, the impairment in COPD patients may have been underestimated. The pattern of neuropsychological impairment in OSAS and COPD patients was generally nonspecific to the hypoxemic-sensitive versus sleepiness-sensitive tasks, with two notable exceptions. The OSAS patients performed more poorly on the continuous performance test, which requires sustained attention and is impaired by increased sleepiness. The COPD patients performed more poorly on the finger tapping test, which loads on motor skill and has been shown to relate to hypoxemia. Yet both groups showed similar complex reasoning, learning and memory deficits. The limitations of this clinical study have to be clearly stated. This treated COPD patient group does not present the ideal comparison group to the OSAS patients for two reasons. First, ideally the OSAS and COPD patients should be matched as to extent and duration of hypoxemia. Obviously, such matching is clinically not possible. Two approaches are used to circumvent this inherent difference, one being the use of tests differentially sensitive to hypoxemia and sleepiness and the other the use of regression analyses. The second problem is that the COPD patients were treated at the time of neuropsychological assessment. This means that the extent of neuropsychological deficit in the COPD patients was probably underestimated. Thus, in comparing OSAS patients it must be kept in mind that they are being compared to treated COPD patients. However, the data regarding OSAS impairment relative to the age and education matched norms are not compromised. Interestingly, differing sets of variables were predictive of the impairment in the two patient groups. In other words, the impairment seen in these two patient groups was generally nonspecific, but the apparent causal factors for the impairment were different. In the OSAS patients the sleepiness and the nocturnal hypoxemia contributed to the impairment. To the extent that the impairment was predictive in COPD, it appeared to be due to hypoxemia, both waking and nocturnal. The weaker predictability in COPD patients is probably due to the difference in time between the diagnosis and neuropsychological testing and to the fact that therapy had been initiated in this time interval. The fact that sleepiness and hypoxemia variables both were predictive of impairment in the OSAS patients may relate to the fact that the saturation variables were correlated with the arousal index. This study did not include a direct measure of the arousal index; indirectly the REI does reflect the number of arousals per hour of sleep. The REI was included in the regression analyses and did not enter into any of the significant "n" variable models in Table 7. That suggests that the REI only provided redundant information and not unique predictability. Previous studies have attempted to attribute the impairments in neuropsychological function seen in OSAS to either sleepiness or hypoxemia alone (1-6). These data and other recent studies have suggested that both factors contribute to the impairments seen in OSAS (8,11). In an attempt to determine which specific functions are impaired by sleepiness and which by hypoxemia, one laboratory has used the strategy of looking Sleep, Vol. 18, No.5, 1995

7 388 T. ROEHRS ET AL. for a differential rate of onset and reversal with treatment of the specific areas of impairment (8,11). From the results of these studies it has been argued that severity of hypoxemia relates to complex executive and psychomotor function and that attention and memory deficits relate to the severity of sleepiness. In the present study the strategy was to compare OSAS deficits with those in COPD, where hypoxemia, but not sleepiness, is present. The previous studies were partially supported. The deficiency in psychomotor and attention function appeared to be specifically related to patient group. On the other hand, the deficits in complex reasoning and memory appeared to be nonspecific. Acknowledgement: This research was supported by NHLBI-SCOR Grant no. PSO HL4221S, Project 6, awarded to Dr. Roth. REFERENCES I. Roth T, Roehrs T A, Conway A. Behavioral morbidity of apnea. Semin Respir Med 1988;9: Berry DTR, ebb B, Block AJ, Bauer RM, Switzer DA. Nocturnal hypoxia and neuropsychological variables. J Clin Exp Neuropsycho! 