Theme : Dreams

Impaired Circadian Waking Arousal in Narcolepsy-Cataplexy

Roger Broughton1, Susanne Krupa1, Brigitte Boucher1, Martin Rivers1 and Janet Mullington2
1Sleep and Chronobiology Research Center, Division of Neurology, University of Ottawa, Ottawa, Ontario, K1H 8L6, Canada and 2 Sleep Disorders Center, Beth Israel Deaconess Medical Center, Boston MA 02215, USA
Abstract
The 24-hour sleep/wake distributions of untreated patients with narcolepsy-cataplexy and matched normal habitual nappers were compared using home ambulatory monitoring. Subjects followed their usual sleep patterns including, for the habitual nappers, a self-selected daytime nap. There were no differences in 24-hour totals of sleep between groups other than a small increase in SWS in narcolepsy. Narcolepsy showed greater amounts of day sleep (stages 2, SWS, REM and total sleep) and less night sleep (stage 2, total sleep). Data were collapsed into 5 min epochs and entered into a matrix. The data in the two groups were then "wrapped" (re-aligned) around the 24 hours with phase 0° as each of the times of: evening sleep onset, onset of SWS, mid-point of night sleep and moment of morning awakening. In habitual nappers alignment beginning at morning wake-up produced the highest amplitude, least temporal dispersion and greatest kurtosis of daytime sleep (naps). The 24-hour sleep/wake distribution curves of both subject groups (data aligned at morning wake-up) based on collapsed data into 5 min bins then underwent curve fitting using 15th order polynomial regression. As with visual analyses of the raw data, the curve fits confirmed that the peak in daytime sleep propensity in narcoleptics was earlier by about 40° (2.66 hours). It was concluded that decreased daytime amplitude of a circadian arousal system was the most parsimonious explanation for the increased amount, broader temporal distribution and relative phase advance of day sleep in narcolepsy and that, as well, such a mechanism could explain a number of other features of the disease.

Current Claim: Decreased intensity of a circadian arousal system explains the increased amount, broader temporal distribution and phase advance of day sleep in narcolepsy compared to the pattern of sleep propensity in normal control subjects.

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A cardinal symptom of narcolepsy is an increase in daytime sleep propensity expressed as marked excessive daytime sleepiness (EDS), more or less irresistible sleep attacks and the desire to take daytime naps. EDS has been shown to be the main cause of narcolepsy's marked negative impact on quality of life measures involving work, education, recreation, memory, visual problems, interpersonal relationships and other aspects (Broughton et al. 1981). It is also the symptom of narcolepsy which is most resistant to treatment (Parkes, 1985; Thorpy and Goswami, 1990). Consequently, it is of considerable importance to understand the pathophysiological mechanism(s) of this EDS-related symptom complex. Numerous mechanisms have been proposed, but none have been formally proven. These include: a disturbance of sleep homeostasis (Tafti et al., 1992) in which, for instance, chronic increased pressure for day sleep would be secondary to chronic inefficiency of night sleep, a primary increase in pressure for both NREM and REM sleep (Hishikawa et al., 1976; Aldrich, 1990), an abnormality of circadian and ultradian rhythms (Kripke, 1976) and an impairment of waking arousal mechanisms leading to a "subvigilance syndrome" (Broughton, 1976; Roth et al., 1980).
One approach to document the differences in 24-hour distribution of sleep/wake patterns between patients with narcolepsy and normal subjects is to perform ambulatory monitoring under normal everyday living conditions. Such investigations have reported few if any differences in daily total sleep measures between groups. For example, the study of Broughton et al. (1988) found that there were no significant differences in 24-hour totals of any sleep stage other than an increase of stage 1 drowsiness in narcolepsy. Narcolepsy therefore appears to involve a circadian redistribution of sleep/wake states with somewhat less at night and more in the daytime. Subsequent ambulatory home recording studies showed that there is no close correlation between the amounts of night sleep and of day sleep (Broughton et al., 1994), a finding recently confirmed for in-lab recordings by Harsh et al. (1998). These results do not support the hypothesis that day sleep is simply a "make-up" of reduced night sleep.

As well as being greater in amount, there is strong evidence that the temporal distribution of day sleep is also different in patients with narcolepsy. Studies from our laboratory have found that the peak of day sleep is earlier by about 2 hours in patients with narcolepsy than in normals both for sleep under normal living conditions (Mullington et al., 1990) and for unintended sleep episodes in patients following a napping protocol (Mullington and Broughton, l993 ). This earlier peak of day sleep distribution in narcolepsy has been further confirmed for actigraphic measures under conditions of normal sleep entrainment (Canellas, 1992) as well as for recorded sleep under conditions of an ultrashort sleep/wake schedule (Lavie, 1991) and temporal isolation (Pollak et al., 1992).

