The pupil

Helmut Wilhelm
Center for Ophthalmology, University of Tubingen,
Tubingen, Germany
Correspondence to Prof. Dr med. Helmut Wilhelm,
Center for Ophthalmology, University of Tubingen,
D-72076 Tubingen, Germany
Tel: +49 7071 2984830; fax: +49 7071 295361;
e-mail: helmut.wilhelm@med.uni-tuebingen.de

Current Opinion in Neurology 2008, 21:3642

Purpose of review
To give an overview on topics of pupillary function selected according to their relevance
in clinical neurology. Mainly publications of the last 3 years have been considered.
Recent findings
The discovery of photosensitive retinal ganglion cells not serving vision, but serving
circadian rhythm and the pupil initiated many studies. There is evidence that pupil
reaction to light might be preserved even if all rods and cones are lost. Spontaneous
pupillary contractions in darkness occur in sleepy subjects and have been used to
quantify the state of alertness. Apraclonidine eye drops have been suggested to
diagnose Horner syndrome. Iatrogenic cause and carotid artery dissection are the most
frequently reported underlying causes of Horner syndrome. Anti-Hu antibodies may be
associated with tonic pupils.
Summary
Pupil studies in blind patients may give new insights into the function of the pupillary
system. Testing for sleepiness by means of pupillography might be used more
frequently. Testing for Horner syndrome still needs to be done with cocaine eye drops.
Clinical evaluation has to be focused on detecting additional signs and symptoms.
Unknown malignancy is very rare. In the tonic pupil (Adie syndrome) autoantibodies may
play a role, in exceptional cases it might represent a paraneoplastic disorder.
Keywords
Adie syndrome, Horner syndrome, photosensitive retinal ganglion cells, pupil,
pupillography, sleepiness
Curr Opin Neurol 21:3642
2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
1350-7540

Introduction
The pupil may be used as an indicator of visual or
autonomic function, but it may also react pathologically.
Publications concerning the pupil therefore cover a wide
field. The review will address the following fields:
(1) ganglion cells not serving vision contribute to the
pupillary light reflex; (2) measurement of sleepiness by
pupillography; (3) diagnosis and handling of Horner
syndrome; and (4) autoimmune causes of tonic pupils.

Pupillary light reaction without rods and

cones?
A blind person with no light perception should not show
any pupillary constriction to light. A patient with retinitis
pigmentosa who has lost all their vision sometimes has an
astonishingly good pupillary response. Some functional
rods and cones somewhere in the peripheral retina, too
few to create any vision, but able to collect all photons
entering the eye and compose a pupillary constriction was
our explanation for this phenomenon.
One more explanation has now to be considered, There
might be receptors that serve the pupil, but not vision. It

could be shown that it was possible to suppress melatonin

production in the pineal gland by light in transgenic mice
lacking both rods and cones [1,2]. It has been postulated
that a third set of photosensitive cells exists supplementary to rods and cones, acting as a sensor for the
circadian rhythm. Candidates for this third system were
neurons containing melanopsin a photosensitive mammalian opsin found in the inner retinal layers [3]. A subset
of retinal ganglion cells of the rat containing melanopsin
was identified by several research groups independently
as a third light-detecting system besides rods and cones,
and probably serving nonvisual purposes such as circadian rhythms [4,5]. Soon it became clear that those
photosensitive retinal ganglion cells were able to constrict the pupil. Lucas et al. [6] examined mice without
the melanopsin gene and compared their pupillary
responses with the wild-type: both the rod and cone system
and the melanopsin ganglion cells contribute to the pupillary light reflex. The responses to dim stimuli were
approximately the same for mice with and without melanopsin ganglion cells, but the smallest pupil diameter at
high light intensities could only be reached in the presence
of melanopsin ganglion cells. This pupillary response can
be blocked by 2-aminoethoxydiphenylborane, which is a