1986;8: Findley U, Barth JT, Powers DC, ilhoit SC, Boyd DG, Suratt PM. Cognitive impairment in patients with obstructive sleep apnea and associated hypoxemia. Chest 1986;90: Greenberg DG, atson RK, Deptula D. Neuropsychological dysfunction in sleep apnea. Sleep 1987;10: KlonoffH, Fleetham J, Taylor DR, Clark C. Treatment outcome of obstructive sleep apnea, physiological and neuropsychologic concomitant. J Nerv Ment Dis 1987;175: Te1akivi T, Kajaste S, Partinen M, Koskenvuo M, Salmi T, Kaprio J. Cognitive function in middle-aged snorers and controls: role of excessive daytime somnolence and sleep-related hypoxic events. Sleep 1988; 11 : Derderian SS, Bridenbaugh H, Rajagopal KR. Neuropsychologic symptoms in obstructive sleep apnea improve after treatment with nasal continuous positive airway pressure. Chest 1988; 94: Bedard MA, Montplaisir J, Richer F, Rouleau I, Malo J. Obstructive sleep apnea syndrome: pathogensis of neuropsychological deficits. J Clin Exp Neuropsychol1991; 13: Scheltens PH, Visscher F, Van Keimpema AR, Lindeboom J, Taphoorn MJ, olters EC. Sleep apnea presenting with cognitive impairment. Neurology 1991;41: Cheshire K, Engleman H, Deary I, Shapiro C, Douglas NJ. Factors impairing daytime performance in patients with sleep apnealhypopnea syndrome. Arch Intern M ed 1992; IS 2: l. 11. Bedard MA, Montplaisir J, Malo J, Richer F, Rouleau I. Persistent neuropsychological deficits and vigilance impairment in sleep apnea syndrome after treatment with continuous positive airways pressure (CPAP). J Clin Exp Neuropsychol 1993;15: Prigatano GP, Parsons 0, right E, Levin DC, Hawryluk G. Neuropsychological test performance in mildly hypoxemic patients with chronic obstructive pulmonary disease. J Consult Clin Psychol 1983;51: Fix AJ, Golden CJ, Daughton D. Neuropsychological deficits among patients with chronic obstructive pulmonary disease. Int J Neurosci 1982;16: Grant I, Heaton RK, McSweeny AJ, Adams KM, Timms RM. Brain dysfunction in COPD. Chest 1980;77: Grant I, Heaton RK, McSweeny AJ, Adams KM, Timms RM. Neuropsychologic findings in obstructive pulmonary disease. Arch Intern Med 1982;142: Prigatano GP, Parsons 0, right E, Levin DC, Hawryluk G. Neuropsychological test performance in mildly hypoxemic patients with chronic obstructive pulmonary disease. J Consult Clin Psychol 1983;51: est JB. Human physiology at extreme altitudes on Mount Everest. Science 1984;223: Grant I, Prigatano GP, Heaton RK, McSweeny AJ, right EC, Adams KM. Progressive neuropsychologic impairment and hypoxemia: relationship in chronic obstructive pulmonary disease. Arch Gen Psychiatry 1987;44: ilkinson RT. Sleep deprivation: performance test for partial and selective sleep deprivation. In: Abt LA, Reiss BF, eds. Progress in clinical psychology. vol. 8. New York: Grune and Stratton, Bonet MH. Performance and sleepiness as a function of the frequency and placement of sleep disruption. Psychophysiology 1986;23: Stepanski E, Lamphere J, Roehrs T, Zorick F, Roth T. Experimental sleep fragmentation in normal subjects. Int J Neurosci 1987;33: Levine B, Roehrs T, Stepanski E, Zorick F, Roth T. Fragmenting sleep diminishes its recuperative value. Sleep 1987;10: Rosenthal L, Roehrs TA, Rosen A, Roth T. Level of sleepiness and total sleep time following various time in bed conditions. Sleep 1993; 16: Carskadon MA, Dement C, Mitler MM, Roth T, estbrook PR, Keenan S. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 1986;9: Rechtschaffen A, Kales A. A manual of standardized. techniques and scoring system for sleep stages of human sleep. Los Angeles: Brain Information Service/Brain Research Institute, University of California at Los Angeles, Steens RD, Pouliot Z, Millar T, Kryger MH, George CF. Effects of zolpidem and triazolam on sleep and respiration in mild to moderate chronic obstructive pulmonary disease. Sleep 1993;16: