Volume 2
Number 2

anterior temporal and the ear lobe electrodes.
Vision was normal except for total loss of con-
vergence for near, unaccompanied by exophoria.

His chief subjective complaint was constant,
overwhelming fatigue. He slept restlessly at night,
had headaches and was always tired, forgetful,
and unable to learn, While he had been a good
student before the accident, he now had to force
himself constantly to stay awake in school, was
too tired to follow the teaching, and inevitably
fell asleep after some time.

The pupillary fatigue test showed that the
patient was unable to remain alert when sitting
quietly in darkness, After 2 minutes his pupils
began to fluctuate, and after 3 minutes he began
to fall asleep. It was thus clear that the extreme
tiredness of which the patient complained was
organically founded.

The second patient, a 36-year-old man, was
suffering from an atypical form of multiple
sclerosis. For 5 years, periods of transitory spastic
paralysis of the left upper and lower extremities,
diplopia, and paresthesias had alternated with
periods of seemingly complete remission. About
a year before the onset of the degenerative
central nervous disease, the patient had first com-
plained of constant fatigue, and this fatigue had
continued since then, persisting even during the
periods of remission. He always felt tired, and
no amount of rest appeared to help; he was even
more tired when he awoke in the morning than
when he went to bed in the evening, and he
dragged himself painfully through the day.

This condition of extreme fatigue was expressed
clearly in his pupillary movements. The reflexes
to light—quite normal during moments of alert-
ness—deteriorated markedly within seconds (Fig.
13,B1, B2). When the patient sat quietly in
darkness, the pupils fluctuated wildly, and, al-
most from the beginning of the test, repeated
sensory stimuli were required to keep the pa-
tient awake (sound stimuli at s in Fig, 13,B3).

Discussion
Mechanisms of fatigue. The spontaneous
pupillary oscillations described in this com-

Pupillary movements during fatigue

munication were found in human subjects
under the influence of that degree of
fatigue which is commonly referred to
when man is conscious of being tired (see
following section under “Physiologic versus
pathologic fatigue” for further definition).
This kind of fatigue differs from the condi-
tion of exhaustion of experimental animals
under the influence of severe stress, which
bririgs about an outpouring of epinephrine,
hypertrophy of the adrenal glands, and
other anatomical changes. These mecha-
nisms do not play a role in man under the
usual conditions of civilized life, and it is
our opinion that the physiologic responses
to catastrophic stress situations should not
be confused with the events which take
place as we gradually tire during an ordi-
nary working day.

The fatigue dealt with by us also differs
from that referred to in texts on the
physiology of work, in which physical
symptoms such as an accumulation of
waste products in muscle, increased heart
rate and volume, accelerated respiration,
increased oxygen consumption, and other
biochemical changes are dominant features.
While the type of stress used in those ex-
periments, and the acute condition elicited,
certainly are important features in human
existence, they are not identical with the
kind of fatigue we mean when we say “I
am tired,” although, of course, this may
be their ultimate result.

The kind of fatigue which causes us to
say “I am tired” is not necessarily asso-
ciated with muscle fatigue, and need not
be connected with other symptoms of
physical stress; it can be reversed from one

stimulus (sound stimulus, marked by arrow s) which is typical for the sympathectomized

pupil.

C and D, The same subject as in Figs. 7 and 8 was used at a time when she was in good’
general condition. On the evening of the test she was tired after a 13 hour day, preceded
by only 3% hours of sleep. Waves of pupillary dilation and contraction accompanied the
waves of drowsiness and awakening. Since the subject made no effort to stay awake, she
fell asleep after 12 minutes (C). At this time, 10 mg. of d-amphetamine sulfate (Benzedrine)
was given orally. One hour later, the subject felt wide awake and slightly tense and excited.
The pupils showed practically no oscillatory activity (D, showing the 11th to 15th minutes

of the test).


Lowenstein, Feinberg, and Loewenfeld

Just like the slow, extensive waves of
pupillary enlargement and narrowing
which accompany each wave of sponta-
neous arousal and decline (a < a in Fig.
7), the fast, superimposed oscillations may
become quite marked (b in Fig. 7). Even
when the tired subject forces himself by a
voluntary ‘effort to remain awake fairly
steadily, these small oscillations sometimes
cannot be suppressed; they are associated
with minute extraocular movements and
appear to be related to the growing in-
ability of the tired subject to fixate evenly.”

Influence of age. Older persons without
pathology affecting the pupillary innerva-
tion show essentially the same pupillary
behavior pattern, except that the system
appears, on the whole, more vulnerable.
The pupils tend to be somewhat smaller
in darkness, the periods of tiredness with
fluctuating movements more frequent, the
change from alertness to drowsiness more
sudden than in normal young subjects.

It is commonly believed that the pupils
become smaller with advancing age, and
it is undoubtedly true that the mean
pupillary diameter of a given number of
arbitrarily chosen old persons will be
smaller than that of an equal number of
young subjects. It has not been established,
however, whether this decline in pupillary
size—like other conditions found with in-
creasing frequency in the older population
—is due to an aging process per se or to
an increased opportunity to accumulate
pathology within a longer lifetime.

