Sleep, 5:S157-S164
© 1982 Raven Press, New York
Pupillometric Assessment of Disorders
of Arousal
Helmut S. Schmidt
Division of Sleep Medicine, Department of Psychiatry, The Ohio State University
College of Medicine, Columbus, Ohio
The autonomic nervous system has long been associated with the sleepwakefulness continuum (1). A number of studies have identified peripheral manifestations that are indicators of this continuum (2,3). The behavior of the pupil is
the most directly observable barometer of autonomic nervous system balance.
Pupillary constriction accompanies increasing sleepiness, and miosis, or
parasympathetic dominance, characterizes sleep onset and the state of sleep (4).
This was confirmed by Berlucchi and associates (5), who also described rapid
transient pupillary dilations synchronous with REM bursts, thought to result from
phasic parasympathetic inhibitions.
A normal alert individual without sleep deprivation (for example, following
normal all-night sleep) can maintain a stable pupillary diameter well above 6 mm in
total darkness for 10 to 15 min without notable pupillary oscillations (2). Figure 1
illustrates a typical pupil reflex response to a standardized light stimulus in a
young adult male. Key measurements are the initial diameter (ID = pupil diameter
at the time of stimulus impact), the extent of contraction (Ee = diameter at point
of maximum contraction minus the ID), and the initial response slope. With
heightened sympathetic tone and high alertness level the Ee in normal subjects is
smaller. Following prolonged awake periods, such as prior to a normal individual's regular all-night sleep, occasional small spontaneous oscillations and an
increased response to an identical light stimulus are observed. This suggests a
weakening of sympathetic (arousal) tone to resist the reflex effect of an identical
parasympathetic stimulus in the presence of lowered arousal level.
The pupillary reflex response to light stimulation, and thus the resultant Ee,
appears to be dependent on five variables: (a) stimulus intensity, (b) stimulus
duration, (c) stimulus frequency, (d) state of retinal (dark) adaptation, and (e) the
state of supranuclear inhibition at the time of stimulus impact. During pupillometric testing, the first four variables are held constant and the resultant Ee is thus
thought to reflect in an inverse relationship the state of supranuclear inhibition
and, indirectly, the state of arousal (6). Thus, the smaller the Ee the higher the
state of arousal is thought to be.
Address correspondence and reprint requests to Helmut S. Schmidt, Division of Sleep Medicine,
The Ohio State University, 473 West 12th Avenue, Columbus, Ohio 43210.
Key Words: Pupillometry-DOES-Diagnosis-Sleep agnosia-MSLT.
S157
H. S. SCHMIDT
S158
\
ID=
-9.00mm
8.83
mm
t
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-7.00 mm
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FIG. 1. This is a normal pupil reflex recording for a young adult male. The light
stimulus (L.S .J, given for 0.1 s, is of 15
ft-candle intensity attenuated by a 4.0 log
neutral density filter. Maximum pupillary constriction (PMC) is indicated by
the arrow. The initial pupil diameter (ID)
is indicated by the verticle scale and the
extent of contraction (Ee) is calculated
by the formula EC = ID - PMC.
I-----l I sec linch
Three systems modulating the pupillary reflex response have been postulated
(7): the noradrenergic-serotonergic hypothalamic modulation primarily determining the ID, dopaminergic mesenphalic modulation of the Eddinger-Westfahl nucleus, and sympathetic stimulation of cortical origin, thought to primarily affect
pupillary diameter and the oscillations observed in sleepy subjects. Lowenstein
and Lowenfeld (2,6), who originally developed the pupillometric technique,
emphasized high-intensity (15 ft-candles) and high-frequency light stimulation in
their studies of acute and chronic fatigue. Fatigability ofthe pupillary response, as
seen by alteration in the stimUlus-response curve, was thus thought to be a measurement of fatigue. Most of their work, however, involved normal subjects or
those with neurologic lesions, and thus had little applicability to the hypersomnolent individuals seen at sleep centers. Yoss et al. (8), however, studied narcoleptics
and found very unstable pupillary diameters during dark adaptation, but with normal
response to high-intensity light stimulation. In previous publications we have
confirmed their findings, except that we have noted in narcoleptics a reduced or
even absent pupillary reflex response to low-intensity light stimulation (9, to). Our
light stimulation technique, adopted from Lee and Knopp (7), emphasizes low
intensity and short duration as potentially more useful in differentiating states of
pathologic sleepiness, and our preliminary observations tend to support the usefulness of this technique.
