KEY POINT

Transient
anisocoria,
if recurrent,
in a patient
with a normal
examination is
most often
benign.

ANISOCORIA
Aki Kawasaki

ABSTRACT
Pupillary size and movement are controlled by the autonomic nervous system,
which innervates two muscles of the iris, the radial dilator (sympathetically innervated), and the circular sphincter (parasympathetically innervated). In the normal
state, the distribution of efferent pupillomotor signal to the iris is symmetric between the two eyes so that pupil size is generally equal under varying lighting
conditions. Similarly, reflex pupillary movements, eg, constriction and dilation, are
identical between the two eyes. Asymmetry in the pupillomotor neural output or
their muscular forces results in impaired pupillary movement on one side and
unequal pupil size between the right and left eyes. This chapter reviews the
evaluation of anisocoria, both transient and persistent, in assuming that only one
side (pupil) is faulty and focuses on the neurologic causes of pupillary dysfunction.
Continuum Lifelong Learning Neurol 2009;15(4):218235.

218

TRANSIENT ANISOCORIA
Transient unilateral mydriasis is a clinical sign that often raises the anxiety
level of the consulting clinician because a dilated pupil may herald the
presence of a potentially devastating
neurologic condition. While this statement is true, benign explanations also
exist. In sorting out the different causes
of transient mydriasis, the patients background medical history, mental status,
and ocular motility findings can rapidly
assert whether the situation at hand is
an emergency. The emergency diagnoses to consider and their circumstances
are described in this chapter.
Brain Herniation
In a patient with an intracranial mass
lesion or acute expanding pathology,
such as edema or hemorrhage, unilateral pupillary dilation may indicate
impending transtentorial herniation. In
such a setting, the patient usually has
declining consciousness and develop-

ing focal neurologic deficits, including

ophthalmoplegia. In an awake, alert,
and neurologically intact patient who
reports transient mydriasis, brain herniation is not a tenable consideration.
Seizure
Seizure-related mydriasis is associated
with an abrupt change in mental status
as well as involuntary contraversive
head or eye movements. It is an extremely rare occurrence.
Cerebral Aneurysm
Because of their peripheral location
within the interpeduncular portion of
the oculomotor nerve, the pupil fibers are particularly prone to dysfunction from compressive lesions. A dilated
poorly reactive pupil may be an early
sign of a symptomatic intracranial aneurysm, but the pupillary dysfunction
is not a transient abnormality and,
moreover, is nearly always accompanied by eyelid or eye muscle weakness.

Relationship Disclosure: Dr Kawasaki has received personal compensation for activities with Bayer S.p.A.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Kawasaki discusses the unlabeled use of topical
pilocarpine, topical cocaine, and topical apraclonidine in the clinical evaluation of anisocoria.

Copyright # 2009, American Academy of Neurology. All rights reserved.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Thus, in the absence of other neurologic deficits, a transient or episodic

dilation of one pupil that recovers
completely between episodes is not
due to an aneurysm.
Assuming that the patient who has
experienced transient anisocoria is
alert and without focal neurologic deficits at the time of examination, a
detailed descriptive account of accompanying symptoms or signs, such as
visual blur, pain, ptosis, impaired eye
movement, and conjunctival injection,
is the first step, and often the only clue,
to determining the mechanism of the
transient anisocoria. In an ideal world,
patients would have had the presence
of mind to observe (or even photograph) their anisocoria in ambient
room light and again with a flashlight
shining on the eyes. This provides
information regarding the responsiveness of the pupils to light stimulation.
An anisocoria that is notable when extra light is added, eg, flashlight or
sunlight, suggests that the mydriatic
pupil is the abnormal one, since it fails
to constrict as well as the contralateral
pupil. Conversely, if the patient notices
anisocoria mostly in dim lighting conditions, then the smaller pupil likely
has a dilating problem and marks the
abnormal side. What then are possible
causes of a transient anisocoria in an
otherwise well patient?
Physiologic Anisocoria
Physiologic anisocoria is presumed to
occur from small and fluctuating differences in the supranuclear modulating
input to the paired parasympathetic
Edinger-Westphal nuclei. Most patients
with physiologic anisocoria demonstrate persistent anisocoria, but the
degree of pupillary inequality can fluctuate from day to day and at times is
so minimal as to go undetected by direct observation. In occasional patients,
physiologic anisocoria is truly an episodic phenomenon, and, more rarely,