The fact that individual old persons may
have pupils which would be considered

‘*The unsteadiness of fixation described here does not
affect our measurements of pupillary diameter by way
of optical distortion, due to wandering of the subjects’
eyes; the eyes are’ under constant observation on the
oscilloscope screen, and their position is therefore con-
trolled within narrow limits, The extraocular movements
occasionally observed during unsteady fixation of the tired
subject were so minute as to be barely perceptible on
the screen (under X5 linear enlargement), Since the
room is completely dark and the fixation point placed at
a distance’ of 6 feet, it is also not likely that the pupil-
lary oscillations are elicited by changes in fixation or
accommodation; we are inclined to regard the unsteadi-
ness of fixation and the pupillary oscillations as parallel
events, elicited together by the same central nervous
mechanism (see below, “Mechanism of spontaneous pupil-
lary movements in complete darkness”),

Investigative Ophthalmology
April 1963

normal even in the young (Fig. 9, A-C)
does not necessarily preclude the existence
of an age trend even in these individuals;
some young persons show pupils of very
large size and greater than average
mobility (Fig. 9, D), and the reactions of
such subjects could undergo some de-
terioration without the development of
obvious pathology. The solution to these
questions will have to await the outcome
of studies in which a larger number of
normal subjects are followed up for an
extended period.

The small, fast pupillary oscillations
which accompany imperfect fixation of the
tired individual tend to be less extensive
in old than in young persons.

Influence of some drugs. A detailed de-
scription of the modifications of sponta-
neous pupillary movements under the in-
fluence of various drugs exceeds the scope
of the present communication and will be
given later. In connection with the prob-
lems dealt with at present it is important
to note that (1) peripherally acting drugs
such as instilled parasympathicolytic or
sympathicolytic substances reduce the ex-
tent of the pupillary movements associated
with the waves of arousal and falling
asleep, by eliminating one of the effector
systems (see below, “Mechanism of spon-
taneous pupillary oscillations,” etc.). They
do not, however, affect the rhythm of
pupillary enlargement and contraction as
such (Fig. 10, A and B); (2) in contrast,
centrally acting drugs such as Benzedrine
or Nembutal may alter (i.e, enhance or
abolish) the waves, together with the sub-
jective feeling of tiredness (Fig. 10, C, D).

The small, fast pupillary play which
accompanies unsteady fixation is no longer
recorded after administration of parasym-
pathicolytic substances, but is relatively
little affected when sympathicolytic drugs
are used,

Mechanism of spontaneous pupillary
movements in complete darkness.

The slow, larger waves of contraction
and dilation. The pupillary sphincter
muscle is activated by parasympathetic



Volume 2
Number 2

10,

il.

REFERENCES

. Lowenstein, 0.: “Der Psychische Restitu-

tionseffekt, Das Prinzip der Psychisch Be-
dingten Wiederherstellung der Ermiideten der
Erschépften und der Erkrankten Funktion,”
Basel, 1937, Benno Schwabe & Co.

. Lowenstein, O., and Loewenfeld, I. E.:

Mutual role of sympathetic and of para-
sympathetic in shaping of the pupillary reflex
to light, Arch. Neurol. & Psychiat. 64: 341,
1950.

Lowenstein, O., and Loewenfeld, I. E.: Dis-
integration of central autonomic regulation
during fatigue and its reintegration by psycho-
sensory controlling mechanisms, J. Nerv. &
Ment. Dis. 115: 1, 121, 1952.

, Lowenstein, O., and Loewenfeld, 1. E.: Types

of autonomic innervation and fatigue, A. M.
A. Arch. Neurol. & Psychiat. 66: 580, 1951.

. Lowenstein, O.: Pupillary reflex shapes and

topical clinical diagnosis, Neurology 5: 631,
1955.

Lowenstein, O., and Loewenfeld, I, E.: Elec-
tronic pupillography. A new instrument and
some clinical applications, A. M. A. Arch.
Ophth, 59: 352, 1958.

. King, G. W.: Recording pupil changes for

clinical diagnosis, Electronics 32: 67, 1959.

. King, G. W.: An improved electronic pupil-

lograph for clinical use, Proc. Nat. Elec-
tronics Conf, 16: 672, 1960.

. Loewenfeld, Irene E.: Mechanisms of reflex

dilatation of the pupil. Historical review and
experimental analysis, Doc. Ophthal. 12: 185,
1958,

Webster's New International Dictionary of
the English Language. ed. 2, Springfield,
Mass., 1960, G, & C. Merriam Co.

Hess, W. R.: Vegetative Funktionen und
Zwischenhim, Helv. physiol. acta, Suppl. IV,
1947.

Pupillary movements during fatigue

Discussion

Dr. Gerhard A. Brecher, Atlanta, Ga, The
authors are unquestionably the world’s leading
pupillographists. They have refined their measure
ment technique by means of modem technology
to such a high degree of precision that it can
now be used for various quantitative investiga-
tions. One of them concerns the present study in
which the effect of fatigue on the pupillary reflex
response is described. Changes in the pupil reac-
tions are only one of the numerous parameters
which are affected during fatiguing. The greatest
difficulty experienced in the past has been that
changes characteristic for tiredness have been
elusive when measurements were attempted. Vo-
litional, short-lasting periods of arousal from en-
croaching fatigue usually result im a level per-
formance of tasks during long-term testing, even
when marked subjective tiredness is experienced.
Thus the degree of innate fatigue remains prac-
tically unmeasurable because it is masked by
volitional efforts until a sudden breaking point is
reached beyond which sleep supervenes. The
pupillary reaction is one of the few reflexes which
in ordinary people cannot be influenced by will.
It is solely the result of autonomic nervous system
outflow. It lends itself easily to measurements of
the time course and extent of the response. The
patterns of pupillary reactions during fatigue
which were described and analyzed in great detail
by the authors can therefore serve in future
studies on fatigue as an objective criterion per-
mitting a quantitative measure of innate tiredness.
The comprehensive material presented here is
most valuable. The basic concepts concerning the
effect of the central nervous processes on. the
pupillary reflex are thoughtfully and almost philo-
sophically developed. The work is superbly exe-
cuted.

