Patterns of Sleepiness in Various Disorders of Excessive Daytime Somnolence

Sleep, 5:S165S174 1982 Raven Press, New York Patterns of Sleepiness in Various Disorders of Excessive Daytime Somnolence F. Zorick, T. Roehrs, G. Koshorek, J. Sicklesteel, *K. Hartse, R. Wittig, and T. Roth Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan, and *Baylor College of Medicine, Houston, Texas Excessive daytime sleepiness (EDS) is the most common complaint of patients seen at sleepwake disorders clinics in this country (1). Nocturnal polysomnography, sleep diaries and histories, physical and mental status examination, and recently the Multiple Sleep Latency Test have been used in evaluating these patients. This information is used to arrive at a specific diagnosis of the EDS according to the recently developed diagnostic classification system of the Association of Sleep Disorders Centers (2). As yet, there have been no reports of the direct measure of the major symptom, daytime sleepiness, in a large number of patients with a wide variety of diagnoses. The Multiple Sleep Latency Test (MSLT), a direct and objective measure of sleepiness, is used increasingly by sleepwake disorders clinics in the diagnostic evaluation of patients with EDS (38). However, comparisons of MSLT results among different diagnostic groups presenting with daytime sleepiness have not been done. The present paper focuses on daytime sleepiness, as measured by the MSLT, in patients with various Disorders of Excessive Somnolence (DOES). In addition to identifying differences among the various patient groups, this information can provide hypotheses regarding the causes of EDS. METHODS The subjects were 161 patients (102 men and 59 women) who received a diagnostic evaluation at the Henry Ford Hospital Sleep Disorders and Research Center for their complaint of EDS. These patients, either selfreferred or physicianreferred, were selected from the population of all patients receiving a specific DOES diagnosis at this center over a 3year period (19791981). Diagnostic evaluation The diagnostic evaluation consisted of interviews, questionnaires, nocturnal polysomnography, and in most cases a MSL T. Before the first clinic visit, patients completed a sleep questionnaire eliciting the history and symptoms of their sleep Address correspondence and reprint requests to F. Zorick,5leep Disorders and Research Center, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan 48202. Key Words: Daytime sleepinessmultiple Sleep Latency TestDisorders of excessive daytime somnolence. S165

S166 F. ZORICK ET AL. complaint. They also kept a 2week diary of their sleep habits and completed the Cornell Medical Index and the Minnesota Multiphasic Inventory. At the clinical interview the sleep history was reviewed, a medical and psychiatric history taken, and a physical and mental status examination given. Then at least one allnight polysomnogram was obtained from each patient. The polysomnogram included the standard central (C3) and occipital EEGs, electrooculogram (EOG), submental electromyogram (EMG), EKG recorded with a V5 lead, respiratory flow, and left tibialis EMG. In addition, depending on the diagnostic impression, respiratory effort and oxygen saturation were recorded or electrodes were placed over both the right and left anterior tibialis muscle to measure EMG activity. All recordings were scored for sleep stages according to the standards of Rechtschaffen and Kales (9). Respiration recordings and tibialis EMG recordings were evaluated by a clinical polysomnographer. Twentyeight percent of the patients had used a medication within 7 days of the polysomnogram. These medications included diuretics, antihypertensives, digitalis, and tricyclic antidepressants. Sedatives and stimulants were discontinued 7 days before the polysomnogram. Patients were requested to refrain from using alcohol or caffeine after 5 p.m. on the day of the recording. In those cases where a MSLT was obtained, patients were instructed at 1000, 1200, 1400, and 1600 h to lie down on a bed in a dark, quiet room and try to fall asleep. Standard EEGs (always including an Oz), EMG, and EOGs were recorded during the naps. Each nap test lasted 20 min if sleep did not occur. If sleep occurred, the nap was terminated 15 min after sleep onset. Patients were instructed not to sleep between naps and were monitored by technicians to ensure wakefulness. On the basis of the entire clinical evaluation consisting of interviews, questionnaires, and nocturnal polysomnography, patients received a specific diagnosis derived from the Association of Sleep Disorders Centers diagnostic classification of sleep disorders (2). This diagnosis was the consensus diagnosis of two clinical polysomnographers. Sample selection From among patients who underwent the evaluation described above and who received a DOES diagnosis, the present sample was selected. Patients were included in the sample if they had received a MSLT on the day immediately following an allnight polysomnogram. Patients were excluded from the sample if they met criteria for more than one diagnostic category, or if they had a predominance of central sleep apnea, or if they had fewer than 30 apneas per hour of total sleep time (i.e. apnea index, AI < 30). In order not to have a large disparity in the size of the groups, a minimum and maximum limit of 10 to 50 patients per group was allowed. The upper restriction only affected the narcolepsy group, for which 50 consecutive patients were chosen. The lower restriction resulted in the exclusion of patients with diagnoses of idiopathic CNS hypersomnolence and alveolar hypoventilation DOES syndrome. With the application of these criteria, patients with six different DOES diagnoses were included in the sample. The six diagnostic categories were sleep apnea