1350-7540 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins

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The pupil Wilhelm 37

potent in-vitro inhibitor of photosensitive retinal ganglion

cells [7].
Gamlin et al. [6,8] examined two macaque monkeys in
vivo by blocking photoreceptor activity and measuring
pupillary responses to light of selected narrow band
wavelengths. The response characteristics of the pupil
were the same as found in vitro by directly recording from
photosensitive ganglion cells in the macaque retina.
Under normal conditions the melanopsin ganglion cells
receive input from photoreceptors. Their spectral sensitivity is highest in the short wavelength range. Several
studies have been presented at the Pupil Colloquium
2007 that showed pupillary light responses to short
wavelength light that can be evoked in patients with
photoreceptor loss, even in completely blind retinitis
pigmentosa patients. Papers on this subject will be
published in the near future.

The pupil as an indicator of sleepiness

The pupil does not only constrict to light, but also dilates
to stimuli like fear, surprise, pain or stress. Such psychosensory pupillary responses are exclusively mediated by
the sympathetic system not only by the peripheral
sympathetic [9], but also by inhibition of the parasympathetic Edinger Wesphal nucleus (NEW) by the central
sympathetic system. According to present knowledge,
this inhibition is exerted by two simultaneously acting
pathways. One derives from the area A1/A5 in the brain
stem and reaches the parasympathetic nucleus via the
hypothalamus. The other derives in a noradrenergic
nucleus, the locus coeruleus, and runs directly to the
NEW [9].
In two patients with damaged dorsal midbrain it could be
demonstrated that the NEW itself and not the pretectal
olivary nucleus is the target area of this central inhibition
[10].
Practically, the most relevant current application of pupillography may be the measurement of daytime sleepiness.
In the state of sleepiness the central inhibition mentioned above becomes unstable and considerable lowfrequency, high-amplitude oscillations of the pupil
diameter occur. At the same time there is a strong miotic
trend in the pupillogram. Sleepiness-related oscillations
can only be assessed in complete darkness by infrared
recording.
The reason for that limitation is their similarity to spontaneous light-induced oscillations that may occur in
steady light [11] without any relation to the state of
vigilance. Those light-induced oscillations are typical
intrinsic oscillations of the pupillary feedback system
and can be modeled mathematically. The phenomenon

of sleepiness-induced oscillations (according to current

terminology and definitions called sleepiness waves)
was first named fatigue waves and has been described
several times since 1964 [1214]; however, it took until
the late 1990s when it was standardized, quantified and
evaluated in several studies in the setting of the Pupillographic Sleepiness Test (PST).
The intensity of these so-called sleepiness waves
increases with the duration of sleep deprivation in normal
subjects [15]. Thus, fluctuations of the pupil diameter in
darkness reflect the current level of a subjects objective
alertness level quantitatively [15,16]. It has been shown
that d, t and a1 activity in the EEG strongly correlate with
slow pupillary oscillations and a decrease in pupil size in
healthy subjects during sleep deprivation and patients
with sleep disorders [1619]. On the other hand, PST
results correlate in the expected direction with sleep
latency measured by the Multiple Sleep Latency Test
in sleep disordered patients and healthy normals [20,21].
The PST as an objective alertness test has been used in
sleep research and sleep medicine since 1997 for diagnosis and therapy control of sleep disorders [15,2225].
The recording time is typically 11 min because monotony
is needed to unmask sleepiness.
Pharmacological studies with a variety of drugs showed
the expected results regarding effects of sedation [26
30]. Within the individual there is a close relationship
between self-assessed alertness level and pupillary unrest
[31], but interindividual correlations have been found
inconsistently [16,21]. According to the neuropsychological model of attention by Posner and Rafal [32], pupillography assesses the tonic central nervous activation
level, as does the Multiple Sleep Latency Test or the
Maintenance of Wakefulness Test. The PST opens a
wide range of possibilities to investigate not only sleep
disorders associated with excessive daytime sleepiness,
but also neurological diseases such as Parkinsons disease
or multiple sclerosis [33]. The advantage of pupillography is that it is objective and much less time-consuming
than any alternative procedure. Additionally, therapy
effects can be monitored and social/medical decisions
made on a safer basis compared to subjective measures
alone.