it may even alternate sides, ie, the

side of the larger pupil switches. Further discussion of physiologic anisocoria is found in the section Anisocoria
Greater in Dim Light.
Intermittent Subacute
Angle-Closure Glaucoma
Angle-closure glaucoma may be a primary disorder caused by a structurally
narrow anterior chamber angle or a
secondary condition resulting from inflammation, trauma, or ischemia. When
the anterior chamber angle closes, the
normal outflow of aqueous humor is
acutely blocked, and intraocular pressure increases rapidly. Conjunctival injection and corneal edema develop
because of hypoxia and secondary corneal decompensation, producing visual blur and haloes. The patient may
notice that the affected eye is red and
tender to touch. The pupil is mildly
dilated and fixed. Factors that may precipitate angle closure include assuming
a prone position, dark or dim lighting,
prolonged near work, stress, sneezing, pharmacologic mydriasis, and certain anesthetic agents. Patients, as in
Case 15-1, can have repeated selflimited episodes of subacute angle
closure before a full-blown attack.
In subacute cases, the angle reopens
spontaneously and symptoms and signs
resolve. An ophthalmic examination is
required to visualize the narrow angle
that is predisposed to closure. Failure
to recognize this cause of intermittent mydriasis can lead to persistent visual loss.

KEY POINTS

Cerebral
aneurysm is
not a cause of
isolated,
transient,
unilateral
mydriasis.
Determining
whether
anisocoria is more
notable in bright
light or in dim
light helps to
identify the
abnormal pupil.
Signs and
symptoms of
angle-closure
glaucoma include
acute headache
and unilateral
mydriasis, which
can resemble
serious
intracranial
pathology.
Corneal edema,
conjunctival
injection, and
normal ocular
motility help
distinguish angle
closure from
oculomotor
nerve palsy.

Paroxysmal Discharge
of Irritated Cervical
Sympathetic Nerves
This phenomenon is a rare cause of
episodic unilateral mydriasis described
in occasional patients with injury to
the cervical spine, upper cord, and
brachial plexus. Typically, other signs
Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

219

" ANISOCORIA

KEY POINT

220

Disorders of the
cervical spine
and cord can
cause transient
mydriasis
and other
intermittent
symptoms related
to paroxysms
of excessive
sympathetic
discharge.

Case 15-1
A 62-year-old retired teacher was referred for recurrent episodes of
headache, visual blur, and mydriasis on the right side. She described
the headache as a dull pain around the right eye, which frequently
appeared at night; the visual disturbance was a fuzziness with haloes
around lights. Symptoms always resolved by the following morning,
and between episodes she felt fine and noticed no visual or pupillary
abnormalities. At the insistence of her husband, the patient sought
medical advice. Her general and neurologic examinations were normal.
Neuroimaging was normal. A tentative diagnosis of subacute angle-closure
glaucoma was made, and following referral to an ophthalmologist, the
diagnosis was confirmed.
Comment. Subacute angle-closure glaucoma causes unilateral eye,
face, or head pain accompanied by blurred vision, typically lasting 30 to
60 minutes. During an attack, the affected eye often becomes red as a
result of conjunctival injection, leading to confusion with cluster headache.
The pupil is poorly reactive, and some patients notice the resulting
anisocoria. The specific historical clues to this ocular diagnosis are the link
to low light (night occurrence with resultant pupil dilation) and seeing
halos (suggesting corneal edema) in the painful eye with mydriasis.

of sympathetic hyperactivity, notably

eyelid retraction, conjunctival blanching, and facial hyperhidrosis, are present in addition to pupillary dilation.
Visual blur is not a common feature.
The pupil light reflex is normal, indicating intact oculo-parasympathetic
function. Some patients later develop
a permanent oculosympathetic deficit
(ie, Horner syndrome) on the same
side, presumably related to progressive
damage to the nerves.
Tadpole-shaped pupil is a related
entity. Episodes of pupillary distortion
with peaking on one side results from
focal spasm of the iris dilator muscle and
represents a benign entity (Thompson
et al, 1983).
Toxic Exposure
A dilated pupil can result from inadvertent contact with plants containing
belladonna alkaloids, such as jimsonweed (thornapple), angels trumpet,
deadly nightshade, and black henbane.
These plants are cultivated as ornamental shrubs, used as medicinal herbs, or
found growing wild along roadsides

and in fields, eg, cornpickers mydriasis.