Preliminary conclusions from our earlier work suggested that the pupil response
to low-intensity light stimulus is reduced or absent in narcoleptics, but normal in
other disorders of excessive somnolence (DOES), i.e., idiopathic CNS hypersomnolence, sleep apnea, and sleep-related myoclonus (10). The dark-adapted
pupillary diameter, however, appeared to be equally unstable for all DOES conditions. It is this latter pupillary instability under standardized testing conditions
that perhaps most closely reflects physiologic sleepiness.
Pupillometry and comparison with MSLT
In addition to a routine four-nap multiple sleep latency test (MSLT; 9 a.m.,
11 a.m., 1 p.m., and 3 p.m.), 12 narcoleptics (mean age 43 ± 14), 13 idiopathic
CNS hypersomnolent OCR) subjects (mean age 37 ± 13), and 6 subjects with
Sleep, Vol. 5 (Suppl. 2), 1982
PUPILLOMETRIC ASSESSMENT OF AROUSAL DISORDERS
S159
DOES sleep-related myoclonus (SRM) (mean age 47.7 :t 6.7) were administered
a standard pupillometry test, as described previously (10), immediately prior to
each nap attempt. Subjects were medication-free and had undergone all-night
polysomnography on the night prior to MSLT.
Sleep latencies for narcoleptics were shortest (not significant, p > .05) on all
naps, but with all groups showing the shortest sleep latencies with the first nap at 9
a.m. (Table 1). Sleep efficiency (total sleep time/total recording time) is higher in
narcoleptic subjects than ICH or SRM patients, who had very similar scores.
These observations are in agreement with the work of other investigators (11,12).
Pupillary diameter and number of oscillations during 10 min of dark adaptation
were measured at 30-s intervals for naps 1 and 3. 1 The presence of movement
artifacts, lid closures, and other factors variably reduced n at each measurement
point. Figures 2 and 3 illustrate pupil diameter fluctuations over 10 min for naps 1
and 3, respectively. Both groups show a reduction in pupil diameter over the 10 min
prior to nap 1, most pronounced in the narcoleptics. This is much less evident
prior to nap 3 and agrees with the decreased need for sleep observed in nap 3, as
indicated by longer sleep latency and lower sleep efficiency.
A surprising finding, however, was the notable difference in the number of
pupillary oscillations for each 30-s interval prior to nap 1 (Fig. 4). Beginning in the
6th min, narcoleptics show fewer oscillations, while ICH subjects show increasingly more oscillations, beginning with the 5th min. Assuming that the oscillations
reflect fluctuations in sympathetic tone, and thus indirectly arousal-sleepiness
balance, one might conclude that as the ICH subjects become sleepier in a dark,
quiet environment, they respond with increasing internal episodic stimulation, in
contrast to the narcoleptics, who seem to lack that ability and drift closer to sleep
onset and increasing lid closures.
Figure 5 shows the interesting profile of oscillation prior to nap 3. Both groups
exhibit markedly increased oscillations (i.e., their ability to oscillate), an observation that coincides with improved overall pupillary diameter, increased sleep
latencies, and lower sleep efficiency. The ability to oscillate-that is, to correct
lapses in sympathetic (arousal) tone, or to normalize autonomic nervous system
imbalances-may thus be an additional important factor to consider in the assessment of sleepiness and its severity. This suggests that with increasing severity
of sleepiness there is a decreasing ability to oscillate and to regain the initial
pupillary diameter.
Responses to attenuated light stimulation have not yet been completely
analyzed. The EC and response curves for ICH patients are essentially normal.