In order to further elucidate the mechanism(s) of EDS and daytime sleep amount and distribution in narcolepsy, the current study compares sleep/wake distribution of untreated narcolepsy patients with that of habitual normal nappers. It was decided to use healthy nappers in the belief that their day sleep distribution, self-selected in the home environment under conditions lacking social or other restraints, would express the timing of the normal afternoon "nap zone". This secondary daily peak of daily sleep propensity has been shown to be essentially identical across a number of very different experimental paradigms and about a quarter the magnitude of that of the major sleep period (Broughton and Mullington, 1992).

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Twelve patients with narcolepsy-cataplexy (8 female, 4 male; mean age 47.3 ± S.D. 14.9 years) were compared to 12 matched normal habitual nappers (8 female, 4 male; mean age 46.1 ± 15.1 years). Patients met the ICSD (1990) criteria for the diagnosis of narcolepsy by having daytime sleep attacks, cataplexy and two or more sleep onset REM periods (SOREMPs) in a five nap MSLT. They were either previously untreated (N=3) or were withdrawn from all stimulants (methylphenidate or pemoline; no amphetamines) for at least a week and from any anticataplexy medication (tricyclics, serotonin reuptake inhibitors, monoamine oxidase inhibitors) for at least 3 weeks. Normal nappers were defined as healthy non-sleep disordered persons taking at least 3 naps a week of 10 min or more in duration, over a period of 5 or more years. Habitual napping patterns were confirmed across a 3 week per-study period using daily sleep logs and continuous actigraphy. All subjects also received a screening PSG to exclude respiratory, movement or other sleep disorders.
Subjects underwent 24 hour ambulatory sleep/wake monitoring using 8-channel portable Medilog 9000 recorders (Oxford Medical Systems, Inc.) with a montage that included C3-A2, O1-A2, C4-A1, EOG and submental EMG channels. These units permit the recording of some 25 hours of sleep/wake data on a single C-120 cassette. The recorders were attached in the laboratory in the late afternoon between 1600-1900h, the subjects were driven home, and they returned 25 hours later for equipment removal. Instructions were given to subjects to follow their habitual sleep/wake, eating and activity patterns; in addition, the normal nappers were requested to take their nap when they felt the urge. Subjects therefore wore the apparatus while at work, while doing housework or other normal daytime activities. Most of the recordings were done during weekdays with only 1 recording in a patient with narcolepsy and none in normal nappers being done on the weekends. The protocol was accepted by the local human ethics committee and subjects signed informed consent forms.

The recordings were later played back using a paper write-out of 15 mm/sec and then visually scored using a 60 sec epoch for sleep/wake stages by the Rechtschaffen-Kales (1968) criteria with stages 3 and 4 being combined as slow wave sleep (SWS). Between group comparisons of the amounts (min) of sleep/wake stages were made using the Student t-test. To simplify data processing the one minute staged epochs were then collapsed into longer 5 min epochs according to the dominant pattern during the 5 min periods and entered into a matrix for subsequent descriptive analyses of circadian sleep/wake distribution. The data were "wrapped" with onset alignment (phase 0°) at different moments in circadian time. These further analyses were accomplished in 3 steps.

First, for the normal napper group, the sleep/wake data were aligned for the times of: evening sleep onset, appearance of nocturnal stage 3 (SWS), middle of nocturnal sleep, and morning wake-up. This analysis was done in order to determine which alignment would produce the tightest temporal distribution of day sleep (naps) and therefore represent the most "synchronizing" daily sleep/wake event in the regulation of the afternoon "nap zone". There have been suggestions in the literature that each could have a role. For example, Broughton (1975) proposed that the night sleep period and daytime nap period were 180° apart; and Dinges (1989) later found the 180° out of phase to be descriptive of the middle of the night sleep and of afternoon napping; Broughton (1975) proposed that the slow wave sleep (SWS) distribution maximum in the first third of night sleep and the afternoon nap reflect a 12-hour SWS rhythm for which there is some experimental evidence (Gagnon et al., 1985; Campbell and Zulley, 1989); and the 2-process model of Borbély (1982) postulates that it is duration of prior wakefulness after morning wake-up which determines increasing daytime sleep pressure. The resultant four distributions of day sleep were compared for their amplitude, temporal distribution and kurtosis.

In the second analysis, the 24-hour distributions of sleep for the patients with narcolepsy and normal nappers were compared aligning each data set at morning awakening (which in narcoleptics as well as nappers produced the tightest distribution of day sleep).

