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CONTINUUM (MINNEAP MINN) 2019;
25(5, NEURO-OPHTHALMOLOGY):
1194–1214.
Address correspondence to
Dr Marc A. Bouffard, Shapiro
Clinical Center, 5th Floor, Beth
Israel Deaconess Medical
Center, 330 Brookline Ave,
Boston, MA 02115, marc.a.
bouffard@gmail.com.
RELATIONSHIP DISCLOSURE:
Dr Bouffard serves as a
consultant for the US
Department of Justice Vaccine
Injury Compensation Program.
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USE DISCLOSURE:
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© 2019 American Academy
of Neurology.
1194
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The Pupil
By Marc A. Bouffard, MD
ABSTRACT
PURPOSE OF REVIEW: Thegoal of this article is to review the anatomy and
physiology of pupillary function and then employ that information to
develop a comprehensive framework for understanding and diagnosing
pupillary disorders.
RECENT FINDINGS: The contribution of rods and cones to the pupillary light
reflex has long been known. A third photosensitive cell type, the
intrinsically photosensitive retinal ganglion cell, has recently been
discovered. This cell type employs melanopsin to mediate a portion of the
pupillary light reflex independent of rods and cones (the postillumination
pupillary response) and photic regulation of circadian rhythm.
SUMMARY: The autonomic nervous system regulates pupil size in response to
stimuli. The parasympathetic nervous system causes miosis in response to
light and near visual stimuli. These stimuli activate supranuclear pathways
that project to the Edinger-Westphal nuclei. The sympathetic nervous
system causes mydriasis in response to a variety of arousing factors, both
physiologic (wakefulness) and pathologic (pain). Abnormalities of
physiologic function cause disturbances of pupil size, shape, and response
to stimuli. The clinical approach to pupillary abnormalities should focus on
the clinical and pharmacologic assessment of the pupil’s expected
response to diverse stimuli.
INTRODUCTION
P
upillary abnormalities are commonly encountered by neurologists in
all practice settings. The presence of abnormal pupils is a frequent
cause of consternation among clinicians, since a given finding, be it
1 mm of anisocoria or a large poorly reactive pupil, could reflect
anything from a completely benign process to an impending
neurologic emergency. Beyond the initial observation of abnormal pupil size,
shape, or response to stimulus, the examiner can interrogate the pupil’s function
in a number of ways, with both bedside examination techniques and
pharmacologic agents, to localize the source of the pupillary abnormality
(TABLE 1-1). Paired with an intimate understanding of the processes that
influence pupillary function at various neuroanatomic sites, diagnoses can
frequently be reached quickly and accurately.
Any didactic approach to pupillary abnormalities must begin with the
normal anatomy and physiology of the pupil. It is only once that fundamental
understanding of what regulates physiology has been established that
pathophysiology can be understood. As complex as pupillary physiology may be,
OCTOBER 2019
each detail is worth touching upon as every major pupillary abnormality has a
logical explanation and can be connected to the dysfunction of an identifiable
neuroanatomic structure or pathway. To that end, the first two sections of this
article recount the anatomy of the pupil and the means by which it is dilated and
constricted to various stimuli. The third section outlines the mechanisms behind
and means by which one can diagnose common pupillary abnormalities:
anisocoria, bilaterally small and large pupils, irregular pupils, and pupils
exhibiting light-near dissociation.

ANATOMY OF THE PUPIL

The anterior surface of the iris is divided into two concentric zones: the
peripheral ciliary zone and the central pupillary zone. These are divided by a
ridge called the collarette. The stroma lies beneath the anterior epithelium, and
the organization of its vasculature is reflected in the radial furrows and ridges
of the overlying epithelium. The pupillary sphincter, responsible for constriction
of the pupil, is a muscle that surrounds the pupil concentrically; it is embedded
within the stroma adjacent to the pupil and is, at most, 1 mm wide. The pupillary
dilator is composed of fibers that are radially arranged around the pupil and run
along the entire underside of the stroma, separating it from the pigment
epithelium that comprises the posterior surface of the iris. It is this posterior
pigmented epithelium that comprises the pupillary ruff, the dark-colored ring
that is often seen separating the iris from the pupillary aperture itself. When the
pupil is dilated, the ruff may disappear. When the pupil is constricted, the
diameter of the ruff is maximized, as the pupil’s constriction results in the ruff
being pulled anteriorly into view from the posterior surface of the iris.

PHYSIOLOGIC FUNCTION OF THE PUPIL

The first step toward approaching pupillary disorders in clinical practice is to
understand pupillary physiology. This can be conceptualized by considering
the two main functions of the pupil: constriction and dilation. Physiologic
constriction of the pupil is mediated by the parasympathetic nervous system’s
cholinergic innervation of the pupillary sphincter and occurs either as a result of
stimulation by light or as a response to fixation on a target at near. Physiologic
dilation of the pupil is mediated by the sympathetic nervous system’s
catecholaminergic innervation of the pupillary dilator.

Pupil Examination TABLE 1-1

1 Examine the pupil for size, shape, and response to light and near stimuli
2 Avoid writing PERRL or PERRLA; whenever possible, measure the pupil sizes in dim light, bright
ambient light, and with direct light
3 Exercise care to not linger asymmetrically when testing for a relative afferent pupillary defect;
“photobleaching” of the retina asymmetrically can cause a transient relative afferent pupillary
defect
4 Obtain information regarding ocular trauma, surgery, and use of eye drops when evaluating
the patient with pupillary abnormalities

PERRL = pupils equal, round, reactive to light; PERRLA = pupils equal, round, reactive to light,
accommodation.

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THE PUPIL

Pupillary Constriction (Miosis)

Constriction of the pupil is mediated by the parasympathetic nervous system.
The two major supranuclear drivers of physiologic pupillary constriction, the
near reflex and the pupillary light reflex, both activate the same two-neuron final
common pupillomotor pathway comprised of the Edinger-Westphal nucleus and
the ciliary ganglion (FIGURE 1-1).