For narcoleptics the EC has ranged from absent to normal, with the response
slope frequently very shallow. The most severe narcoleptics are not only those
least responsive to treatment but also those whose response to light stimulation
appears to be the most abnormal. Whether the response to light stimulation correlates with the ability to oscillate awaits further analysis.
The reduced and even absent EC in some narcoleptics suggests high adrenergic
1
Data analysis is still in progress for the other naps.
Sleep. Vol. 5 (Suppl. 2). 1982
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TABLE 1. Values obtained from Multiple Sleep Latency Tests in patients with narcolepsy, sleep-related myoclonus,
and idiopathic eNS hypersomnolence
Narc.
ICH
SRM
Narc.
ICH
SRM
REM
Latency
(Narc.)
2.17 ± 2.77
(2)
3.54 ± 4.52
(12)
3.54 ± 3.50
5.85 ± 3.84
(3)
6.71 ± 3.6
(4)
7.0 ± 4.87
(13)
7.35 ± 4.21
(10)
4.34 ± 2.71
(5)
7.83 ± 5.32
(6)
7.40 ± 6.90
(5)
7.70±5.11
(5)
.89 ± .13
(2)
.84±.14
(12)
.82 ± .18
(2)
.85±.18
(0)
.65 ± .26
(14)
.66 ± .16
(14)
.62 ± .28
(14)
.50 ± .34
(4)
.68 ± .35
(6)
.63 ± .33
(6)
.58 ± .35
(6)
.61 ± .26
(6)
6.36 ± 5.06
(7)
9.0 ± 9.32
(6)
3.17 ± 3.27
(6)
9.94 ± 6.80
(9)
Sleep latency
Nap 1
(n)
Nap 2
(n)
Nap 3
(n)
(12)
Nap 4
(n)
3.40 ± 4.53
(0)
Sleep efficiency
-------r
% Total sleep
time in REM
(Narc.)
27.56 ± 34.4
(12)
15.47 ± 22.5
(12)
27.6 ± 35.3
(2)
43.7 ± 29.6
(0)
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FIG. 2. Pupillometry of narcoleptic and idiopathic eNS hypersomnolence patients performed at approximately 9:00 a.m. immediately prior to nap 1. Pupil diameter in total darkness was measured at
30-s intervals for 10 min.
tone at the subcortical, but above brain stem, level. This correlates well with
associated signs of peripheral adrenergic excess as found by us in some narcoleptics (13). A paradoxical situation is, therefore, evident: excessive sleepiness at the
cortical level, as perceived by the patient and documented by instability of the
patient's dark-adapted pupil, and increased supranuclear noradrenergic activity at
the subcortical level, as documented by the reduced EC to light stimulation. The
latter suggests hypothalamic involvement in the development of narcolepsy.
Pupillometry and sleep agnosia
Pupillometry is also showing itself to be useful in differentiating sleep agnosia, 2
another little-understood syndrome, from other hypersomnolence disorders.
Physiological measurement of sleepiness is particularly important for this syndrome, as one of its primary characteristics is lack of subjective awareness of
sleepiness. These patients are not generally seen in sleep disorders centers, because they deny any awareness of sleepiness or sleep attacks, although they
sometimes describe themselves as "tired." Typically, though, they develop serious problems at work because of recurrent "blackouts," "syncope," or "seizures," frequently associated with falling and injury, but without definite etiology.
One patient was only aware that he had slept when he dreamed. Repeated EEGs
and computed tomography scans as well as cardiac catheterization and pacing
studies were all normal. Another patient, a 35-year-old male who repeatedly
"passed out" during sexual intercourse without awareness of doing so, underwent
a series of cardiac studies that revealed second-degree A V blocking. He was
eventually given a cardiac pacemaker after being admitted to the coronary care
2
Term suggested by Howard Roffwarg.
Sleep. Vol. 5 (Suppl. 2). 1982
H. S. SCHMIDT
S162
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FIG. 3. Dark-adapted pupil diameter in narcoleptic and idiopathic CNS hypersomnoience subjects
immediately prior to nap 3 (approximately 1:00 p.m.). There was variation in n at each 30-s measurement point, particularly for the narcoleptic subjects as a result of lid closures or other artifacts.
unit following repeated blackouts. His MSLT sleep latency scores ranged from 0
to 2.0 min (x 1.2 min), whereas the SSS scores ranged randomly between 2 (functioning at a high level) and 6 (fighting sleep, preferring to lie down). Pupillometry
documented frequent large oscillations and normal response to light stimulation.