The third analysis consisted of curve-fitting the two 24-hour distributions using polynomial regression (BMDP statistical package) which provides an accurate fit of the data without prior assumptions as to its shape (Broughton et al., 1993). The resultant curve-fits were compared and subtracted to show the 24-hour differences in sleep/wake distribution. The sleep propensity process was defined as the curve of the proportion of subjects asleep during each time unit across the 24-hour period. As in Borbély et al., (1989) a sleep propensity of 1.0 indicates that all subjects are asleep and a sleep propensity of 0.0 indicates that no subjects were asleep.

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Figure 1

Figure 2

Figure 3

Figure 4
In the normal nappers, the three weeks of sleep logs and actigraphic recordings confirmed habitual napping with a mean frequency of 5.4 naps/week and mean nap duration of 27 min, with all naps occurring in the afternoon. Comparing the two groups, there were no significant differences in 24-hour totals of sleep stages other than a somewhat greater amount of SWS for patients with narcolepsy (Table 1). In the daytime portion, patients with narcolepsy compared to normal nappers showed more stage 2, SWS, REM sleep and total sleep; and, at night, they had less stage 2 and total sleep.
In order to help clarify the nature of the normal main sychronizing circadian sleep/wake event for the timing of the afternoon nap, the distribution of day sleep was compared using the four alignments for the habitual nappers. Visual analysis (Figure 1) of the results showed clearly that day sleep was most tightly distributed when the data was aligned by the time of morning awakening and was more broadly distributed for the other three alignments. This narrower distribution was confirmed numerically as a greater amplitude, lower temporal distribution (variance) and greater kurtosis for day sleep with this alignment of the data (Table 2). A similar analysis of day sleep distribution in narcoleptics confirmed that for this population as well, the tightest distribution of day sleep was with alignment of 24-hour distribution of sleep/wake data at the time of morning wake-up. These data for both groups are available in an earlier abstract publication (Broughton et al., 1995).

The 24-hour sleep/wake distributions of the two groups were therefore compared using this alignment. These distributions are plotted in Figure 2. Both data sets showed a biphasic (circasemidian) distribution of night sleep and day sleep. Visual comparison of the two patterns clearly revealed several differences. In narcolepsy, day sleep was considerably greater in amount, much broader in distribution, and peaked earlier. The late afternoon so-called "wake maintenance zone" (Strogatz 1986), on the other hand, peaked in both groups at about 170° after wake onset; but its breadth (which can be appreciated as the negative of sleep distribution) was much broader and its amplitude considerably lower in patients with narcolepsy.

Curve fitting using polynomial regression found that an excellent fit was made using 15th order regression which explained 96% of the variance in the narcolepsy data and 98% for that of the habitual nappers. Polynomial regression does not have any preconception of the shape of the data. The curve-fits are superimposed on the averaged raw data in Figure 2 and shown in isolation in Figure 3. They indicated that in narcolepsy the peak in day sleep occurred 70° after morning awakening and in habitual nappers at 110°, a difference of 40° or 2.66 hours. The night sleep period began with essentially identical timing in the curve-fits for the two groups. Subtraction of the fitted average sleep propensity curve of the habitual nappers from that of narcoleptics (Figure 3) indicated that narcolepsy has similar amounts of sleep during the afternoon nap zone associated with two peaks of greater day sleep, one at about 60° and the other 180° after morning wake-up, and with some reduction of night sleep.

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In normal persons with habitual naps the 24-hour sleep/wake totals were essentially identical to those reported for monophasic normal sleepers using the same recording technique (Broughton et al., 1988). This suggests that habitual napping is associated with a more or less equivalent decrease in sleep need at night. Comparison of the 24-hour totals of sleep in the two populations confirmed earlier studies indicating that, under normal living circumstances, sleep in narcolepsy presents a circadian redistribution without any important overall increase (Broughton et al., 1988).
In habitual nappers, the alignment of data for different points in the circadian sleep/wake day indicated that the distribution of day sleep (napping) was of lower amplitude and broader distribution for alignments at evening sleep onset, initial nocturnal SWS and mid-sleep point, and that it was tightest for alignment at morning awakening. For the initial period after morning wake-up these results are compatible with the process-S hypothesis of Borbély (1982) in which increased daytime wakefulness is associated with increased sleep pressure until, in nappers, day sleep appears. However, this daytime period of increased sleep propensity (nap zone) is then followed by a prolonged period of low sleep propensity equivalent to the afternoon "wake maintenance zone" of Strogatz (1986) and the "forbidden zone for sleep" of Lavie (1986) leading to a biphasic daily pattern. This pattern has been referred to as circasemidian (Lat: about a half day) by Broughton (1975) and hemicircadian (about two per day) by Kronauer and Jewett (1992).