Dr. Loewenfeld (closing). We can only thank
Dr. Brecher for his kind words.


Volume 2 Pupillary movements during fatigue

wo Fn nw a

§ 3 . 13 Ad is
min.

Fig. 8. Spontaneous pupillary oscillations in a chronically tired subject.

The ordinate represents the right pupil’s diameter (in millimeters), the abscissa time (in
minutes; cf, Fig. 3). The record was obtained from the same subject as in Fig. 7, 2 weeks
later (A1-A4) and 2 years later (B).

Intermittent periods of irregular pupillary movements appeared during the second minute of
observation (AI). They became more frequent and extensive with time until, finally, the sub-
ject became unable to rouse herself and the test had to be discontinued (12th minute, A4).
It should be noted that the pupillary oscillations shown during fatigue are not related to
lid-closure reactions (indicated by round dots). In complete darkness, spontaneous closing
of the eyelids is not accompanied by pupillary contraction, except at the moment of falling
asleep (last lid closure in A4 of this record).

Two years later, the effects of the operation had been overcome completely; the subject felt
well and was no longer chronically tired, The record shows no irregular pupillary movements
(12th to 15th minutes shown in B), and the subject was able to continue in a series of
similar experiments for several hours.


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Fig. 5. Spontancous pupillary movements in normal, young, tired subjects (identical twins).
The subjects A and B, identical twin brothers, had graduated from dental school some weeks
before. On the day of examination they were tired because until late the previous night, they
had packed their bags preparatory to leaving for army service overseas, The tests were done
in immediate succession, at 10:30 a.m. (A) and at 11:30 a.m. (B), respectively.

In Al and BI the original pupillograms are shown. In these records, the ordinate represents
pupillary diameter (in millimeters), the abscissa time (in 0.1 second units), whereby the
solid lines represent the right pupils, the broken lines the left pupils. The eyes were in
darkness except for the intervals framed at 1, when the right eye was exposed to 1-second
light flashes of about 15 footcandle intensity. The arrows s mark the time of presentation of
sensory stimuli (sudden sound). Note the close similarity in the reaction pattern of the two
brothers.

In A2 and B2 the time axis of the graphs was compressed in the manner described above
(Fig. 3), At the beginning of each record, the right eye had been adapted to the stimulating
light for 1 minute. The first measurement shows the pupillary diameter at the moment when
this light was turned off. After the initial dilation in darkness, the pupils began to oscillate
(a,a). Within the following minutes, these oscillations became increasingly frequent and ex-
tensive, and, beginning with the 5th minute of examination, repeated sensory stimuli were
required to keep the subjects awake (sound stimuli, marked by arrows s). Again, the pattem
of pupillary behavior was strikingly similar in the two brothers.



Volume 2
Number 2

(cholinergic) fibers running with the third
nerve, the dilator muscle by sympathetic
(adrenergic) nerves from the superior
cervical ganglion. The possible effector
mechanisms for any kind of pupillary
movement are thus: (a) parasympathetic
stimulation (contraction) or inhibition
(dilation), and (b) sympathetic excitation
(dilation) and relaxation (contraction).

Which of these two mechanisms is re-
sponsible for the waves of pupillary en-
largement and narrowing which appear
spontaneously as the tired subject sits in
darkness? There is no doubt that both of
them participate, activated by discharges
originating in the central nervous system.
This conclusion is based on the following
facts:

PROOF OF THE CENTRAL NERVOUS ORIGIN
OF THE PUPILLARY WAVES.

1. The pupillary waves coincide with

304

24

Pupillary movements during fatigue

cycles of activity in many other systems.
Thus, with each moment of arousal shown
by the tired subject, the palpebral fissures
widen, the head is lifted slightly, the eyes
are fixed in the primary ‘position, the
striated muscle tone is enhanced all over
the body, respiratory and heart rates may
be affected, etc. Obviously, these many
effector systems cannot be brought into
action simultaneously by separate periph-
eral mechanisms.

2. In normal man and animals the spon-
taneous waves of pupillary contraction and
dilation in darkness are equal on the two
sides,

3, When the spontaneous mechanism of
arousal ceases to function and the subject
falls asleep, sensory (or, in man, psycho-
sensory) stimuli will bring about the com-
plete awakening syndrome with all its
physiologic effects: When, however, the

Fig. 4. Number and extent of small, fast pupillary oscillations in normal, alert subject.

The data were obtained from the same subject as in Fig. 3. The ordinate represents the
number of small oscillations (b in Fig. 3) which occurred within a 20-minute period in
darkness (average of 3 experiments). The abscissa shows the amplitude of these oscillations

(in millimeters).

Most of the short pupillary oscillations were exceedingly inextensive (below 0.1 mm.), and

only a few of them measured up to 0.3 mm.


Lowenstein, Feinberg, and Loewenfeld

sympathetic or the third nerve, decrease
the extent but do not alter the rhythm
of the spontaneous movements (see be-
low, “Spontaneous pupillary movements
in patients with various neurological de-
fects”).