The degree of pupil dilation and loss of
reactivity to light varies, depending on
the amount of plant alkaloid exposure.
Accommodative paresis accompanies
the mydriasis so the diminished near
vision in one eye is a very helpful finding in young patients. In all cases, the
mydriasis resolves in 1 to 7 days. Additional discussion of pharmacologic
causes of anisocoria is found in the
Pharmacologic Mydriasis and Pharmacologic Miosis section.
Migraine Attack
Anisocoria during a migraine attack is
a well-described association, but the
mechanism is not fully established and
may vary between patients or be multifactorial. In some patients, migrainous
vasospasm causing local and reversible
ischemia of the ciliary ganglion leads to a
dilated, poorly reactive pupil and accommodative palsy. In others, sympathetic dysregulation, occurring either as
increased or decreased activity, which
may be unilateral or bilateral and asymmetric, has been described (Demarinis

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

et al, 1998). It has also been suggested

that some cases of anisocoria during
migraine simply represent an exaggeration of an underlying physiologic
anisocoria.
Benign Episodic Mydriasis
Also called a springing pupil, benign
episodic mydriasis is a descriptive term
for recurrent episodes of isolated unilateral mydriasis occurring in young adults,
usually migrainous women (Case 15-2)
(Jacobson 1995, Woods et al, 1984). The
mydriasis typically appears in the same
eye but can alternate sides and may occur
either during a migraine or independent
of headache. The duration of mydriasis
is usually several hours, but it may persist for days. When examined during an
episode, some patients have a normal
pupil light reflex, whereas others show a
poor reaction to light with impaired accommodation. Some patients note visual
blur, and others have orbital pain or a red
eye. Benign episodic mydriasis probably
represents a heterogeneous group of disorders, including migraine-associated anisocoria and physiologic anisocoria, with
different mechanisms that result in transient and episodic anisocoria. It is called

benign because it is not associated with

any systemic or neurologic condition.
ANISOCORIA GREATER IN
BRIGHT LIGHT
When observing the pupils in a patient
seated quietly in room light, small spontaneous oscillations of the pupil are
sometimes noted. This phenomenon,
known as hippus, is a normal finding.
The baseline pupil size in room light is
greatest (7.0 mm to 7.5 mm) during the
teenage years and then gradually decreases with increasing age. Asymmetry of pupil size measuring 0.4 mm
or more is visible to the unaided eye
and is considered anisocoria. If anisocoria is present, the first step is to check
the pupil light reflex of each eye. Dim
the room light and ask the patient to
fixate a distant target. This prevents any
unwanted pupillary constriction related
to accommodation, ie, the near reflex
consisting of miosis, convergence, and
accommodation (lens thickening to facilitate near focus). Shine a bright focal
light (a disposable commercial penlight
is usually not bright enough) directly
onto one pupil for 3 seconds and note
the amplitude and velocity of the pupil

KEY POINT

Benign episodic
mydriasis is a
diagnosis of
exclusion based
on a clinical
description and
a normal
examination
between
episodes.

Case 15-2
A 21-year-old woman recently developed severe and recurring headaches.
A friend pointed out that her pupils were not the same size. When
the patient examined herself in a mirror later that same day, her pupils
appeared isocoric. One week later, the patient noticed that her right
pupil was much larger than her left pupil. Fearing a brain tumor, she
sought urgent medical consultation. Examination revealed no anisocoria;
specifically, her pupils measured 2.5 mm in bright light and 7.0 mm in
darkness, with a brisk pupillary light reflex in each eye. Vision, eyelid
function, and ocular motility were normal. A diagnosis of springing
pupil and tension-type headaches was made.
Comment. Springing pupil, also known as benign episodic mydriasis,
is a diagnosis of exclusion in the patient with transient anisocoria
who has no systemic or neurologic condition known to affect pupils
and who demonstrates no abnormalities on ophthalmic and neurologic
examination.

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

221

" ANISOCORIA

KEY POINTS

222

In the evaluation
of anisocoria,
remember to
inquire about
any previous
infection,
inflammation,
trauma, or
surgery involving
the eyes,
including laser
procedures.
Look for
irregularity of the
pupillary margin,
distortion of
pupillary shape,
or difference in
iris color as these
suggest a
mechanical
(non-neurologic)
cause of
anisocoria.