THE FINAL COMMON PATHWAY (EDINGER-WESTPHAL NUCLEUS/CILIARY

GANGLION/PUPILLARY SPHINCTER). The first neuron of this final common
pupillomotor pathway is located in the Edinger-Westphal nucleus. The Edinger-
FIGURE 1-1
Each eye responds to light by sending a signal down
the ipsilateral optic nerve (ON). Fibers subserving
the temporal retina (nasal visual field) do not cross
in the optic chiasm (OC) and feed into the ipsilateral
optic tract, whereas fibers from the nasal retina
(temporal visual field) decussate in the chiasm and
contribute to the contralateral optic tract (OT).
Axons encoding visual information synapse in the
lateral geniculate nucleus (LGN) with neurons that
form the axons of the optic radiations (OR), which
project to the ipsilateral occipital cortex (OCC).
However, fibers governing pupillary reaction to
light peel off the OT, enter the dorsal midbrain
through the brachium of the superior colliculus, and
synapse in the olivary pretectal nucleus (PTN). From
there, half the fibers synapse with the ipsilateral
Edinger-Westphal nucleus (EW), a subnucleus of the
oculomotor nucleus, and half decussate in the
posterior commissure to reach the contralateral EW.
The neurons of the EW form the parasympathetic fibers
of the oculomotor nerve, which then synapse in the
ciliary ganglion (CG) located within the orbit. The final
pathway is formed by neurons of the CG, whose axons
innervate the pupillary constrictors as well as the ciliary employing acetylcholine to
muscles, which govern changes in lens shape to allow
accommodation. Through this circuitry, light into either
eye will cause constriction of both pupils. Note that
output from the visual cortex down to the dorsal
midbrain helps govern the accommodation reflex.
Figure courtesy of Marc Dinkin, MD.
Westphal nuclei are paired
structures that lie in the dorsal
rostral midbrain. The axons
\of the cholinergic Edinger-
Westphal cell bodies form the
pupillomotor fibers that travel
with the third cranial nerve after
exiting the midbrain. In the
subarachnoid space, the
pupillomotor fibers lie on the
mediodorsal aspect of the third
nerve, in proximity to the
posterior communicating artery.
After entering the cavernous
sinus, the pupillomotor fibers
become more diffusely
distributed around the periphery
of the third nerve. When the
third nerve divides into its
superior and inferior divisions in
the anterior cavernous sinus, the
pupillomotor fibers exclusively
travel on the inferior division,
which also innervates the
inferior rectus, inferior oblique,
and medial rectus (the superior
division innervates only the
levator palpebrae and superior
rectus). This inferior division of
the oculomotor nerve enters the
orbit via the superior orbital
fissure, where the pupillomotor
axons synapse on the cell bodies
that form the ciliary ganglion,
activate nicotinic II receptors.
The ciliary ganglion is located
in the inferior orbit just posterior
to the globe. The “final common
pathway” is common in an

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anatomic sense, but there are cell bodies within it that distinctly mediate pupil KEY POINTS
constriction in response to light or reflexive pupil constriction in response to the
● The pupillary sphincter
tracking of a target as it approaches the eye (as part of the near triad). This muscle is located
distinction gives rise to the observation that some pathologic processes affect the concentrically near the inner
pupil’s response to one stimulus but not the other, evidenced by the fact that margin of the iris and
96.5% of the cell bodies in the ciliary ganglion send their axons to innervate the mediates pupillary
constriction via cholinergic
ciliary body, which controls the shape of the lens (accommodation) and pupillary
stimulation from
sphincter in response to tracking a target as it approaches the subject. Only a parasympathetic neurons.
minority of cell bodies—approximately 3.5%—give rise to axons that innervate
the pupillary sphincter in response to the pupillary light reflex.1 The axons ● The pupillary dilator is
involved in pupillary constriction that exit the ciliary ganglion form the short composed of muscles
radially arranged around the
ciliary nerves, which then insert into the sclera and distribute diffusely until pupil that are stimulated by
reaching their targets, employing acetylcholine to activate muscarinic receptors the sympathetic nervous
on the pupillary sphincter and ciliary body. syndrome via adrenergic
input.
ACTIVATION OF THE FINAL COMMON PUPILLOMOTOR PATHWAY BY LIGHT. The ● The pupil constricts to
afferent limb of the pupillary light reflex begins in the retina. Each eye contains both light and viewing of a
approximately 60 million rods and 3 million cones.2 Rods subserve low-light near target. These two
vision, and cones, the peak concentration of which is found at the macula, reflexes share the same
anatomic efferent limb,
subserve high-resolution color vision. Until recently, it was assumed that rods
the first-order neuron of
and cones were the sole mediators of the pupillary light response and that the which is located in the
1.2 million retinal ganglion cells found in each eye did no more than transmit the parasympathetic Edinger-
signal received from rods and cones to the brain to mediate image formation in Westphal nucleus and the
second-order neuron of
the occipital lobe and to convey the pupillary light reflex to the midbrain.
which is located in the ciliary
However, a third photosensitive cell type has been recently discovered within the ganglion. However, the
ganglion cell layer. A minority (<5%) of retinal ganglion cells are intrinsically parasympathetic neurons
photosensitive. These intrinsically photosensitive retinal ganglion cells employ that mediate the near reflex
melanopsin to mediate direct depolarization by light in a manner completely outnumber those involved in
the pupillary light reflex by a
independent of rod- and cone-mediated photoactivation.3 Each of these three ratio of 30:1.
photoreceptor cell types has a distinct contribution to the pupillary light reflex.
To briefly summarize, rods and cones are responsible for rapid modulation in ● Rods, cones, and
pupillary size with changes in ambient light sensitivity, whereas intrinsically intrinsically photosensitive
retinal ganglion cells all
photosensitive retinal ganglion cells mediate a slower but more sustained contribute to the pupillary
pupillary response to light.4 The overlap of intrinsically photosensitive retinal light reflex.
ganglion cell function with rod and cone function is only partial; intrinsically
photosensitive retinal ganglion cells do not generate vision-forming signals as ● Retinal ganglion cells
stimulate the ipsilateral
rods and cones do, but they do project to the suprachiasmatic nucleus, serving
olivary pretectal nucleus in
as the sole retinal regulator of circadian rhythm.5 The net luminance-generated response to light. Each
signal from rods, cones, and intrinsically photosensitive retinal ganglion cells olivary pretectal nucleus
is relayed via retinal ganglion cells through the optic nerve, chiasm, and innervates the bilateral
tract until exiting the tract just anterior to the lateral geniculate nucleus and Edinger-Westphal nucleus,
although the contralateral
synapsing on the ipsilateral pretectal olivary nucleus. The axons originating from Edinger-Westphal nucleus is
each olivary pretectal nucleus innervate both the ipsilateral and contralateral more highly innervated.
Edinger-Westphal nucleus (the contralateral is reached through the posterior
commissure at the very dorsal midbrain), although the contralateral
Edinger-Westphal nucleus receives more innervation than the ipsilateral.

ACTIVATION OF THE FINAL COMMON PUPILLOMOTOR PATHWAY VIA THE NEAR

REFLEX. The near triad refers to the constellation of ocular adaptation that
must be achieved to maintain focus and single vision on an object at near.