5. In the introduction to this paper we
have described the changes in extent and
form which the light reflex undergoes
under the influence of emotional excite-
ment or of fatigue (see text and Fig. 1).
These reflex changes are observed when
light stimuli are presented during waves
of spontaneous arousal and drowsiness of
a tired subject. During each period of
awakening, the light reflexes of the dilating
pupil are reduced and show W- or V-
shapes; with each following decline, the
reflex shapes reveal the increasing loss of
supranuclear inhibition. As shown previ-
ously,® »°- #°2-262 parasympathetic inhibition
is a central nervous mechanism whereby

Investigative Ophthalmology
April 1963

supranuclear impulses act upon the oculo-
motor nucleus and prevent it from sending
efferent parasympathetic impulses to the
pupillary sphincter, while the peripheral
cholinergic nerve-muscle apparatus is not
inhibited at all.

THE EFFERENT MECHANISM: We _ have
stated already that pharmacological, sur-
gical, or clinical interference with either
the sympathetic or the parasympathetic
nerve supply to the iris results in reduc-
tion of the amplitude of the movements
(see previous paragraph and “Influence of
some drugs”). It is obvious, therefore, that
both mechanisms participate in their pro-
duction. During periods of awakening—be
they spontaneous or reactive—sympathetic
stimulation and inhibition of the oculomo-
tor nucleus participate in dilating the
pupil. During periods of increasing
sleepiness, sympathetic activity decreases
and supranuclear inhibition is gradually

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Fig. 7. Spontancous pupillary movements in a chronically tired subject.

The right pupil’s diameter is recorded as the ordinate (in millimeters) against time as the
abscissa (in 0.1 second [A] or in 1 second units [B]). In B1-B3 the graphs were reduced to
one-half the size shown in A, both for time and for amplitude.

The subject, a 38-year-old woman who was otherwise normal, was chronically tired some
months after a major abdominal operation. At the beginning of the test the pupils showed
normal diameter and light reflexes (A). The pupils remained relatively quiet during the first
minute of the fatigue test (B1). Soon, however, irregular slow fluctuations appeared’ and the
fast oscillations became marked (b,b in B2, showing pupillary movements during the 8th
minute of the test). Shortly thereafter, both types of oscillations became exaggerated; the
pupils dilated and contracted in extensive waves, with frequent periods of sleep and spon-
taneous arousal (B3, recorded during the 16th minute of observation).



Reprinted from INVESTIGATIVE OPHTHALMOL-

OGY, Vol. 2, No. 2, April 1963, published by the
C. V. Mosby Company, St. Louis.

Pupillary movements during acute and
chronic fatigue

A new test for the objective evaluation of tiredness

Otto Lowenstein,* Richard Feinberg,** and Irene E. Loewenfeld®

Spontaneous pupillary movements in darkness were recorded (1) in healthy subjects of dif-
ferent ages when they were rested or fatigued, (2) in chronically tired subjects without known
neurological defects, and (3) in patients with various neurological lesions. In some of the
experiments, local or systemic drugs were used.

While the pupils are large and quiet in darkness when the subject is alert, they oscillate
under the influence of tiredness. Waves of spontaneous pupillary contraction and dilation ac-
company periods of increasing sleepiness and spontaneous arousal until, at the moment im-
mediately preceding sleep, the pupils become very small.

The mechanism of these movements was analyzed and a simple test described which allows
the objective determination of the degree of acute fatigue in a given subject at a given time.
In the light of these results, the concepts of “normal” and of “pathologic” fatigue were

discussed,

A. described by us previously,’ a light
stimulus of a given intensity and duration
will not necessarily elicit a pupillary reflex
of predictable extent and speed. When
normal man or animals are subjected to
sensory or emotional stress, the pupils
enlarge, and a light reflex elicited under
such conditions will be inhibited. It can be
completely suppressed if the interfering
stimulus is sufficiently strong (Fig. 1, a >

This work was supported by the Harriman Fund
and by a grant of the U. S. Public Health
Service (Sens, Dis,. B-253).

*From the Department of Ophthalmology, Labora-
tory of Pupillography, Columbia University,
College of Physicians and Surgeons, and the
Presbyterian Hospital, New York, N, Y.

*°From the Georgetown Clinical Research Insti-
tute, Aviation Medical Service, Federal Avia-
tion Agency, Washington, D. C.

d). When, on the other hand, the subject
is tired, and when the eye is exposed to
repeated light stimuli at fairly short inter-
vals, the pupils become smaller and the
reactions less and less extensive. Finally,
when the subject is almost asleep, the
miotic pupil hardly reacts to light (Fig. 1,
ag).

Fig. 1 clearly shows that these changes
in the pupillary reflexes are not merely a
matter of amplitude. The size of the pupils
and the shape of their reflexes vary with
the degree of excitement or drowsiness.
The characteristic square, W-shaped, V-
shaped, and flattened reflexes can be
seen.

The very same reaction patterns are ob-
served in patients with lesiogs or irritation
at various locations within the nervous
network of pupillary control; and they can
be produced at will in experimental animals



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Fig. 9. Pupillary movements in a normal subject 72 years of age (A-C) and in his daughter
aged 32 (D).

In each record, the right pupil’s diameter is shown as the ordinate (in millimeters) against
time as the abscissa (in 0.1 second units [A,D] or in minutes [B,C; ef. Fig. 3]).

When the subject was not tired, his pupils were large and his reactions to light showed the
extent and shape found in the majority of healthy young persons (A). The record B was ob-
tained when he was very tired (6 r.m.). At the beginning of the trace, his right eye had
been adapted to light, and the first measurement represents the pupillary diameter at the
moment when this light was tumed off. After the initial, fast dilation in darkness, the pupils
started to oscillate, and, beginning during the second minute of the test, intermittent sensory
stimuli were required to keep the subject awake (sound stimuli, marked by arrows s). After
the 6th minute, he was unable to continue the test. He was given an opportunity to rest and
he slept for about an hour. The second record, taken at 8 p.m, under the same experimental
conditions, showed no pupillary irregularities for more than 20 minutes (first 5 minutes shown
in C).