PATTERNS OF SLEEPINESS IN EDS S167 (obstructive type), narcolepsy, periodic leg movement/restless legs, insufficient sleep, no objective findings, and psychiatric disorder. RESULTS Demographic and polysomnographic characteristics The present sample included 42% of patients seen at the Henry Ford Hospital Sleep Disorders Center with complaints of EDS from 1979 to 1981 (161 of382 total patients). A description of the demographic characteristics and nocturnal polysomnography results for the patients in the sample is presented in Table 1. The number of patients in each of the six diagnostic groups in the sample represents between 40 and 60% of all patients in a given diagnostic group. While the sample data are not an exact reflection of the prevalence of the various DOES diagnoses at this center, the selection criteria used to form the study sample did not introduce a large bias in the diagnostic and demographic characteristics of the sample. In comparing the study sample with the total population, two systematic differences were found. The population of psychiatric disorder patients had an even number of men and women, but the sample group had 38% men. Secondly, the sleep apnea group is slightly underrepresented in the sample, because a stringent criterion (AI> 30) was used. There appeared to be no major differences among the six diagnostic groups in age at the time of presentation. Patients in the noobjectivefindings group tended to be somewhat younger (mean age 32.6, SEM ± 2.95 years) and patients of the periodic leg movement group (51.4 ± 2.68 years) and the sleep apnea group (47.2 ± 1.35 years) somewhat older. With regard to age of onset, the most notable was the narcolepsy group. Patients with narcolepsy reported the earliest onset of symptoms (20.5 ± 1.32 years). A somewhat later onset of symptoms was reported among patients with sleep apnea (42.1 ± 1.19 years) and periodic leg movements (40.7 ± 4.88 years). On the allnight polysomnographic evaluation, patients in the insufficient sleep diagnostic category had the shortest sleep latency (latency to stage 2 sleep of 7.52 ± 1.25 min). The longest latencies were found among patients in the psychiatric disorder and noobjectivefindings groups. Their latencies of 33.4 ± 2.94 and 27.0 ± 5.65 min, respectively, are similar to the latencies of normal subjects sleeping the first night in the laboratory. Patients with a diagnosis of insufficient sleep slept the longest in the laboratory (495.4 ± 14.43 min) and the sleep apnea group had the shortest total sleep time (409.0 ± 10.09 min). Multiple Sleep Latency Test findings Each patient had a total of four 20min opportunities to fall asleep on the MSL T during the day following their allnight polysomnographic evaluation. The percentage of those naps with sleep (stage 1, 2, or REM) is shown in Table 2 for each of the six diagnostic categories. Only patients with a diagnosis of no objective findings or psychiatric disorder did not consistently fall asleep at every opportunity. For these two groups sleep occurred in 75% of the naps. When a patient remained awake throughout a nap, a latency to stage 1 sleep of 20 min was scored. Sleep, Vol, 5 (Suppl, 2), 1982