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THE PUPIL

The near triad consists of miosis, convergence, and accommodation. During

accommodation, the ciliary muscle relaxes the zonular fibers that connect it to
the lens, allowing the lens to relax into its default, more biconvex configuration
and thus maintaining focus at near. The near triad employs the same final
common pathway involving the cell bodies of the Edinger-Westphal nuclei and
ciliary bodies as described above.
Supranuclear control of the near triad should intuitively be mediated by a
combination of afferent and efferent structures, as one would expect for a
system required to initiate motor signals based on visual input. Animal studies
have demonstrated the role of the peristriate visual cortex (areas 19 and 22) and
the lateral suprasylvian areas,6,7 which seems to comport well with this
assumption. Several midbrain nuclei, including the raphe interpositus, superior
colliculus, and mesencephalic reticular formation, aid in the organization of
these cortical signals and their appropriate transmission to the neurons in the final
common pathway (the Edinger-Westphal nuclei for miosis and accommodation,
the medial rectus subnuclei of the third cranial nerve for convergence).7,8

Pupillary Dilation (Mydriasis)

Dilation of the pupil is accomplished by the stimulation of the pupillary dilator
by the sympathetic nervous system. The sympathetic pathway that innervates
the pupillary dilator is a three-neuron system. The majority of the first-order
neurons are located in the paraventricular and arcuate nuclei of the ipsilateral
hypothalamus and send axons caudally through the lateral brainstem and
cervical spinal cord to synapse on the second-order neurons that form the
ciliospinal nucleus of Budge.9 However, a number of other cell groups also
project onto the ciliospinal nucleus of Budge, including those that mediate
changes in sympathetic tone in response to wakefulness and pain.10
The ciliospinal nucleus of Budge extends from the C8 to T2 spinal cord levels.
The axons of these cell bodies exit the spinal cord and traverse the superior
thorax in the region of the lung apex and subclavian artery, where they adhere to
and ascend rostrally in proximity to the common carotid artery to synapse, via
acetylcholine and type II nicotinic acetylcholine receptors, on the third-order
neurons that form the superior cervical (stellate) ganglion.
The superior cervical ganglion is located adjacent to the carotid bulb. Its
third-order axons go on to innervate three distinct targets: the Müller tarsal
muscles (both superior and inferior), the pupillary dilator, and the sweat glands
of the face. Those axons destined to innervate the pupillary dilator and superior
and inferior tarsal muscles adhere to the internal carotid artery, accompanying it
through the cavernous sinus, where they are in proximity to the ipsilateral
abducens nerve, and then follow the ophthalmic artery toward the orbit. They
arrive in the orbit via the short ciliary nerves (which arise from the ciliary
ganglion) and via the long ciliary nerve (which arises from the ophthalmic
branch of the trigeminal nerve [V1]). These third-order neurons innervate their
target muscles using epinephrine and norepinephrine to stimulate β1-adrenergic
receptors. The third-order neurons in the superior cervical ganglion destined to innervate
the sweat glands of the face send their axons along the external carotid artery.

PATHOLOGIC PUPILLARY REACTIONS

The commonly encountered abnormalities of pupillary function in adults
logically originate from disruption of the physiologic pathways described

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above. The discussion that follows focuses on the main patterns of KEY POINTS
pupillary abnormalities, etiologies of each category of pupillary dysfunction,
● The near triad
key physical examination techniques, the use and interpretation of encompasses pupillary
pharmacologic tests for pupillary denervation, and considerations for miosis, convergence, and
diagnostic testing. accommodation.
Accommodation refers to
Pupils of Asymmetric Size (Anisocoria) relaxation of the ciliary body
and a resulting increase in
Asymmetry in pupil size is referred to as anisocoria. The sections that follow the concavity of the lens to
focus mainly on the characteristics of the pupils in the absence of the allow for focus on an object
appropriate sympathetic or parasympathetic influences; however, at each at near; accommodation
stage, it should be kept in mind that any evaluation of anisocoria should be does not refer to the miosis
that accompanies it as part
augmented by a careful examination of lid position, lid function, and of the near triad.
extraocular movement. Although versions (ie, eye movements with both eyes
open) are tested in all patients, more detailed motor function testing should ● Axons originating from
be considered (eg, cover-uncover testing to examine for ocular misalignment the third-order sympathetic
neurons in the superior
that might not be easily appreciated). Additionally, measurement of the
cervical ganglion that
margin-to-reflex distance 1 (MRD1) and margin-to-reflex distance 2 (MRD2) is innervate the superior and
encouraged. The MRD1 is tested by instructing the patient to look at a light held inferior Müller tarsal
directly in front of the face; the distance (using a ruler) between the lower muscles and the pupillary
dilator form a plexus around
margin of the upper lid and the light reflex on the cornea is the MRD1. The
the internal carotid artery.
MRD2 is the analogous measurement using the upper margin of the lower lid. Axons originating from
Measurement of levator excursion (maximal difference in position of the lid in third-order sympathetic
downgaze and upgaze) is also helpful and is abnormal in patients with third neurons in the superior
nerve palsy involving the levator palpebrae. This is also known as levator cervical ganglion that
innervate the sweat glands
function. of the face adhere to the
Much discussion of anisocoria revolves around the assessment and external carotid artery on
implications of pathologically mydriatic and miotic pupils, and within that route to their target.
context, it is critical to bear in mind what the acceptable range of “normal”
● Every examination of
is with reference to physiologic anisocoria. A small difference (1 mm or patients with anisocoria
less) in pupil size is commonly encountered in normal subjects. Because should include a detailed
damage to neither the sympathetic nor parasympathetic pathways is assessment of eye
present, the relative difference in pupil size should remain stable in bright movements (including
cover-uncover testing) and
and dim ambient lighting. The pupils should react well to both light and
of lid position and function.
near stimuli and exhibit no dilation lag. This is known as physiologic
anisocoria. ● Anisocoria resulting
from parasympathetic
denervation is maximized in
MONOCULAR MYDRIASIS. Monocular mydriasis results from disruption of
the light (when both pupils
parasympathetic input to the pupillary sphincter. The anisocoria should be should constrict maximally).
maximized in conditions of bright ambient light when the fellow eye
constricts and the affected eye fails to do so. Mydriasis may be due to
damage to the oculomotor nerve before synapsing on the ciliary ganglion,
damage to the ciliary ganglion or its axons on their route to the pupillary
sphincter, pharmacologic dilation of the pupil, or damage to the sphincter
itself.
The first step in assessing any patient with monocular mydriasis is to evaluate
for a third nerve palsy with a careful examination of levator palpebrae, inferior
rectus, medial rectus, superior rectus, and inferior oblique function (TABLE 1-2).
Chronic mydriasis in complete isolation of these findings is extraordinarily
unlikely to result from a third nerve palsy, but evolving third nerve palsies,
particularly compressive ones, may present with pupillary abnormalities before

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THE PUPIL

other signs are discernible. Four questions should be answered when any third
nerve palsy is encountered:
u Is the third nerve palsy complete (every muscle profoundly affected)?
u Is the pupil involved?
u Is pain present?
u Are there signs of aberrant regeneration?