The subject’s daughter, who resembled him in personality and temperament, had unusually
large and reactive pupils (D; see discussion in text).



Lowenstein, Feinberg, and Loewenfeld

lost. The consequent relative preponder-
ance of the parasympathetic outflow is re-
vealed by the smallness of the pupils at
the time immediately preceding sleep.
The fast, small oscillations. The small,
fast pupillary movements associated with
imperfect fixation of gaze are no longer
recorded when the pupil has been dilated
by parasympathicolytic drugs. This fact
gives support to the opinion that these
oscillations are cholinergic in nature, but it
does not prove the point completely. Be-
cause of the small initial extent of the fast
oscillations, they may escape the sensitivity
of our instrument when they are reduced,
without being abolished entirely. But since
they are only little affected when the sym-
pathetic innervation is blocked (see above,
“Influence of some drugs”), it appears that
they are, indeed, due mainly to arasym-
pathetic impulses.
Spontaneous pupillary movements in
patients with various neurological defects.
Lesions in the efferent pathways. We
have, then, established that the pupillary
waves of dilation and contraction of the
tired subject are central nervous in origin,
and that both of the available efferent
mechanisms—sympathetic activation and
relaxation as well as parasympathetic in-
hibition and activation—take part in their
development. It is not surprising, therefore,
that clinical lesions in the peripheral sym-
pathetic or the third nerve paths diminish
the amplitude but do not change the
rhythm of the oscillations (Fig. 11).
Diencephalic lesions. Records of spon-
taneous pupillary movements are of diag-
nostic significance in those patients in
whom central nervous lesions have led to
the development of pathologic shapes of
the light reflex such as shown in Fig. 2,
e — g. Because of the complete analogy in
the light reflex shapes of very tired normal
subjects and of patients with lesions in the
diencephalic-mesencephalic region, it is
often difficult to evaluate the clinical
significance of the pupillary reflex pattern
which a patient may show at the particular
time of examination. How much of the

Investigative Ophthalmology
April 1963

deterioration of the reflexes is due to acute,
reversible tiredness, and how much to ir-
reversible damage?

The cases shown in Fig. 12 serve as
examples. In both patients a diencephalic
lesion had reduced the supranuclear in-
hibitory impulses to the oculomotor nu-
cleus. The pupils were smaller than normal
in darkness; the light reflexes were inexten-
sive and showed the square form typical of
this type of lesion.** But while Patient B
was not tired and his pupils remained quiet
in darkness, those of Patient A fluctuated
extensively. Since acute fatigue was not
present in Patient B, the pathologic light
reflex pattern had to be due entirely to
the organic condition. In contrast, in
Patient A, acute tiredness may have con-
tributed to the deterioration of the reflex
pattern.

Pathologic fatigue. Every clinician en-
counters patients in whom constant, ex-
treme fatigue forms a major part of the
subjective complaints. In these cases, it is
important to establish objectively the
presence or absence of organic dysfunc-
tion, in order to differentiate between
symptoms of true, physically founded
fatigue and similar, physically unfounded
complaints which may be voiced by pa-
tients who are, for example, mentally de-
pressed. The cases shown in Fig. 13 serve
as examples.

The first patient (Fig. 13,A), a 16-year-old
boy was a passenger on a school bus which
collided with a truck. He lost consciousness and
remained in a soporlike condition for about 4
days. He was difficult to rouse, and when aroused,
was disoriented and excited, only to fall back
into deep sleep as soon as left alone, Neurological
routine examination and skull x-rays were nega-
tive. The electroencephalogram showed diffuse
abnormality, more on the right than on the left
side.

At the time of examination, 3 years after the
accident, he was tense, restless, and jittery; his
movements were slow and circumstantial. The
patella reflexes were hyperactive, slightly more so
on the left than on the right side, but no pyramidal
symptoms were found. A slight facial paresis of
central type was present on the left side. The

electroencephalogram showed paroxysmal dien-
cephalic dysfunction, and spike potentials at the



Volume 2
Number 2

Pupillary movements during fatigue

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Fig. 6. Pupillary oscillations in an extremely tired normal subject.

The right pupil’s movements were plotted as described above (Fig. 3). The subject, a 38-
year-old man, was very tired after a strenuous series of lecture trips. In addition, he had a
slight cold on the day of examination. After an initial period of wakefulness, he became
drowsy. His pupils began to fluctuate wildly over a large range, in successive waves of spon-
taneous arousal and following decline (a, in A). Shortly after the 12th minute of the test
he fell asleep, and was awakened by a sudden, loud sound (s in B). The pupils dilated
extensively, but recontracted as again he drifted toward sleep (15th minute, line C). A
second sound stimulus was followed by continuous conversation which kept him awake

during the remainder of the test (17th minute).

cortical and/or diencephalic connections
are blocked, as, for example, in anes-
thetized animals, stimulation of sensory
nerves fails to produce the awakening syn-
drome, and only fragmentary physiologic
effects are elicited. This failure to produce
the entire group of awakening symptoms
is not caused by an interruption of the
efferent outflow to the periphery but by a
breakdown of transmission at the cortical
and/or diencephalic level, as proved by
the fact that hypothalamic stimulation

readily elicits all the physiologic effects
normally associated with awakening, even
in deeply anesthetized animals.® » °"
4, As mentioned above (see “Influence
of some drugs”), the movements may be
increased or decreased in extent and fre-
quency by centrally acting depressant or
stimulating drugs. In contrast, elimination
of one of the peripheral effector mecha-
nisms by instillation of sympathicolytic or
parasympathicolytic drugs, or by surgical
or clinical interruption of the peripheral


Volume 2 Pupillary movements during fatigue
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Fig. 3. Spontaneous pupillary movements in young, normal, alert subject.