He responded remarkably well to protriptyline, 15 mg per day, and L-tryptophan,
2 g at bedtime (no further blackouts, normal pupillometry, and absence of
second-degree AV blocking).
Three such patients have been identified and studied. All are male and have
sleep-related myoclonus, normal REM latencies, and no REM sleep during
MSLT. One patient was provisionally diagnosed by the referring physician to
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FIG. 4. The frequency of pupillary oscillations (defined as a pupil diameter change >0.2 mm) in
narcoleptic and idiopathic CNS hypersomnolence subjects. Recorded over a 10-min period prior to
nap I, at approximately 9:00 a.m.
Sleep, Vol. 5 (Suppl. 2), 1982
PUPILLOMETRIC ASSESSMENT OF AROUSAL DISORDERS
S163
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FIG. 5. The frequency of pupillary oscillations (defined as a pupil diameter change >0.2 mm) in
narcoleptic and idiopathic eNS hypersomnolence subjects. Recorded over a 100min period prior to nap
3, at approximately 1:00 p.m.
have narcolepsy, and his frequent falls, occasionally resulting in injury, were
thought to be cataplectic episodes. It became evident, however, that he would
first fall asleep, then slump to the floor and arise without awareness of having
been asleep. MSLT ruled out a diagnosis of narcolepsy, but, in conjunction with
pupillometry, documented underarousal and a strong tendency to precipitous
sleep onset.
Automatic behaviors and "blackouts" were described in narcolepsy as far back
as 1934 by Daniels (14). Such episodes, however, appeared to have been associated with awareness of sleepiness and of its having occurred. Furthermore, it
is not clear how many of his patients may actually have had a hypersomnolence
disorder other than narcolepsy. Whether sleep agnosia is another, though very
important, symptom of DOES sleep-related myoclonus, or constitutes a new
syndrome of hypersomnolence is uncertain at this time.
Conclusions
Pupillometry is a powerful and relatively simple tool for the assessment of
normal and pathologic sleepiness. It compares very well with MSLT results and
shares with MSLT a high degree of sensitivity in measuring tendency for sleep
onset. Subjective sleepiness remains somewhat of an elusive phenomenon, influenced by a variety of sociocultural factors, including the process of aging. The
older subject may have a higher propensity for sleep onset yet be less aware of
sleepiness and sleep need. Some patients lack the ability to sense diminished
Sleep, Vol. 5 (Suppl. 2), 1982
S164
H. S. SCHMIDT
arousal level, or sleepiness, and their sleep need. This syndrome of sleep agnosia
can result in serious morbidity, and a high level of awareness of its existence by
the clinician can prevent misdiagnosis and inappropriate treatment.
Improved quantification and special techniques suggest that pupillometry has
much to offer for our search for more accurate assessment and diagnosis of
disorders of pathologic sleepiness. The results of our studies to date are encouraging. Pupillometric differentiation of the narcolepsy syndrome from other
DOES may be possible, and pupillometry has promise in shedding new light on
this and other DOES conditions. The changes in pupillary stability prior to the
different naps in MSLT are of considerable interest, but must be examined in
more detail and compared using age-matched controls, in light of previous studies
suggesting an ultradian rhythm in spontaneous pupillary oscillations in normal (15)
and narcoleptic (16) subjects. The conditions of pupillometric assessment were,
however, considerably different in these latter studies. These observations
suggest that pupillometry may also be sensitive to subtle changes in ultradian
rhythms and may thus have usefulness in the assessment of biological rhythm
disorders.
Acknowledgments: I thank Sarah Schrier for assistance in the preparation of the manuscript, and Dr. Elizabeth Jackson for assistance in the collection of part of the data.
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Sleep, Vol. 5 (Suppl. 2), 1982