Common causes of third nerve palsies include compression (aneurysmal or

otherwise) and microvascular ischemia. It is important to note that most cases of
aneurysmal compression are painful, although slow-growing aneurysms may
present in a manner similar to compression from meningiomas or other
slow-growing tumors. The third nerve is more resilient to trauma than the fourth
and sixth cranial nerves. Traumatic third nerve palsies are thus unlikely to occur
with mild head trauma or in isolation without accompanying fourth and sixth
nerve palsies. Midbrain lesions (eg, infarction, hemorrhage) are encountered
frequently but rarely in neurologic isolation. Nuclear third nerve palsies involve
ipsilateral inferior rectus, inferior oblique, and medial rectus weakness; bilateral
levator palpebrae weakness; and contralateral or bilateral superior rectus
weakness (the nucleus is contralateral to the innervated eye but the fascicles
originating from each superior rectus nucleus decussate and pass through the
contralateral superior rectus nucleus). “Peripheral-appearing” third nerve palsies
may also result from more anterior midbrain damage wherein the fascicles rather
than nuclei are damaged.
Damage to the ciliary ganglion or its axons results in a mydriatic pupil referred
to as a tonic pupil owing to its slow constriction and sluggish redilation. The pupil
is often irregularly shaped with sectoral hypokinesis or vermiform writhing
movements that may not be seen with the naked eye but are often easily seen
with the aid of a slit lamp. These pupils constrict better to near visual stimuli
than to the light stimuli; this is presumably because of the 30:1 ratio of
parasympathetic fibers mediating the near reflex to those mediating the pupillary
light reflex and, therefore, their relative preservation in the face of injury.
Cholinergic hypersensitivity of the pupillary sphincter develops 1 to 2 weeks after
ciliary ganglion lesions. To test for hypersensitivity, dilute pilocarpine (a direct
cholinergic agonist) is used. Instillation of one drop of dilute pilocarpine
(0.125%) (typically compounded by the hospital pharmacy) into both eyes
should cause the affected mydriatic eye to become miotic after approximately
45 minutes; the fellow eye is generally unaffected. Thus, a positive test is clearly
seen when the anisocoria reverses. Less frequently, both pupils may constrict; the
test may still be interpreted as positive if the larger pupil constricts 0.5 mm or
more than the fellow pupil. Although it has been traditionally taught that a

TABLE 1-2 Approach to the Unilaterally Large Pupil

1 Assess for clinical evidence of third nerve palsy and note any light-near dissociation
2 Assess for irregular pupillary margin (if compatible with tonic pupil, should constrict to 0.125%
pilocarpine)
3 If no evidence of third nerve palsy or tonic pupil, administer two drops of 2% pilocarpine; if
no constriction, then the mydriasis is pharmacologic

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pilocarpine concentration of 1% is generally required to constrict mydriatic KEY POINTS
pupils in patients with third nerve palsies, care must be taken as this rule is not
● Chronic mydriasis in
absolute, and, on occasion, mydriatic pupils due to a third nerve palsy may also complete isolation is
constrict to dilute (0.125%) pilocarpine.11 The majority of tonic pupils are benign extraordinarily unlikely
and idiopathic, in which case it is called an Adie pupil, but the history and to result from a third
examination should take into account findings suggestive of giant cell arteritis,12 nerve palsy.
generalized dysautonomia,13,14 orbital inflammation (eg, sarcoid),15 neoplasm,16
● Tonic pupils are irregular,
Guillain-Barré syndrome,17 or trauma, since tonic pupils may infrequently result display sectoral hypokinesis
from any of these processes, among others. Adie pupils are generally monocular, (which may require the aid
seen in female patients, and isolated, though they may be accompanied by loss of a slit lamp to visualize),
of deep tendon reflexes of the lower extremity, in which case the term Holmes- are slow to redilate after
constriction (thus their
Adie syndrome is used. name), and demonstrate
Pharmacologic dilation of the pupils can result either from administration light-near dissociation
of sympathomimetics (eg, phenylephrine) or from anticholinergics (eg, (reacting better to near
tropicamide eye drops, ipratropium nebulizers, inadvertent transmission of stimuli than light). They may
be idiopathic, occur
scopolamine from retroauricular patches to the eye). Instillation of 1% to 2% frequently in young women,
pilocarpine should constrict any mydriatic pupil other than those that have been and are only rarely
pharmacologically dilated (more concentrated pilocarpine drops are not only associated with other
unnecessary but should be avoided given the risk for retinal detachment). The pathologic processes.
Ninety percent of cases
patient should also be queried about any source of iris trauma, either surgical or are monocular.
accidental, that might have resulted in a mydriatic irregular pupil.
● Constriction of a
MONOCULAR MIOSIS. Pathologic miosis typically results from denervation of the mydriatic pupil by dilute
pilocarpine (0.125%) was
sympathetic input to the pupillary dilator. Thus, the amount of anisocoria will
traditionally thought to be
be maximized under conditions of dim ambient light when the denervated eye specific to tonic pupils.
will fail to dilate and the fellow eye will dilate maximally. Careful observation However, this is incorrect;
may reveal slow dilation after a light stimulus is removed from the affected pupil; preganglionic third nerve
this is referred to as dilation lag. palsies resulting from
compression and trauma
The sympathetic fibers that subserve mydriasis do not travel in isolation; may result in a mydriatic
they are accompanied by the fibers that innervate the Müller tarsal muscles and, pupil responsive to 0.125%
until the carotid bifurcation, by the fibers that supply sudomotor function to pilocarpine.
the sweat glands of the face as described above. A complete Horner syndrome,
● Pilocarpine 2% will cause
which comprises ipsilateral mild ptosis, miosis, and facial anhidrosis, results constriction of any mydriatic
from damage to the sympathetic pathway proximal to the divergence of the pupil other than one that is
sympathetic fibers that supply the sweat glands of the face (adherent to the pharmacologically dilated.
external carotid artery) and those that innervate the pupillary sphincter and
● Anisocoria resulting from
tarsal muscles (both adherent to the internal carotid artery, with those
sympathetic denervation of
innervating the tarsi leaving the internal carotid most distally). Horner syndrome the pupil is maximized in the
may be incomplete, even if the lesion is proximal. The relative difference in dark (when both pupils
MRD1 between eyes usually does not exceed 1 mm to 2 mm in a patient with should dilate maximally).
Horner syndrome, although the interpalpebral distance (MRD1 + MRD2) may
be smaller by 2 cm to 4 cm and the lower lid often elevates in patients with
Horner syndrome, creating a “pseudoenophthalmos” or “inverse ptosis.” Some
patients with Horner syndrome have accompanying features that are absent
from the classic triad but may be helpful clues in cases of partial Horner
syndrome. Among the most prominent are conjunctival injection due to
vasodilation resulting from decreased sympathetic tone and decreased
intraocular pressure relative to the fellow eye resulting from a decrease in
aqueous humor production by the ciliary body, a process that is stimulated by
the sympathetic nervous system.