5168 F. ZORICK ET AL. TABLE 1. Demographic and nocturnal polysomnographic variables Age at Age of Sleep Total Percent presentation onset latency sleep time Diagnosis n men (years) (years) (min) (min) Sleep apnea 41 98 47.2 ± 1.35 42.1 ± 1.19 21.4 ± 3.57 409.0 ± 10.09 Narcolepsy 50 52 42.2 ± 1.59 20.5 ± 1.32 14.3 ± 1.90 446.5 ± 9.38 Periodic leg movements 12 67 51.4 ± 2.68 40.7 ± 4.88 11.3 ± 2.36 431.3 ± 26.38 Insufficient sleep 23 57 41.9 ±2.57 27.6 ± 2.82 7.5 ± 1.25 495.4 ± 14.43 No objective findings 22 45 32.6 ± 2.95 24.2 ± 2.51 27.0 ± 5.65 482.3 ± 11.94 Psychiatric 13 38 43.9 ± 3.73 32.3 ± 2.94 33.4 ± 8.09 459.9 ± 25.43 Values are mean ± SEM. The mean latency to stage 1 sleep on the four naps was calculated for each patient. These latencies for each diagnostic group are presented in Fig. 1. To test the hypothesis that latencies among patients with apnea or narcolepsy would be shortest and those of patients with psychiatric disorders or no objective findings would be longest, with the remaining two groups falling between, a priori orthogonal tests using t ratios were performed (10). The mean latency of the apnea group was significantly shorter than that of the insufficient sleep group (t = 3.00, p <.01). This comparison is illustrated in Fig. 2, where means on each of the four naps are presented. In Fig. 3 the latencies on each of the naps for the periodic leg movement and psychiatric disorder groups are compared. The periodiclegmovement group's latency was significantly shorter (t = 3.06, p <.01). In addition, the combination of apnea and narcolepsy groups was significantly different from the remaining groups (t = 11.5, P <.001), and the combination of periodic leg movement and insufficient sleep groups was significantly different from the noobjectivefindings and psychiatric disorders groups (t = 7.02, P <.001). The percentage of those naps in which stage 2 sleep occurred is presented in Fig. 4. Stage 2 occurred most frequently in the naps of patients with insufficient sleep (84%). The incidence of stage 2 in patients with insufficient sleep was significantly greater (X 2 = 15.06, P <.001) than that of patients with narcolepsy (60%), but not significantly greater for patients with apnea (78%) or periodic leg movements (81%). The apnea and narcolepsy groups differed significantly (X 2 = 12.70, P <.001). Finally, stage 2 occurred in only half of the naps of patients with a psychiatric disorder or no objective findings. TABLE 2. Incidence of naps with sleep (stage I, 2, or REM) Diagnosis Sleep apnea Narcolepsy Periodic leg movements Insufficient sleep No objective findings Psychiatric Number of naps 164 200 48 92 88 52 Percent with sleep 99 100 98 99 75 75

PATTERNS OF SLEEPINESS IN EDS S169 15 C g OIl 01 <II 9 iii 6,.. u c:! <II 3..J I I "I T 1000 1200 1400 1600 Hours FIG. 2. Mean latency to stage 1 sleep on each of the four naps for patients with sleep apnea and insufficient sleep.

S170 F. ZORICK ET AL. 12 9 6 3 _ Psy PLM 1000 1200 1400 1600 Hours FIG. 3. Mean latency to stage 1 sleep on each of the four naps for patients with periodic leg movements and psychiatric disorders. 80 N 60 CIJ en <II iii = it 40 :: III a. <II Z C CIJ 20 CIJ Q. = Ap Nar PlM IS NOF Psy Diagnosis FIG. 4. Percentage of naps with stage 2 sleep for each diagnostic group.

PATTERNS OF SLEEPINESS IN EDS S171 TABLE 3. Mean latency to stage 2 sleep Diagnosis Mean (min) SEM Sleep apnea 9.09 0.26 Narcolepsy 7.36 0.32 Periodic leg movements 10.78 0.55 Insufficient sleep 10.76 0.46 No objective findings 15.27 0.46 Psychiatric 12.67 0.62 The mean latency to stage 2 was calculated, and is presented in Table 3 (means were calculated for each patient by using only naps in which stage 2 occurred). Again planned comparisons using the t ratio were performed to test the hypothesis that the latencies of patients with no objective findings or a psychiatric disorder would be greater than any of the other diagnostic groups. The combination of these two groups was significantly different from the combination of the remaining four groups (t = 2.98, p <.01). These two groups did not differ from each other, and there were no differences among the other four groups. Whereas the incidence of stage 2 in the naps of patients with narcolepsy was relatively low, the incidence of REM was quite high (72%), as expected. The percentage of naps with REM for the six diagnostic groups is presented in Fig. 5. Aside from the narcolepsy group, no other group had REM in more than 20% of the naps. As hypothesized, latency to REM as shown in Fig. 6 was shortest for patients with narcolepsy. By planned comparisons, the narcolepsy group was found to differ from the group closest to it: patients with apnea (t = 5.93, p <.01) and a combination of all other groups (t = 3.32, p <.01). 60 80 w... "i 40 III Q. ", z C GI 20 u Il. Ap Nar PLM IS NOF Psy Diagnosis a:.<: FIG. 5. Percentage of naps with REM sleep for each diagnostic group.