The subject, a 21-year-old man, was not tired at the time of examination. The pupillograms of
the right eye are shown. The eyes were in darkness, except for the time framed at I, when the
right eye was exposed to a 1-second light flash of about 15 footcandle intensity. The pupillary
diameter is recorded as the ordinate (in millimeters). In A and C the original pupillograms are
shown, In these records, the abscissa represents time in 0.1 second units. In B, the time axis
of the graph was reduced in the following manner: the pupillary diameter at the beginning of
each successive second was taken from the original pupillographic record, and was plotted
as a single measurement (small squares); 60 such measurements thus show the pupillary
movements which occurred within each minute.

A, Normal light reflex.

B, The pupil remained large and relatively quiet in darkness. The record shows the move
ments during the 5th to 10th minutes of the test; the subject was able to continue the ex-
periment for more than 2 hours without remarkable changes in pupillary behavior.

C, Slow (a) and fast (b) pupillary oscillations of small extent (see description in text).

of sudden, spontaneous arousal and gradual
slipping into a doze, the pupils dilate
rapidly (a, a in Figs. 5 and 6), then re-
contract gradually in an unsteady, waver-
ing decline.

The more the subject is fatigued and
the less he tries to suppress his sleepiness,
the shorter is the time of initial mydriasis,
and the deeper and more frequent the
following pupillary oscillations. Eventually,
the spontaneous intervals of reawakening
cease altogether and the subject actually
falls asleep. At the moment immediately
preceding the final closing of the lids and
movement of the eyes upward, the pupils
are quite small. At this time a psycho-
sensory stimulus such as a sudden sound,
conversation, etc., restores the waking con-
dition and—depending upon the type and
intensity of the stimulus—may maintain it
for some time (s in Figs. 5 and 6).

Spontaneous pupillary movements in
chronically tired subjects without known
neurological defect. In these times of
high-pressure activity many persons habit-
ually fail to sleep sufficiently, and it is easy
for anyone to find a number of acquaint-
ances who are chronically tired. Although
these persons are neurologically in good
condition, it is difficult for them to stay
awake over an extended period when they
are not engaged in some activity.

The pupils of such chronically tired sub-
jects show the characteristics just de-
scribed, in an exaggerated manner. After
a brief, initial period of wakefulness the
pupillary diameter begins to drift erratically
over a wide range, the eyelids begin to
droop, and fixation becomes unsteady. Soon
afterward the pupils contract strongly, the
eyes move upward, and the subject falls
asleep (Figs. 7 and 8).


Lowenstein, Feinberg, and Loewenfeld

moment to the next by psychosensory
stimulation. When we are weary after pro-
longed, monotonous activity, and are
gradually drifting toward sleep, an unex-
pected pleasant or unpleasant event which
touches our emotions, a sudden idea which
stimulates our imagination, instantly re-
verses the fatigue process; the condition of
alertness is restored, and it may be main-
tained for a long time.

Alertness and sleepiness depend, then,
not only on the amount of energy spent,
or the time elapsed since a previous period
of sleep, but also upon the degree of
corticodiencephalic activity evoked by

Investigative Ophthalmology
April 1963

sensory or emotional stimuli—provided by
the environment—or by spontaneous
mental activity.

In this connection, it is interesting that
normal monkeys, when examined at any
time during the day, are almost completely
unable to maintain alertness when left in
darkness, provided that they are seated
comfortably and are prevented from
moving around by having their extremities
tied by elastic bandages. While these
vivacious animals react most vigorously to
sensory stimulation, they appear to be
devoid of spontaneous corticodiencephalic
activity. When they are in darkness, and

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Fig. 11. Pupillary movements after damage to the peripheral sympathetic chain (A) or to the

third nerve (B).

Pupillary diameter is recorded as the ordinate (in millimeters) against time as the abscissa
(in 0.1 second units [Al, B1] or in minutes [A2, B2; cf. Fig. 3]). In Al and B1, the solid
lines represent the right pupils, the broken lines the left pupils. In A2 and B2 the movements
of the right pupils are shown by dots, those of the left pupils by crosses.

Al and A2, The patient was a 28-year-old man. His right sympathetic chain had been injured
surgically when a tumor was removed in the area of exit of the sympathetic fibers from the
spinal cord (C;—T:). The right pupil was smaller than the normal left one; the second
redilation phase of the light reflex was missing, as is typical for sympathetic lesions (Al).
Spontaneous pupillary fluctuations in darkness were reduced only slightly (A2).

BI and B2, The patient, a 9-year-old boy, had been unconscious for 3 months after an
automobile accident. Among many other sequelae of his injuries, the right third nerve was
impaired intracranially. The right pupil's light reflex was sluggish and much less extensive
than that of the left pupil (BI). Pupillary oscillations, which appeared after a short time in
darkness, were reduced in extent but not altered in character on the injured side (B2).



PRIM.»

Lowenstein, Feinberg, and Loewenfeld Investigative Ophthalmology
April.1963

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Fig. 12, Pupillary movements in two patients with diencephalic lesions.