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THE PUPIL

The detection of Horner syndrome should be followed by investigation as to

its cause:

u First-order Horner syndrome (accompanied by ipsilateral ptosis and anhidrosis of the

ipsilateral face and body)
u Second-order Horner syndrome (accompanied by ipsilateral ptosis and ipsilateral facial
anhidrosis)
u Third-order Horner syndrome (accompanied by ipsilateral ptosis of the upper and lower
eyelids without anhidrosis)

The first-order neurons originate in the hypothalamus, which is rarely the

site of injury. The most common location for first-order neuron injury is in the
dorsolateral medulla; this is a common component of Wallenberg syndrome but
may occur more rostrally. Spinal cord lesions rostral to the ciliospinal nucleus
of Budge are encountered, particularly in patients with a Brown-Séquard
syndrome. The second-order neuron is often injured by thoracic neoplastic
disease; the classic association is with the Pancoast tumor in the lung apex, but
any pathology in this location (eg, aneurysm, sarcoidosis) may be responsible.
The common carotid artery is a less frequent site of injury for the second-order
neuron. The third-order neuron ascending the carotid is prone to injury in the
setting of carotid dissection. Bearing this differential diagnosis in mind, a
targeted examination should be done in detail, both clinically and radiographically.
The typical radiographic profile includes MRI of the brain and cervical spine
with contrast (which may, at some institutions, be protocoled to image the lung
apex; a chest CT with contrast can be done otherwise) and a magnetic resonance
angiogram (MRA) of the head and neck (including the great vessels). The
workup for isolated, painless, incidentally discovered cases of Horner syndrome
is frequently unrevealing but must be performed given the potentially serious
etiologies above. Rare cases of Horner syndrome are associated with idiopathic
headache syndromes, including the family of trigeminal autonomic
cephalalgias, idiopathic Raeder paratrigeminal syndrome, and migraine with
autonomic features. Even transient Horner syndrome should not be attributed
to these entities without a careful clinical and radiographic investigation.
Eye drops may be used to rapidly determine whether miosis is pathologic or
simply reflects physiologic anisocoria. Traditionally, a combination of cocaine
and hydroxyamphetamine eye drops has been used to detect sympathetic
denervation of the pupil. Cocaine reduces presynaptic reuptake of
catecholamines secreted into the synaptic cleft. Thus, instillation of cocaine
drops into both eyes for approximately 45 minutes leads to accentuation of
anisocoria in patients with Horner syndrome; the normally innervated pupil
becomes excessively mydriatic, and the denervated pupil fails to dilate
commensurately. A postcocaine increase in anisocoria of 1 mm or greater is
interpreted as a positive test. On a subsequent date, hydroxyamphetamine
eye drops can be used to help differentiate third-order neuron lesions from first-
or second-order neuron lesions. Instillation of hydroxyamphetamine causes
third-order neurons to secrete catecholamines. Thus, a miotic pupil from a
third-order Horner syndrome will not dilate in response to hydroxyamphetamine
as the damaged neuron cannot respond to the secretagogue. If the Horner
syndrome is due to a first- or second-order neuron lesion, the third-order neuron
remains intact and will respond to a secretagogue, dilating the pupil.

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 Because of issues surrounding substance control, cocaine and KEY POINTS
hydroxyamphetamine eye drops are difficult to obtain. This two-step test has
● The ptosis that results
largely been abandoned in favor of apraclonidine testing. Decreased stimulation from sympathetic
of the pupillary dilator from a lesion of any order neuron in the sympathetic denervation is often subtle
chain results in increased expression of catecholamine receptors on the pupillary (1 mm to 2 mm), and
dilator; this usually occurs within a few days of injury but may take up to a week frequently both the upper
and lower lids are affected
to occur. This phenomenon allows a weak α-2 agonist, such as apraclonidine
(as both the superior and
0.5%, to dilate the supersensitive pupil. Two drops of apraclonidine 0.5% into inferior tarsus receive
normal eyes should not result in sympathetic stimulation of a normal pupillary sympathetic innervation),
dilator. However, in pupillary dilator muscles that have been denervated long which sometimes results
in the optical illusion
enough to become hypersensitive, the abnormal pupil will dilate in response to
of enophthalmos
apraclonidine, whereas the unaffected fellow pupil generally does not change in (pseudoenophthalmos).
size (drops must be instilled into each eye as the nonmiotic pupil serves as a
control). A clearly positive test occurs when reversal of anisocoria is seen after 45 ● Apraclonidine, a weak
to 60 minutes (CASE 1-1). The benefits of apraclonidine over cocaine, other than α-2 agonist, has largely
supplanted cocaine and
its accessibility, include the fact that it is much easier to discern reversal of hydroxyamphetamine in
anisocoria than an exacerbation of anisocoria (the latter of which may require confirmation of sympathetic
careful measurements) and that the ptosis that typically accompanies miosis in denervation of the pupil.
Horner syndrome generally also responds to apraclonidine. The benefits of Denervation supersensitivity
may take up to 1 week to
cocaine over apraclonidine are that cocaine can be used immediately after the occur; apraclonidine testing
pupil becomes miotic and that it may be used in infants, in whom apraclonidine will not detect acute
may cause respiratory depression (its use in infants is strictly contraindicated; sympathetic denervation of
consultation with a pediatric ophthalmologist or neuro-ophthalmologist should the pupil. Apraclonidine
cannot be used in young
be sought before instillation of drops in children).
children because of the
Not all pathologically miotic pupils result from sympathetic denervation. The possibility of respiratory
main exception is the tonic pupil when it has been present chronically. As depression.
described above, tonic pupils are large and irregular at the outset. However,
within months to years, a tonic pupil may evolve into a miotic pupil. This ● Tonic pupils, which are
mydriatic at the outset, may
presumably reflects a reinnervation phenomenon. It is important to note that the eventually become miotic
light-near dissociation of the tonic pupil persists even after the pupil has and irregular.
progressed from abnormally large to abnormally small.

EPISODIC ANISOCORIA. Episodic anisocoria is an uncommon phenomenon with a

relatively short differential diagnosis:

u Benign episodic anisocoria

u Iatrogenic (eg, manual contamination with scopolamine patch, datura plant)
u Seizure
u Intermittent increase in sympathetic tone in patient with previously unnoticed unilateral
Horner syndrome
u Primary headache syndromes with intermittent Horner syndrome (eg, migraine, trigeminal
autonomic cephalalgias)

The syndrome of intermittent mydriasis with cholinergic supersensitivity has

been described and mainly occurs in young women, many of whom have
migraines (although this is distinct from the episodic anisocoria that can occur as a
feature of migraine or trigeminal autonomic cephalalgia); interestingly, a minority
may develop a generalized ganglionopathy.18 Although transient anisocoria is a
generally benign phenomenon, it may sometimes be a clue to more serious

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THE PUPIL

processes. Transient mydriasis may be seen during and briefly after seizures.
Ictal anisocoria is poorly characterized and does not have clear localizing value.
Both pupils may dilate during seizures. Furthermore, the anisocoria of Horner
syndrome may be subtle, particularly when patients are in bright ambient
lighting (generally the only time at which nonphysicians ever make note of their
pupil size). When patients with Horner syndrome experience circumstances of
elevated sympathetic tone (eg, pain, fright), the fellow pupil may physiologically

CASE 1-1 A 52-year-old man was referred to the neuro-ophthalmology clinic for
evaluation of anisocoria detected by his optometrist during a routine
evaluation. The patient was unaware of any pupillary asymmetry and
denied any history of head or neck pain or trauma. He had no significant
past medical history, took no medications, and had quit smoking several
years before evaluation.
His examination demonstrated orbital fat atrophy with high lid creases
in both eyes, a margin-to-reflex distance 1 (MRD1) of 1.5 mm in the right
eye and 2 mm in the left eye (the lids were subsequently retracted for
photography) and a margin-to-reflex distance 2 (MRD2) of 4 mm in the
right eye and 4.5 mm in the left eye. He had normal afferent visual
function, and his pupils were 3 mm right eye/4.5 mm left eye (dark),
2.5 mm right eye/3 mm left eye (ambient light), and 2 mm right eye/
2.5 mm left eye (direct light). The ocular motor examination and general
neurologic examinations were normal.
His pupil size was measured before and after administration of 0.5%
apraclonidine. Preapraclonidine, his right pupil was smaller, a finding that
was accentuated in dim lighting (FIGURE 1-2A). Postapraclonidine, a reversal
of anisocoria in the same ambient lighting was noted, confirming the
presence of a partial Horner syndrome (FIGURE 1-2B).