Example of a patient who has an anisocoria

that is more notable in bright light. A,
The patient is seated in a dark room,
and the pupils are viewed with tangential illumination. The
pupils are dilated and slightly unequal in size. B, The room
light is turned on, and extra illumination with a bright
flashlight is added. The patients anisocoria is much more
obvious now and the left pupil likely the faulty one as it
is not constricting well.

FIGURE 15-1

constriction of the illuminated eye. If

one pupil reacts less vigorously and/or
with less amplitude to both direct and
consensual light stimulation, this is the
faulty pupil. When pupilloconstriction is
subnormal in one eye, the magnitude
of anisocoria is obviously greater under bright light compared to dim light,
and the larger pupil is clearly the abnormal one (Figure 15-1). In general,
the causes of a large poorly reactive pupil can be distilled down to mechanical
anisocoria, oculomotor nerve palsy, tonic
pupil, and pharmacologic mydriasis
(Table 15-1). These are discussed in
the following paragraphs.
Mechanical Anisocoria
The term mechanical anisocoria is used
when impaired pupil movement results from defects in the iris framework,
in particular, damage to iris sphincter
muscle. The sphincter cannot constrict
normally and does not respond normally

TABLE 15-1

"

Causes of
Anisocoria
Greater in Bright
Light

Mechanical Anisocoria
Ocular trauma
(eg, sphincter tear)
Iridectomy
Angle-closure glaucoma
Iris tumor or mass

"

Neurologic Anisocoria
Oculomotor nerve palsy
Postganglionic
parasympathetic nerve
palsy (eg, tonic pupil)

"

Pharmacologic Anisocoria
Topical anticholinergics
Topical sympathomimetics
Aerosolized bronchodilators

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

to topical pharmacologic agents. In

severe cases of sphincter damage, the
pupil may be widely mydriatic and light
fixed and near fixed. Ocular conditions
that can lead to structural iris defects
are trauma, infection, intraocular surgery, inflammation (prior uveitis), laser
treatment, angle-closure glaucoma, and
pseudoexfoliation. A thorough history
and, if possible, slit-lamp examination
is adequate for identifying most causes
of mechanical anisocoria. Clues that iris
damage is the cause of anisocoria include
distortion of the pupillary shape, iris
transillumination defects, synechiae, intraocular inflammation, and pigment dispersion (Figure 15-2).
Neurologic Anisocoria
The neurologic basis for a large, poorly
reactive pupil is interruption within the
oculo-parasympathetic pathway, which
mediates pupillary constriction and lens
accommodation. This is a two-neuron
pathway (Figure 15-3). The first, or
preganglionic, neuron originates in the
Edinger-Westphal subnuclei of the oc-

FIGURE 15-3

Schematic illustration of the two-neuron

oculo-parasympathetic pathway.

Reprinted with permission from Kashii S, ed. Clinical neuro-ophthalmology.

Tokyo: Kanehara and Co., Ltd, 2007:130.

ulomotor nuclear complex in the dorsal midbrain. Parasympathetic axons join

the motor axons to form the oculomotor nerve, which exits the ventral aspect
of the midbrain. Passing through the
anterior cavernous sinus into the orbit, the preganglionic parasympathetic
fibers synapse in the ciliary ganglion
in the orbit. The ciliary ganglion is the
site of the second, or postganglionic,

223

FIGURE 15-2

Example of a mechanically deformed and

dilated pupil due to metastatic melanoma
to the iris.

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

" ANISOCORIA

KEY POINT

A subtle
oculomotor nerve
palsy might
appear as isolated
anisocoria, but
careful
examination
almost always
reveals
accompanying
motor deficits.

neuron. Postganglionic parasympathetic

fibers are carried in the short ciliary
nerves, which pierce the back of the
globe and travel anteriorly in the sclera
to reach the iris sphincter and the ciliary muscle. The neurotransmitter at the
postganglionic synapse is acetylcholine.
Oculomotor nerve palsy. The preganglionic oculo-parasympathetic fibers
run peripherally alongside their confrere ocular motor fibers within the

oculomotor nerve. Injury to the oculomotor nerve that damages the pupil
fibers will almost always involve one or
more of the motor fibers as well. Only
with very rare exception is an isolated
pupil abnormality the sole manifestation of an oculomotor nerve palsy.
Thus, in a patient with a large, poorly
reactive pupil, it is important to ask about
diplopia and look very closely for eyelid
and motility deficits (Bartleson et al, 1986)