Pupillary diameter is shown as the ordinate (in millimeters) against time as the abscissa (in
0.1 second units [Al and BI] or in minutes [A2, A3, and B2, B3; ef. Fig. 3]). In Al and B1,
the solid lines represent the right, the broken lines the left pupils. In A2, AS, and B2, B3,
only the right pupils’ movements are shown,

A, The patient was a 58-year-old woman who had shown high blood pressure for 20 years.
At the time of examtination she had suffered for about 5 weeks from mental depression with
constant feelings of fatigue. Her pupils were small, with square, “tonohaptic” light reflexes,
indicating loss of supranuclear inhibitory impulses to the oculomotor nucleus.*: 5: ¢ In darkness,
the pupils oscillated almost at once, and during the 6th minute of the test the patient fell
asleep (A2, A3). (Continued on next page.)



Lowenstein, Feinberg, and Loewenfeld

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Fig. 2. Reactions to light in patients with pathologic conditions within the nervous network
of pupillary control.

‘The patients sat in darkness and looked at a small, dark red fixation point (distance 6 foot,
15° above the horizontal plane). During the times framed at a —> g, 1-second light stimuli
of about 15 footcandle intensity were presented.

a, Light reflex in a normal, 66-year-old man.

b, c, Mydriatic pupil with inhibited, W- and V-shaped responses in a 21-year-old man who
was chronically restless and excited (cyclothymic personality ).

d, Very large pupil with strongly inhibited light reflex in a 20-year-old schizophrenic patiént
while spontaneously excited. At other times, this patient showed reactions to light of almost
4 mm. extent and of normal shape.

, Small pupil with square, “tonohaptic” light reflex in a 51-year-old woman suffering from
Ppostencephalitic parkinsonism.

f, Flat, w-shaped light reflex of the miotic pupil in a 64-year-old man with cerebral arterio-
sclerosis.

g, Inextensive and slow, v-shaped light reflex in a 50-year-old woman with tabes dorsalis and

Investigative Ophthalmology
April 1963

miotie pupils.

plane. He has been instructed to look
steadily at this point, with reasonable con-
centration but without excessive effort (“as
steadily as you can manage comfortably”).
In this condition, the spontaneous move-
ments of the pupils are recorded.*

Results

Spontaneous pupillary movements in
young, normal, alert subjects. In darkness
the pupils of healthy, young, alert subjects
are large, equal on the two sides, and rela-
tively quiet. While there are differences
among individuals, these are limited to a
fairly narrow range. Thus, in a normal
person below 35 years of age, the pupillary
diameter in darkness usually does not

All records were obtained with our electronic pupil-
lograph, an infrared-sensitive scanning device described
elsewhere.

measure less than 7 mm., and spontaneous
fluctuations rarely exceed + 0.5 mm. The
pupils, however, are almost never entirely
immobile. When observed for some time,
they show two main types of oscillations:
(1) slow waves of dilation and contrac-
tion, lasting from about 4 to 40 seconds
and measuring up to + 0.5 mm. (a in
Fig. 3, C); (2) superimposed, fast and
very inextensive oscillations, i.e., contrac-
tions and redilations of from 0.5 to 1 second
duration and about from 0.1 to 0.3 mm.
extent (b, b in Fig. 3, C, and Fig. 4).
Spontaneous pupillary movements in
young, normal, tired subjects. When the
same healthy, young subjects are tired, the
large, stable pupillary diameter may be
maintained for some time; but, as the
subject relaxes after some minutes in
darkness, the pupils become smaller and
begin to oscillate. In ever deepening waves



|

Volume 2
Number 2

Pupillary movements during fatigue

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Fig. 1. Effects of emotional excitement and of fatigue upon the pupillary reflex to light in
normal rats.

The pupillary diameter is plotted as the ordinate (in millimeters) against time as the abscissa
(in 0.1 second units), Becausé of the smallness of the rat’s eyes, the ordinate was enlarged
by a factor of 4, as compared to the human pupillograms (Figs. 2-13). The reactions of the
left eye are shown, The animals were in darkness, except for 1 second periods framed at
a— g, when light stimuli of about 15 footcandle intensity were presented.

The animals were young adult black rats of a tame strain which could be handled easily.
For immobilization, they were sown into a small bag of cotton material, with only their heads
protruding, and then held on a fairly heavy brass plate by elastic bandages. This support
prevented the animals from losing their balance when they moved inside their wrappings, and
appeared to make them comfortable, so that they occasionally fell asleep. Sensory stimuli
consisted in sudden shouting and blowing into the animal’s face.

a, Normal light reflex in alert but not excited rat.

b-d, Inhibited reactions, elicited after sensory stimulation. With increasing emotional excite-
ment, the pupil enlarged and the light reflexes became less and less extensive. They showed
the characteristic W- and V-shapes found in all mammals under similar conditions.

e-g, Light reflexes elicited while the animal was sleepy. Note the square, w-, and flattened

v-shapes of the reduced responses.

by electrical stimulation or surgical de-
struction at the same sites (Fig. 2).

The striking similarity between the re-
flex forms of fatigue and excitement on the
one hand, and those of pathologic condi-
tions on the other, shows that the effects of
emotional or of sensory stimulation, as
well as those of fatigue and drowsiness,
are not diffuse or disorganized. While the
subject gradually falls asleep, specific
nervous centers cease to function in orderly
sequence, and they are called back into
action by increasing psychosensory stimu-
lation.* ‘

There is, however, one great differ-
ence between the effects of physiologic
fatigue and excitement and those of patho-
logic conditions. While physiologic reflex
changes are transitory and instantly rever-

sible, the pathologic reaction patterns are
permanent. They may deteriorate further
but they cannot be restored to normal
form.