Horner syndrome: how to diagnose and how

to evaluate
The oculosympathetic pathway is long and complicated,
and may therefore be damaged on different levels. It
starts in the hypothalamus, travels down to the level of
T1 or T2, there leaves the central nervous system and
travels upward again in the sympathetic chain, joins the
common and internal carotid artery, and leaves it in
the cavernous sinus to accompany first the abducens

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38 Neuro-ophthalmology and neuro-otology

nerve and then the first branch of the trigeminus nerve

before reaching the pupillary dilator muscle and Mullers
muscle of the upper eye lid. This pathway contains two
synapses, one at the upper thoracic spine level (Budge
Waller centrum) and one in the superior cervical ganglion.
Thus, three neurons can be distinguished the first central
in the brainstem and spine, the second between the
thoracic spine and superior cervical ganglion, and the third
after the superior cervical ganglion.
The diagnosis of Horner syndrome is based on clinical
features, pupil dynamics and pharmacological testing.
Horner syndrome consists of miosis, ptosis but not
enophthalmos. Friedrich Horner himself spoke of apparent enophthalmos [34]. Only in animals with functional
intraorbital muscles is enophthalmos possible when the
sympathetic innervation is interrupted [35]. In humans,
only a rudimentary sign is visible, i.e. a higher position of
the lower eye lid (upside down ptosis) because of a
paresis of small retractor muscles of the lower eyelid that
are sympathetically innervated [36]. Additionally,
disturbances of sweating and skin innervation can be
observed if the site of the lesion lies centrally from the
branching of the vaso- and sudomotor fibers, usually close
to the carotid bifurcation. The interruption of those fibers
may result in a harlequin syndrome, i.e. one half of the
face is pale and the other half normal colored or reddish
with the division exactly in the midline [36,37]. Astonishingly, the side with the sympathetic deficit is usually the
paler one. One would expect that absence of sympathetic
innervation leads to dilatation of the arteries and thus a
more reddish skin color than on the healthy side; however, vessels and perspiratory glands are denervated and
this leads to supersensitivity against circulating adrenaline.
Physiological anisocoria, i.e. different pupil size with
normal light reaction, is the only differential diagnosis
to Horner syndrome. Horner syndrome is very rare and
physiological anisocoria is a frequent condition. We
therefore need tests to diagnose Horner syndrome
definitely to avoid unnecessary work-up of physiologic
anisocoria. It is well known that a pupil without sympathetic innervation dilates much slower. This can be
visualized by infrared video. In darkness the pupils begin
to dilate after a latency period of 0.51 s and have reached
their largest diameter after approximately 5 s. A sympathetic denervated pupil, however, also dilates much slower
than the normal pupil. It takes more than 10 s, usually
around 15 s, until it has reached its final diameter in the
dark a behavior named dilation lag [38,39]. Therefore,
ansiocoria should be the most pronounced after 45 s in
darkness and it should be less after 1215 s. The difference between the ansiocoria after 5 and 12 s is considered
as a good indicator of Horner syndrome. Crippa et al.
[40] showed that this test is variable. If it is carried
out only once, about half of all patients with Horner