COMMENT Apraclonidine is a rapid means by which a clear diagnosis of Horner

syndrome can be established, particularly in patients in whom another
cause exists for ptosis, which confounds the examination, as was the
case here (levator dehiscence with age-related orbital involutional
changes). Both the ptosis and anisocoria seen in Horner syndrome are
generally subtle. Patients with partial Horner syndrome (without the aid
of hydroxyamphetamine drops to aid in localization) should undergo MRI
from the midbrain to the upper thoracic spinal cord with and without
contrast, contrast-enhanced chest imaging to evaluate for neoplasm
and subclavian artery abnormalities, and angiography of the head and
neck. MRI of the orbits may also be useful to detect distal third-order
neuron lesions. This patient underwent magnetic resonance angiography
(MRA) of the head and neck and MRI of the brain, orbits, and cervical
spine with and without contrast, all of which were normal. The workup
for isolated, incidentally discovered, painless cases of Horner syndrome
is often unrevealing but must be undertaken nevertheless given the
potentially serious etiologies.

1204 OCTOBER 2019

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dilate; the patient may only notice anisocoria under these circumstances, incorrectly
identifying the normal mydriatic eye as the abnormality. As such, patients reporting
episodic anisocoria must be closely inspected for a Horner syndrome. Patients
should also be questioned as to unintentional exposure to anticholinergics; patients
may scratch a scopolamine patch worn for nausea or touch plants that produce
anticholinergic compounds (eg, datura) and then touch the eye, causing
intermittent anisocoria. Some over-the-counter eye drops contain pheniramine, an

FIGURE 1-2
Testing for Horner syndrome in the patient in CASE 1-1 showing the pupils before apraclonidine
(A) and 1 hour after the administration of one drop of 0.5% apraclonidine in each eye (B).

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THE PUPIL

anticholinergic that causes mydriasis, which can occasionally be asymmetric.

Aerosolized ipratropium, used for asthma, may cause dilation in one eye if the face
mask is ill fitting. Rarely, episodic sectoral spasm of the iris results in “tadpole”
pupils, which can herald an incipient Horner pupil.19

Bilaterally Small Pupils

Bilaterally small pupils may result from bilateral sympathetic denervation of the
pupillary dilator (as described earlier in the article), from factors causing
predominance of parasympathetic tone over sympathetic tone, or from chronic
reinnervation:

u Parasympathetic excess
◇ Sedating medications
◇ Cholinergic agonists (eg, pilocarpine)
u Sympatholysis
◇ Diencephalic lesions
◇ Pontine tegmentum lesions
◇ Bilateral peripheral Horner syndrome
u Chronic ganglionopathies
◇ Argyll Robertson pupils
◇ Chronic tonic pupils

Structural lesions may cause sympatholysis and bilaterally small pupils. The
most pronounced example is seen in cases of pontine tegmental damage, which
may not only cause deafferentation of the ciliospinal nucleus of Budge from
the hypothalamus (thus causing bilateral central Horner syndrome) but also
disruption of ascending afferent algesic stimuli that serve as drivers of
pupillodilation under normal circumstances. Thus, pontine tegmental damage can
cause pinpoint pupils in excess of what is seen in second- or third-order neuron
Horner syndromes. Diencephalic lesions may produce pupils that are small but
generally not to the extent seen with bilateral pontine tegmental damage.
Stimulation of the parasympathetic nervous system resulting in bilaterally
small pupils is often pharmacologic. The most common nonstructural causes of
bilaterally small pupils are medications and drugs of abuse belonging to the
opiate and barbiturate class, but any sedating medication can cause bilateral
miosis. Under circumstances of fatigue or sedation (wherein parasympathetic
tone predominates), the pupils become miotic (the Westphal-Piltz
phenomenon), even in dim conditions when one might expect the pupils to
dilate because of lack of input to the pupillary light response.
Chronic reinnervation may similarly cause bilaterally miotic pupils. The
most common scenario causing reinnervation is that of the ciliary
ganglionopathy in the chronic stage, yielding the chronic tonic pupil. Tonic
pupils are mydriatic in the acute and subacute setting. After several months to
years, however, tonic pupils generally become miotic while retaining their
features of light-near dissociation and irregularity with sectoral hypokinesis.
The exact mechanism by which the tonic pupil develops is not certain, but it is
clear that reinnervation can cause such changes because miosis has been seen
as a form of aberrant regeneration following third nerve palsies. Syphilis may
be another cause of ciliary ganglionopathy. The localization of the Argyll

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Robertson pupil (the eponym used to describe the small, irregular pupils KEY POINTS
exhibiting light-near dissociation that are seen in syphilis) has been a
● Bilaterally small pupils
long-standing subject of debate.20 Owing to the lack of sectoral hypokinesis in may result from bilateral
some reports (which would be expected to be seen in ciliary ganglion sympathetic denervation
damage), it has been hypothesized that syphilitic involvement of the dorsal of the pupillary dilator,
midbrain might account for the Argyll Robertson pupil. However, debate from factors causing
predominance of
continues as to whether the Argyll Robertson pupil localizes to the dorsal
parasympathetic tone over
midbrain or the ciliary ganglion.20 Pathologic evidence of syphilis sympathetic tone, or from
involvement in the dorsal midbrain is lacking; it is known that syphilis affects chronic reinnervation as
other ganglia (ie, the dorsal root ganglia), and neither small nor irregular seen with bilateral tonic
pupils.
pupils are classically seen in dorsal midbrain syndromes (which yield
midsized pupils). As such, identification of small irregular pupils with ● Bilaterally small irregular
light-near dissociation in both eyes should prompt the neurologist to consider pupils should prompt
both chronic idiopathic tonic pupils and Argyll Robertson pupils. consideration of chronic
tonic pupils and Argyll
Bilaterally Large Pupils Robertson pupils.
Treponemal syphilis
Bilaterally large pupils are seen when sympathetic input to the iris exceeds serologies should be
parasympathetic input. This is either through exaggerated sympathetic ordered.
stimulation of the pupillary dilator or decreased parasympathetic stimulation of
the pupillary sphincter:
u Increased sympathetic innervation of the pupillary dilator (eg, cocaine)
u Decreased parasympathetic innervation of the pupillary sphincter
◇ Loss of supranuclear input to both Edinger-Westphal nuclei
→ Severe bilateral blindness
◇ Defects of the final common pathway
→ Edinger-Westphal nucleus
→ Third nerve palsies
→ Ciliary ganglion (tonic pupils, 10% are bilateral)
→ Neuromuscular junction (anticholinergics, botulinum toxin)
→ Iris injury