In order to evaluate the extent of or-
ganic damage in a given patient, it is
important to determine the degree of
acute, reversible tiredness accidentally
present at the time of examination and to
differentiate between these fatigue symp-
toms and those of pathologic impairment
of pupillary innervation. For this purpose
we have found the following test most
useful.

The patient sits, with his head com-
fortably supported, in complete darkness,
and looks at a small, red fixation point
situated at a distance of about 6 feet and
approximately 15° above the horizontal


Lowenstein, Feinberg, and Loewenfeld Investigative Ophthalmology
‘April 1963

eC Fao

| |

Fone

min.

Fig. 10. Influence of some drugs upon spontaneous pupillary oscillations of tired subjects.
Pupillary diameter is plotted as the ordinate (in millimeters) against time as the abscissa
(in minutes; cf. Fig, 3), whereby the dotted lines represent the right pupils, the lines of
crosses the left pupils (A,B). In C and D, only the right pupil’s movements are shown. The
round dots in A and C indicate lid closures.

A, The subject, a Si-year-old man, had been chronically fatigued all his life, without a
definitely established cause, except for a congenital heart condition. On the day of examination
he was tired; his pupils were small and showed irregular fluctuations. Occasionally, he
closed his eyes and appeared to go to sleep but roused himself spontaneously. When his
right pupillary sphincter was paralyzed by conjunctival application of 2 drops of a % per
cent solution of Cyclogyl, the pupillary oscillations were reduced in extent but their rhythm
was not altered.

B, ‘The subject was the same as in Figs. 3 and 4. On the day preceding the examination, his
left eye had been treated with 2 drops of a 5 per gent solution of guanethidine (Ismelin),
and on the morning of the test a complete temporary Horner's syndrome had developed on
the left side. He felt sleepy, and his pupils showed extensive oscillations, They were re-
duced in extent and speed. but otherwise unaltered by the sympathicolytic drug. Note
especially the slowness of the pupillary dilation following a sensory (continued on next page)



Volume 2
Number 2

otherwise unstimulated for only a few
minutes, they appear bored; their eyelids
droop, their pupils contract, and soon they
fall asleep.

We have proved in detail that the
changes in pupillary reaction pattern,
which are among the physiologic expres-
sions of these events, are central nervous
in nature** (see also preceding section,
“Mechanism of spontaneous __ pupillary
movements in complete darkness”).

Physiologic versus pathologic fatigue.
In the patients represented in Fig. 13, the
light reflexes elicited at moments of alert-
ness were normal. There was, then, no
organic lesion present within the nervous
network of pupillary control, and the patho-
logic reflex shapes shown so frequently were
all due to reversible, acute tiredness. What,
then, distinguishes the findings in these
patients from physiologic fatigue in normal
subjects? And further, can we ever speak
of “normal fatigue”?

“Fatigue” has, unfortunately, become a
rather overworked word, its precise mean-
ing eroded by multiple use. At this point,
we should define our meaning of the term.
According to Webster's Dictionary, its
general meaning is “weariness from labor
or exertion, exhaustion of strength, loss of
power due to continued work but re-
movable by rest,” and the physiologic
definition “condition of cells or organs
which have undergone excessive activity
with resulting loss of power or capacity
to respond to stimulation,”*° and these
definitions agree closely with the one used
by us in earlier work, namely, “the revers-
ible reduction and eventual exhaustion of
a living function during its repeated activa-
tion.”® 2

Enclosed within these definitions is, then,
the answer to the first question asked
above. The patients represented in Fig. 13
were always tired; their condition of ex-
haustion was not preceded by activity, and
it was not removable by rest. These fea-
tures distinguish pathologic from physio-
logic fatigue.

As is usual in life, conditions are not

Pupillary movements during fatigue

always marked off as clearly. There are
many individuals who, though not actually
ill, fatigue more quickly than they should;
that is, they become tired after activity
which in the majority of healthy persons is
not adequate to produce a like degree of
exhaustion. Where, then, shall we draw
the line between physiologic and patho-
logic fatigue?

Three main groups of individuals make
up the vast army of the chronically tired,
namely, (1) those who are tired because
of a habitual lack of adequate rest, (2)
patients in the incipient or convalescent
stages of acute illness and patients with
chronic pathologic conditions, and (3)
those in whom the cause of chronic fatigue
is unknown.

When excessive fatigue is part of an
acute-or long-lasting pathologic condition,
it is reversible insofar that it disappears
when the disease has been overcome. This
type of fatigue is, then, a physiologic ac-
companiment of the condition; while indi-
cating the presence of a pathologic state it
is itself no more “abnormal” than the rise
in temperature which accompanies in-
fectious diseases. There are, however,
central nervous conditions in which fever
is a localizing sign, just as pathologic as
hemiplegia. Idiopathic chronic fatigue
may, like “central fever,” be a primary sign
of diencephalic dysfunction. If, in a given
case, the organic nature of the chronic
tiredness can be established by the pupil-
lary behavior, it should be treated as
the danger signal which it is.

Since we have established that the pupil-
lary symptoms that accompany fatigue are
central nervous in origin (see previous dis-
cussion), must we then assume that in
every case of general disease the brain is
affected, and that fatigue is due to dis-
organization of corticodiencephalic activity,
ie., that it reveals an only milder and still
reversible degree of pathologic disintegra-
tion?

We would answer this question in the
negative. Fatigue and alertness, sleep and
waking are part of normal homeostatic