syndrome will not show any dilation lag. If carried out

four times, in 83% at least one test will show dilation lag.
Dilation lag was never found in patients with physiologic
anisocoria. This test is therefore highly specific, but is not
very sensitive unless it is repeated several times.
Pharmacological testing is unavoidable if Horner syndrome must be excluded with maximal certainty. The
classical test uses cocaine eye drops, 410%, which cause
a normal pupil to dilate approximately 2 mm. Cocaine
acts by inhibiting the re-uptake of spontaneously
released noradrenaline into the synaptic cleft. If the
sympathetic innervation is interrupted there will be no
spontaneous delivery of noradrenaline and the pupil will
not dilate (or only dilate very little) [41]. This is a well
established test for Horner syndrome. Getting cocaine
eye drops is troublesome, however, and handling a substance that could be used as an illegal drug implies
inconveniences and risks. Therefore, researchers became
interested in new drugs that could be used instead of
cocaine. Several years ago it could be demonstrated that
apraclonidine 1% dilated the involved but not the normal
pupil of six patients with Horner syndrome, thus reversing the anisocoria [42]. Apraclonidine, easily available
and used in glaucoma treatment (0.5%), would receive a
warm welcome as a test drug for Horner syndrome. This
was not completely new as in 1989 clonidine eyedrops
had already been suggested as a test for Horner syndrome
[43]. Clonidine and its predrug apraclonidine are weak
sympathomimetics, able to dilate the pupil mildly. In
patients with sympathetic denervation of the pupil it
should lead to a marked dilation, demonstrating denervation supersensitivity. In Horner syndrome, however, the
pupil is only denervated if the site of the lesion is within
the third neuron that travels from the cervical superior
ganglion to the dilator muscle. One would therefore
expect that apraclonidine dilates the pupil significantly
only in lesions of the third neuron from the superior
cervical ganglion to the dilator muscle. Its effect should
not differ from normal controls in patients with lesions of
the first or second neuron in the sympathetic innervation
of the eye, because the dilator muscle is not denervated
in those cases. Astonishingly enough it seems to work in
each Horner syndrome by dilating the affected pupil and
not or only minimally influencing (or even constricting)
the uninvolved pupil, thus reversing the anisocoria.
Reversal of anisocoria by apraclonidine has therefore
been recommended as a new test for Horner syndrome.
Are we ready to replace cocaine by apraclonidine, as
Kardon [44] asked in an Editorial? We do not yet know
if all patients with uninvolved third neuron (i.e. Horner
syndrome caused by lower cervical or thoracic or brainstem lesions) show reversal of anisocoria, and we do not
know if supersensitivity to apraclonidine is present early
enough, even in the first days after development of

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The pupil Wilhelm 39

Horner syndrome. A test that is positive only in longstanding Horner syndrome is of limited value. More
studies are therefore necessary and some were presented
recently. One cross-over study with apraclonidine and
cocaine included only nine real Horner syndromes, but 10
diabetic patients with supposed (but not proven) bilateral
sympathetic deficit [45]. Most other reports comprise
still smaller series or case reports [42,4648] or reports
from children where transsynaptic degeneration might
cause all Horner syndromes to behave like third neuron
lesions [4952]. Currently it is not yet clear if apraclonidine might be useful to diagnose Horner syndrome.
In third-order neuron lesions, indirect sympathetic acting
drugs like hydroxyamphetamine, tyramine or pholedrine
are not able to dilate the pupil sufficiently. Thus, those
drugs can be used to localize the lesion in Horner syndrome [5358]. None of them is currently available
commercially. If apraclonidine fails to dilate pupils of
first- or second-order neuron lesions it might still serve to
localize the lesion, because a third-order neuron lesion
should always dilate.
From clinical experience and supported by earlier studies
[5961] we know that in quite a few cases a Horner
syndrome remains idiopathic, i.e. no cause can be identified. This could not be improved by careful use of MRI
in a smaller study [62]. No clear guidelines exist about
how far the clinical evaluation should go in a patient with
Horner syndrome.
Many publications about Horner syndrome can be
retrieved in the literature (most of them single case reports
or small series). Iatrogenic Horner syndromes form the
great majority, especially after peridural anesthesia or
subclavian/jugular venous puncture (12 reports between
2005 and 2007 [6374]). This is far from new, however.
The first case report is from 1975 for obstetric anesthesia
[75,76] and 1980 for jugular vein puncture [77]. The
explanation for the oculosympathetic lesion by anesthesia
far away from this pathway has been that the anesthetic
travels cranially. The neuro-ophthalmological examiner
must be aware that Horner syndrome might be a complication of both jugular and subclavian puncture or spinal
anesthesia.
The second large group is carotid artery dissection
(CAD). Painful Horner syndrome is a classical symptom
of this disorder threatening cerebral circulation [78]. The
incidence of CAD is estimated at 1.7/100 000 and Horner
syndrome has been encountered in 25% [79] or 37% [80].
The prognosis is quite good: 70% recover without sequelae [80] and recurrence is extremely rare [79]; however,
serious deficits remain in 15% [80]. This indicates that
the exclusion of CAD in Horner syndrome is important,
especially in acute and painful Horner syndrome.