Factors promoting excess sympathetic stimulation of the pupillary dilator,

such as drugs (either iatrogenic [such as phenylephrine and tricyclic
antidepressants] or recreational [such as cocaine]), may be the cause.
Physiologically large pupils (eg, from anxiety) are rarely prominent enough to
prompt medical attention. Decreased parasympathetic signaling to the pupil may
be a result of defective supranuclear input to the Edinger-Westphal nucleus or to
damage to the final common pathway itself. Commonly encountered
supranuclear defects resulting in large pupils include severe bilateral optic
neuropathy that prevents light signals from reaching the olivary pretectal
nucleus and tectal lesions disrupting the connection between the olivary
pretectal nucleus and the Edinger-Westphal nucleus. Commonly encountered
defects of the final common pathway (Edinger-Westphal nucleus/ciliary
ganglion/iris) include lesions affecting the third nerve, ciliary ganglionopathies
(the acute tonic pupil, Miller Fisher syndrome, diabetes mellitus), disorders of
the neuromuscular junction (mainly botulism, which prevents acetylcholine
release from the ciliary ganglion neuron, and never myasthenia gravis), and
iatrogenic anticholinergics (such as tropicamide drops used for dilation,

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THE PUPIL

scopolamine contamination from antiemetic patches, or ipratropium blown into

the eye rather than airways) (CASE 1-2).
If the cause of large pupils is not ascertainable after checking the response
to light and the response to near, testing acuity, carefully assessing the
ocular motor examination (both for defects of supranuclear and final common
pathway function), and examining the iris in as much detail as possible for
sphincter rupture or surgical trauma, drops can be used to aid in localization.
The use of pilocarpine, both full strength and dilute, is discussed in the
section on anisocoria; this can just as easily be employed when both pupils are
large and do not react well to either light or near stimuli. Dilute pilocarpine
(0.125%) can be used to determine if the pupil is parasympathetically
denervated; this is most commonly seen in tonic pupils, which are bilateral

CASE 1-2 A 24-year-old man was referred to the neuro-ophthalmology clinic

for evaluation of photophobia. He reported sensitivity to bright light
requiring the aid of sunglasses for approximately 6 weeks. He denied
any eye pain under conditions of dim light, changes in his vision,
accompanying neurologic deficits, recent head or orbital trauma, or
symptoms suggestive of rheumatologic disease. He had no significant
past medical history.
Examination demonstrated normal visual acuity and color vision. The
pupils were large: 8 mm in both eyes in dim light, 7.5 mm in both eyes in
ambient light (FIGURE 1-3A), and reacted only to 6.5 mm in both eyes with
bright direct light (FIGURES 1-3B and 1-3C). The pupils constricted to 3 mm
when he was asked to follow a target as it approached the bridge of his
nose (FIGURE 1-3D). The slit-lamp examination demonstrated sectoral
hypokinesis of the iris in both eyes. No anterior chamber or vitreous cells
were seen. There was no ptosis or limitation of ductions. His general
neurologic examination was normal.

COMMENT The presence of bilaterally large pupils that react poorly to light but briskly
to the near reflex implicates an abnormality of the afferent or efferent limb
of the pupillary light reflex. This patient’s excellent acuity implicates the
efferent limb. The absence of any ocular motor abnormalities or ptosis
exonerates the third nerves, and the presence of sectoral hypokinesis
confirms bilateral tonic pupils as the diagnosis. Hemoglobin A1c was normal
and fluorescent treponemal antibody absorption (FTA-ABS) was
nonreactive. This patient’s idiopathic tonic pupils remained stable and
isolated at follow-up.
When in doubt as to the diagnosis of a tonic pupil, dilute pilocarpine
(0.125%) can be employed to test for denervation of large pupils consistent
with tonic pupils, bearing in mind that, rarely, constriction may occur in the
setting of third nerve palsies. Dilute pilocarpine may similarly aid in the
treatment of patients who are photophobic from their large pupils. Full-
strength pilocarpine should not generally be used as this may cause ocular
pain and, in rare cases, retinal detachment.

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in approximately 10% of cases. Pilocarpine 1% to 2% should constrict
all mydriatic pupils except in cases due to iatrogenesis (eg, tropicamide
or scopolamine).

Irregularly Shaped Pupils

Evaluation of pupillary shape can be difficult without high magnification,
making a slit-lamp examination optimal in characterizing and diagnosing
abnormally shaped pupils. Many neurologists encounter these scenarios, and an
overview of the possible causes may aid in knowing which questions to ask the
patient and when to seek the consultation of an ophthalmologist. Abnormally
shaped pupils can be due to congenital and acquired causes.

FIGURE 1-3
Light-near dissociation in the patient in CASE 10-2. A, Pupil size in normal ambient lighting. B, C,
Pupils show a lack of constriction to light. D, Pupillary constriction to fixation on a near target
is preserved.

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THE PUPIL

CONGENITAL. The most common congenital abnormalities of pupil shape a

neurologist will encounter include coloboma, aniridia, and corectopia. A
confident diagnosis of congenital abnormality of the iris is best made by an
ophthalmologist because of the need for a slit-lamp examination.
Colobomas are focal areas of excavation of the iris. These are the result of
defective iris closure during its formation. Other structures may be similarly
affected, including the optic nerve. Colobomas may be sporadic or syndromic,
most notably in association with CHARGE syndrome (coloboma of the eye, heart
defects, atresia of the choanae, renal abnormalities and retardation of growth

CASE 1-3 A 46-year-old woman was referred to the neuro-ophthalmology clinic for
evaluation of irregular pupils by her optometrist, who followed her for
refractive error. She was a developmentally normal adult and was
unaware of any pupillary abnormalities; because of dark irides, it was
difficult to ascertain from old photographs whether this was long-
standing. She denied any history of eye surgery, ocular trauma, uveitis,
iritis, or accompanying neurologic symptoms. Her past medical history
was notable only for a history of systemic hypertension. She did not use
any eye drops.
Her afferent examination revealed normal visual acuities and color
vision in both eyes. The pupillary examination demonstrated slightly
irregular pupils bilaterally that measured 4 mm in both eyes in dim light
and 3.75 mm in both eyes in ambient light, 3.5 mm in both eyes to
direct light stimulation, and 2 mm in both eyes when tracking a target
approaching the bridge of her nose (FIGURE 1-4). The slit-lamp examination
demonstrated mild sectoral hypokinesis in both eyes, with no evidence
of synechiae or intraocular inflammation. The eyelids were normally
positioned (margin-to-reflex distance 1 was 4 mm in both eyes), and her
ocular motor examination was normal. The remainder of the general
neurologic examination was normal.