The pattern of the 2/day sleep/wake distribution has been found to be very similar in normals across a number of quite different experimental paradigms including: sleep latency under both habitual entrained conditions (Richardson et al., 1982) and the constant routine (Carskadon and Dement, 1992), sleep amount in ultrashort sleep studies (Lavie, 1986) and percentage probability of being asleep during temporal isolation (Zulley and Campbell, 1985). Direct scaled superimposition of these results (cf. Broughton and Mullington, 1992, Figure 1) revealed that these patterns are essentially identical across such diverse experimental paradigms.

It has been proposed (Broughton, 1994) that the afternoon "nap zone" is due to increasing sleep propensity related to increasing prior wakefulness (process-S) being reversed by an SCN-dependent circadian arousal process such as that shown to exist in primates by Edgar et al. (1993). Our findings are compatible with this hypothesis for which our laboratory as well has some recent direct experimental evidence in man using light treatment to phase delay and phase advance the circadian clock which similarly shifts the daytime period of worst performance in a sleepiness-sensitive task (Krupa et al., 1998).

As found in our earlier studies (Mullington et al., 1990; Mullington and Broughton, 1994), and in those of others (Lavie, 1991; Pollak et al., 1992), both the raw and curve-fit data showed that the peak of day sleep propensity in narcolepsy occurs some 2-2.5 hours earlier than in normals. The more rapid accumulation of sleep in narcoleptics early after morning wake-up could reflect either an enhanced process-S or a weakened circadian arousal system, or both. However, the most parsimonious explanation of the overall pattern of day sleep in narcoleptics is that it is due to reduced intensity of a circadian arousal process such as that of Edgar et al. (1993) and whose anatomical connectivity and neurochemistry are currently being worked out by Jouvet (personal communication). This mechanism is similar to earlier proposals of reduced daytime arousal (Broughton, 1976; Roth et al., 1980) as well as with the similar conclusion of Danz et al. (1994) based on effects of imposing a 3 hour ultrashort sleep schedule in narcolepsy. It also adds an explanation for the consistent phase advance of day sleep in narcolepsy. In this conceptualization, schematised in Figure 4, the weakened circadian arousal process would not only lead to more day sleep and to its broadened temporal distribution but by intersecting process-S earlier after wake-up, would also give rise to the characteristic earlier peak in day sleep distribution.

Reduced intensity of the circadian arousal process as the cause of the daytime sleep and sleepiness in narcolepsy would also explain a number of its other features. These include the general lack of correlation between night sleep and daytime sleep and sleepiness (Broughton et al. 1994; Harsh et al. 1998), the relative ineffectiveness on improving daytime sleepiness levels, of attempts to consolidate night sleep with hypnotics (Broughton and Mamelak, 1979; Thorpy and Goswami, 1990), the not uncommon appearance in the development of the disease of EDS and daytime sleep episodes before there is any deterioration of night sleep quality (Billiard et al. 1983) and, of course, the well-known effectiveness of stimulant medications whose mechanism is to intensify daytime arousal mechanisms (Parkes, 1985), an action which is particularly specific for the new stimulant modafinil (Bastugi et al. 1988; Billiard et al. 1994; Broughton et al. 1997). None of these features of the disease is easily explained by hypotheses involving an abnormality of sleep homeostasis, a primary increase in sleep pressure, a change in biorhythm periodicity, or other previously proposed mechanisms of daytime sleepiness in narcolepsy.

In summary, our experimental results are compatible with an impaired circadian arousal process as the basis of the daytime sleepiness and sleep attacks of narcolepsy. Such a mechanism does not, however, explain the pathognomonic symptom of narcolepsy, which is that of cataplexy, a phenomenon known to express dissociated REM sleep atonia in wakefulness triggered by emotional stimuli. This symptom, along with the frequent occurrence of sleep paralysis and certain other features of the disease such as the appearance of ambiguous sleep stages (Barros-Ferriera and Lairy, 1975) and the occasional absence of REM atonia with the appearance of REM sleep behavior disorder (Schenck and Mahowald, 1992), suggests the co-existence of impaired circadian arousal with an abnormality of those mechanisms which normally bind together the REM sleep components into an integrated state, and which can be considered as an apparent problem of "state boundary control" (Broughton et al. 1986).

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This work was supported by a grant from the Medical Research Council of Canada of which the senior author was also a recipient of a Career Investigator Award.

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