Another association is of importance the combination of

sixth nerve paresis and Horner syndrome [8183]. This
usually indicates a lesion (neoplasm) of the cavernous
sinus where the sympathetic fibers join the sixth nerve for
a short way [82]. The combination of Horner syndrome
and sixth nerve paresis is therefore a localizing sign of
high value, and an indication to rule out a mass lesion in or
around the cavernous sinus [84,85].
Among all the case reports it is strikingly rare that Horner
syndrome indicates previously unknown malignancy.
There are reports about mediastinal or pleural lesions
causing Horner syndrome; however, Pancoast tumor
appears very rarely as a cause of Horner syndrome. Only
2% of all bronchial carcinomas may be considered as
Pancoast tumors [86] and a large clinic reported only
105 cases from 42 years of experience [87]. It would
therefore be astonishing if an isolated Horner syndrome would be the first sign of mediastinal or pleural
malignancy. Only two patients with nasopharyngeal
carcinomas were reported in whom the oculosympathetic paresis was the only sign of the tumor [88]. Even
in thyroid disease with Horner syndrome a benign
goiter is much more common than thyroid carcinoma
[89,90].
Another well-known malignant etiology behind Horner
syndrome is neuroblastoma in children. Mahoney et al.
[91] found six tumors (four neuroblastomas, one Ewing
sarcoma, and one xanthogranuloma) among 28 children
with Horner syndrome of unknown etiology. It has to be
mentioned that only in 18 of those 28 children has
imaging been complete and that in none of the children
with neuroblastoma was urine catecholamine level raised.
Jeffery et al. [92] found one neuroblastoma among
31 congenital Horner syndrome patients, and two neuroblastomas and one rhabdomyosarcoma among 11
acquired (not iatrogenic) Horner syndrome patients.
George et al. [93] found in the first year of life two
neuroblastomas and one ganglioneuroma among 23
Horner syndromes. Those retrospective studies indicate
clearly that neuroblastoma, although a rare disease, is
quite frequently found in children with Horner syndrome
of unknown etiology. Imaging of the brain, neck and
chest is necessary; urine catecholamine testing alone is
not sensitive enough, especially in small tumors [92].
With good reason we can tell an adult patient with a
Horner syndrome of unknown etiology that they do not
need to worry unknown malignancy is very rare. Careful clinical examination is necessary, however, and
especially a sixth nerve paresis needs to be excluded.
History taking (hints on CAD?) and clinical examination
are more important than extensive imaging in adult
patients. In children, however, imaging is necessary in
Horner syndrome with unknown etiology.

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40 Neuro-ophthalmology and neuro-otology

Tonic pupil
Tonic pupil, or Adie syndrome when associated with
tendon reflex disorder, is considered as a benign condition and further evaluation does not usually reveal any
relevant pathology [94]. There are, however, recent
reports of tonic pupil in the course of malignant/neoplastic disorders [95100], infectious or inflammatory disease
[101104], or Fisher syndrome or other systemic disorders [105]. The common denominator of all these
disorders might be an autoimmune process. In quite a
few cases anti-Hu antibodies have been found
[95,96,106,107]. Maybe such antibodies play a role even
in idiopathic tonic pupils. As tonic pupil is a rather
frequent disorder, which is often subject to extensive
work-up, it is still an open question whether the association with a serious disease is by chance or whether tonic
pupil really might be a paraneoplastic disorder. In the vast
majority of cases no malignancy will be found.

Conclusion
The last few years have introduced melanopsin ganglion
cells as possible receptors for the pupillary light reflex, in
addition to rods and cones.
Pupillography has been established as a method to
measure sleepiness.

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Cocaine testing is still recommended as the primary test

for Horner syndrome. Careful history taking and clinical
examination is most important in adult Horner syndrome,
whereas children with Horner syndrome of unknown
etiology should undergo imaging.

23

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