COMMENT This developmentally normal adult without ocular trauma or inflammation

referred for evaluation of abnormally shaped pupils was found to have
midsized irregular pupils with light-near dissociation in both eyes. This
constellation, particularly in the setting of an otherwise normal neurologic
examination, is suggestive of either bilateral tonic pupils or Argyll
Robertson pupils. Because Argyll Robertson pupils are seen in tertiary
syphilis and titers of nontreponemal tests (ie, Venereal Disease Research
Laboratory, rapid plasma reagin [RPR]) may decrease over time even in
patients who are not treated, treponemal testing (ie, fluorescent
treponemal antibody absorption [FTA-ABS] or Treponema pallidum particle
agglutination assay [TPPA]), which does not normalize even in late syphilis,
is mandatory. This patient’s treponemal and nontreponemal syphilis
serologies were negative, and a diagnosis of bilateral chronic tonic pupils
was made. The patients in CASE 1-2 and CASE 1-3 also illustrate the evolution in
pupil size over time as acute tonic pupils become chronic.

1210 OCTOBER 2019

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and/or development, genital abnormalities, and ear abnormalities), which
arises from mutations in the CHD7 gene and is frequently encountered as a
new mutation.21
Patients with aniridia have hypoplastic irides resulting in a correspondingly
large pupil, caused by a mutation in the transcription factor PAX6. Frequently,
the iris is not the only defective structure, as the PAX6 gene acts as a transcription
factor for other structures as well (eg, cataracts and glaucoma frequently
accompany the condition).22 Two-thirds of cases are inherited in an autosomal
dominant manner.

FIGURE 1-4
Pupil irregularity in the patient in CASE 1-3. A, The
pupil in normal ambient lighting. B, The pupil has
an abnormal shape and shows lack of response to
light. C, The pupil shows brisk reaction to fixation
on a target at near.

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THE PUPIL

Corectopia is an off-center pupil (beyond its slightly nasal position in the iris
that is often found in normal subjects) that may be congenital or acquired. When
congenital, corectopia is often present as a component of Axenfeld-Rieger
syndrome, which frequently involves pediatric glaucoma and hypertelorism and
is autosomal dominant. About 40% of patients have abnormalities in either the
PITX2 or FOXC1 genes.23

ACQUIRED. Trauma, surgical or accidental, is a common cause of acquired

pupillary irregularity. It is important to recall that disruption of the pupillary
sphincter at one location does not render the entire muscle unable to function.
Inflammation of the iris (iritis) may result in adhesions of the lens to iris called
posterior synechiae, in which this physical tethering may cause a misshapen
pupil. Tonic pupils and Argyll Robertson pupils tend to be irregular as well,
although sometimes appreciation of this feature requires the aid of the slit
lamp (CASE 1-3). The exact mechanism by which this occurs is not clear, but it
may reflect chronic reinnervation after ciliary ganglion injury. As mentioned,
not all cases of corectopia are congenital. Brainstem pathology may cause
corectopic pupils as well.

Pupils Exhibiting Light-Near Dissociation

Pupils that react poorly in response to the light reflex but well in response
to the near reflex (ie, light-near dissociation) are frequently encountered.
The converse, in which the pupil’s reaction to light is pristine but miosis
with a near pursuit target is impaired, is not expected. This is likely because
of two facts. First, more fibers mediate the near triad than the pupillary
light reflex, so the system is inherently less susceptible to damage. Second,
the anatomy of the pupillary light reflex’s reflex arc places it in more danger of
sustaining structural damage than that of the near triad’s supranuclear
components. Presumably patients with damage to the supranuclear circuits
mediating the near triad would be too neurologically devastated to be tested.
Light-near dissociation has three common localizations: the dorsal midbrain,
the ciliary ganglion, and the optic nerve:

u Dorsal midbrain syndrome

u Ciliary ganglionopathy
◇ Tonic pupil (in isolation or with hyporeflexia [Adie pupil])
◇ Syphilis (Argyll Robertson pupils)
◇ Diabetes mellitus
u Amaurotic pupil

In the dorsal midbrain, the majority of axons traveling from each pretectal
olivary nucleus, which decussate through the posterior commissure to synapse
on the Edinger-Westphal nuclei, are prone to mechanical injury as they are
superficially positioned. In addition to midsized pupils that react poorly to light
but briskly to near stimuli (as the pathways mediating the near triad lie more
anteriorly in the midbrain), the dorsal midbrain syndrome includes retraction
of the upper eyelids, supranuclear vertical gaze palsy (as the third nerve
nucleus is classically unaffected), and convergence-retraction movements in
attempted upgaze.

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 The second localization of light-near dissociation is at the ciliary ganglion. KEY POINTS
Because of the disproportionately low number of cell bodies dedicated to
● When in doubt as to the
mediating pupillary constriction associated with the pupillary light reflex (as etiology of an irregularly
opposed to the high proportion mediating constriction as part of the near shaped pupil, enlist the aid
response), ganglionopathies often present with light-near dissociation. As of an ophthalmologist who
described earlier, tonic pupils and Argyll Robertson pupils are the most can employ a slit lamp to
look for important anatomic
common examples.
details and signs of
The third localization of light-near dissociation is at the optic nerve. A severe inflammation that are
optic neuropathy causes a sluggish reaction to light or, in severe cases in which difficult to observe with the
the eye is unable to perceive light at all, no reaction to light shined ipsilaterally naked eye.
(this is referred to as an amaurotic pupil). It should be noted that if light is shined
● The most common
into the unaffected fellow eye, the pupil of the eye with low vision should still congenital causes of
have a normal consensual response (the defect is afferent, not efferent). irregular pupils include
Similarly, pursuit of an approaching target that triggers the near response should coloboma, aniridia, and
cause pupillary constriction, even in an amaurotic pupil. It is reported that pupillary decentration,
referred to as corectopia.
patients with no light perception vision in both eyes can still trigger the near
response via proprioceptive cues (eg, “looking” at one’s own thumb). ● When evaluating irregular
pupils, consider trauma,
inflammation with synechiae
formation, tonic pupils, and
CONCLUSION
Argyll Robertson pupils.
Familiarity with the pupil’s function in health and disease is essential for every
neurologist. This knowledge enhances the bedside examination, prompts the ● Light-near dissociation
correct diagnostic tests, and aids in the rapid and accurate diagnosis of many typically localizes to the
neurologic disorders. ciliary ganglion, dorsal
midbrain, or bilateral
optic nerves.

ACKNOWLEDGMENT
The author would like to thank Nurhan Torun, MD, FRCS(C) for her critical
appraisal of this manuscript. The author has had the great luck to draw upon
Dr Torun’s expertise endlessly, and he remains her pupil.

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