Case 15-3

224

A 38-year-old healthy accountant had developed a severe, unremitting,

left temporal headache that often kept him awake at night. Within
1 week, he noted vertical diplopia especially when reading. His
examination showed normal vision, eyelids, and orbits. Sensory function
was intact. He had a mild anisocoria and the pupil light reflex on the
left side was mildly sluggish. Ocular ductions and versions were full, but
in downgaze, the patient reported diplopia. Cross-cover testing revealed
a small left hypertropia in downgaze.
Comment. This
patient has an
acute, painful,
partial oculomotor
nerve palsy
with pupillary
involvement on
the left side
(Figure 15-4). The
only finding to
indicate that he
does not have an
isolated anisocoria
is a small ocular
misalignment
in downgaze.
Following
hospitalization
and appropriate
investigations, a
diagnosis of TolosaHunt syndrome
(idiopathic
FIGURE 15-4 Patient with an acute painful left
inflammation of
oculomotor nerve palsy with pupillary
the cavernous
involvement. A, The eyes are aligned in
primary position, the eyelids are symmetric, and a small
sinus) is made.
anisocoria is noticeable in room light. B, Ocular ductions
Treatment with oral
appear full (downgaze shown), but a small left hypertropia
steroids results in
is revealed by cross-cover testing.
complete recovery.

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

(Case 15-3). In some cases, the ocular

motor deficit is very subtle and not
evident by testing ocular ductions alone.
Cross-cover testing in all gaze positions or
formal orthoptic testing is mandatory to
reveal such subtle motility deficits. Formal
measurements of eyelid position and
levator function should be noted.
Pupillary dysfunction in the setting
of an acute oculomotor nerve palsy
raises the possibility of compressive pathology and is considered a neurologic
emergency. Diagnoses to consider include aneurysm, pituitary apoplexy, cavernous sinus inflammation, skull base
lesion, and meningeal infection, among
others (Kupersmith et al, 2006). On the
other hand, acute unilateral mydriasis
as an isolated finding represents peripheral pathology at the level of the
orbit or the eye in nearly all cases.
Tonic pupil. A tonic pupil represents a lesion in the postganglionic
parasympathetic pathway, ie, damage
to the ciliary ganglion in the orbit or
the short ciliary nerves (Figure 15-5).
In the acute stage of denervation, the
iris sphincter and ciliary muscle are
paralyzed. Patients report a dilated
pupil, photophobia, brow ache, and,
in young patients, blur at near. The
denervation injury, however, is typically
incomplete, so only the involved sectors of iris sphincter are paralyzed; this
is sometimes visible as a focal flattening of the pupil margin (Table 15-2,
Figure 15-6). Dynamic observation of
sectoral sphincter palsy requires high
magnification with a slit lamp (Kardon
et al, 1998). It is a powerful clinical
finding because, in the absence of structural iris damage, it is diagnostic of
postganglionic oculo-parasympathetic
damage and effectively rules out oculomotor nerve palsy and pharmacologic mydriasis.
Like many denervated end organs,
the iris sphincter develops a supersensitivity to cholinergic agonists within a
few weeks (earliest is 5 to 7 days) fol-

lowing injury. Dilute pilocarpine (0.125%

or less) is the most commonly used
pharmacologic agent for testing for cholinergic denervation supersensitivity of
the iris sphincter. The proposed criterion for a positive response is either (1)
the affected pupil constricts 0.5 mm
more than the unaffected pupil or (2)
the suspected pupil, which was larger
than the normal pupil before instillation of pilocarpine, becomes the smaller
pupil after instillation (Table 15-3,
Case 15-4). Despite its popular use
among clinicians, this pharmacologic
test is neither specific nor particularly
sensitive for tonic pupil. The presence
of cholinergic supersensitivity is also
found in a dilated pupil with preganglionic denervation, ie, oculomotor nerve
palsy ( Jacobson and Vierkant 1998).
The absence of cholinergic supersensitivity does not rule out tonic pupil

KEY POINT

For practical
purposes, isolated
unilateral
mydriasis is not
due to an
oculomotor
nerve palsy.

225

Site of lesion causing Adie pupil. The

ciliary ganglion and/or postganglionic
fibers are damaged. There are separate
postganglionic fibers for pupil constriction and for
accommodation.

FIGURE 15-5

Reprinted with permission from Levin LA, Arnold A, eds.

Neuro-ophthalmology: the practical guide. New York: Thieme, 2005.