5172 F. ZORICK ET AL. c 'E 15 12 9 w II: 6.. CII III iii.2 3 Ap I I ii ii ii I Nar PLM IS Diagnosis I I NOF Psy FIG. 6. Mean latency to REM sleep for each diagnostic group. DISCUSSION Three major findings emerged from this analysis of MSLT results in patients with a variety of DOES diagnoses. First, three different degrees of sleepiness appear among these patients. Patients with obstructive sleep apnea and narcolepsy have severe sleepiness, consistently falling asleep within 4 min. The periodiclegmovement and insufficient sleep groups have a more moderate sleepiness, usually falling asleep within 5 8 min. Finally, patients with psychiatric disorders or no objective findings have a sleepiness similar to that of normals (11). Next, the nature of the sleep seen among these patients was quite different. Patients with apnea, periodic leg movements, and insufficient sleep had more naps with stage 2 sleep than the other groups. With one exception, latency to stage 2 was shorter as well. The exception was patients with narcolepsy, who had a low incidence of stage 2, but a short latency in those cases in which stage 2 occurred. Finally, the incidence of REM was appreciably higher in the naps of patients with narcolepsy than in those of any other group. A high REM incidence in naps of patients with narcolepsy has been reported previously (12). But what is notable in this analysis is that the latency to REM is also significantly shorter than that of any other group. These findings illustrate the value of the MSLT as a clinical tool in the differential diagnosis of complaints of EDS. Previous studies have found that the MSLT differentiates normals from patients with pathological sleepiness (7,8). These data show that the MSLT effectively differentiates among patients with various DOES. Sleep, Vol. 5 (Suppl. 2). 1982

PATTERNS OF SLEEPINESS IN EDS S173 diagnoses. Consistent differences in degree of sleepiness and in the nature of the sleep obtained on the nap tests were found among these patients. The present results also provide information pertinent to hypotheses regarding the causes of daytime sleepiness. Sleepiness probably is caused by a number of different factors. That these patients displayed different levels of sleepiness and that the nature of the sleep obtained was different suggests a differential causation ofeds. The various factors causing sleepiness may act alone or in combination to produce the sleepiness of the different diagnostic groups. The factors that might be considered include sleep deprivation, sleep disruption, biological rhythm disruption, drugs, and primary CNS dysfunction. Data have shown that sleep loss increases daytime sleepiness in normal subjects (4). Chronic sleep loss is probably the cause of the sleepiness of patients with a diagnosis of insufficient sleep. These patients showed the highest incidence of naps with stage 2 sleep, and the latency to stage 2 was relatively short as well. There appears to be a pressure for "deeper" stages of sleep. Interestingly, the sleep tendency of the insufficientsleep group was consistent across the four nap tests as well as nocturnal sleep onset (see Fig. 2). If these patients were displaying a disturbance of circadian rhythm (i.e., sleep phase delay or advance), one would expect to see a variation in sleep tendency through the day. While no direct information currently exists, there is evidence suggesting that disruption of sleep by brief arousals increases daytime sleepiness (8). This factor could be causing the sleepiness of patients with sleep apnea and periodic leg movements. However, even though these patients showed a similar incidence of stage 2 and REM sleep in their naps, there was a difference in the degree of sleepiness of these two groups. Whether or not this variation is the result of a different number of arousals from sleep or of a different pathophysiology producing the arousals is unclear. The EDS associated with narcolepsy generally is considered one manifestation of a primary CNS dysfunction. The unique combination of symptoms, the abnormal manifestations of REM sleep, and the developmental aspects that characterize narcolepsy all suggest a basic CNS disorder. The naps of patients with narcolepsy in this series were quite different from those of any other diagnostic group. There were fewer naps with stage 2 sleep and appreciably more naps with REM. Idiopathic CNS hypersomnolence is another category in which the sleepiness is possibly the consequence of a CNS disorder. There were too few cases in this series to provide an adequate analysis for the present paper. Other possible causes of the complaint of EDS are biological rhythm disruption and the use of or discontinuation of drugs and alcohol. It is known that many biological processes vary rhythmically over 24 h (circadian rhythms) in phase with sleepwake behavior. Repositioning sleepwake behavior disrupts the circadian rhythm and probably increases sleepiness at certain times of day (13). There were no patients with a circadian rhythm disorder in the present series, and the relative degree and nature of sleepiness in such patients is unknown. Finally, it has been established that some CNS depressants increase daytime sleepiness (14). Little is known about how discontinuation of CNS depressants affects daytime sleepiness.

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