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

" ANISOCORIA

KEY POINTS

226

The presence of
cholinergic
supersensitivity
is not definitive
evidence of an
Adie pupil but
must be
considered with
the other
clinical findings.
Sectoral palsy of
the iris sphincter
is the earliest
and most
specific feature
of an Adie pupil.
The clinical
features of an
Adie tonic pupil
evolve over time.
When the
pupillary light
reflex is poor,
always check the
near response. If
the near response
is better than the
light response,
then light-near
dissociation
is present.

TABLE 15-2

Time
Course
Day 1

Time Course and

Features of an
Idiopathic Tonic
(Adie) Pupil

Features
Acute unilateral
mydriasis appears
Pupil does not
constrict to light or to
near effort
Sectoral palsy of iris
sphincter is visible

Week 1

Denervation
supersensitivity
develops

Week 8

Pupil remains
unresponsive to light
Pupil shows a slow
sustained constriction
to near effort
Pupil redilation after
near constriction is
also slow

Week 16

Baseline pupil size (in

room light) decreases
Other features remain

because only about 80% of cases demonstrate this finding.

Following acute denervation, the
short ciliary nerves tend to regrow and
seek their end organs (Loewenfeld and
Thompson, 1981). During this reinnervation stage, resprouting accommodative
fibers reconnect to the ciliary muscle,
leading to improvement of near vision
with time. A relative abundance of
accommodative fibers results in aberrant
reinnervation of the iris sphincter as well.
Thus, the pupil near reflex is also
restored, but the constriction movement, as well as the redilation after a
near effort, is slow and delayed, ie, tonic.
Because the number of surviving pupilloconstrictor fibers is sparse, the pupil-

lary light reflex never improves and in

some cases gets worse. The combination
of a poor pupil light reflex with a better
pupil near response is termed lightnear dissociation.
After several months to years, the
baseline size of an idiopathic tonic pupil
begins to decrease due to tonic firing in
the accommodative fibers innervating
the sphincter. It is not unusual for a
chronic tonic pupil to be the smaller
pupil in room light and the larger pupil
in dim light because tonicity prevents it
from full constriction and full dilation. A
chronic tonic pupil still demonstrates
the classic features of a poor light
response, sectoral sphincter palsy, and
light-near dissociation.
Pharmacologic mydriasis. Topical mydriatic agents can be divided into
two categories: (1) parasympathetic
inhibitors (anticholinergic substances)
and (2) sympathomimetics. Products
containing atropinelike anticholinergic
substances include scopolamine patch,
certain insecticides, plant-based belladonna alkaloids such as Jimson weed,
and anticholinergic inhalants used to
treat respiratory disease. A pupil dilated by an anticholinergic substance,
eg, an atropinized pupil, is enormously
large, on the order of 8 mm to 9 mm,
and nonreactive to light and near stimulation. It is distinguished from an
acutely denervated pupil by the absence of sectoral palsy and unresponsiveness to full-strength (1% or 2%)
pilocarpine eyedrops. An atropinized
pupil will not constrict to full-strength
pilocarpine, whereas a neurologically
denervated pupil, such as a tonic pupil
or oculomotor nerve palsy, constricts
vigorously to full-strength pilocarpine
and, in most cases, also constricts to
dilute (0.125%) pilocarpine because of
denervation supersensitivity.
Sympathomimetics are adrenergiclike substances that cause pupillary dilation by excessively stimulating the
dilator muscle, but they do not paralyze

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

the sphincter muscle. Thus, the pupil

retains a light reflex although it has less
amplitude compared with the normal
pupil and will constrict quite well to fullstrength pilocarpine. Mydriasis from a
sympathomimetic agent can be suspected from conjunctival blanching
and eyelid retraction in the eye with
the larger pupil. Examples include epinephrine, phenylephrine, ephedrine,
hydroxyamphetamine, cocaine, ocular
decongestants, and adrenergic inhalants. Even in patients using eyedrops
in both eyes, asymmetric absorption can
lead to anisocoria.
ANISOCORIA GREATER IN
DIM LIGHT
If the pupillary light reflex is normal in
both eyes, then it can be assumed that the
oculo-parasympathetic system and iris
sphincter are intact. The next step is to
examine and compare the magnitude of
anisocoria in darkness between the two
eyes. This is easily done by turning off
the room light and holding a penlight or
handheld flashlight at the patients chin
to illuminate the eyes indirectly. Anisocoria that is greater in dim light is most
commonly a physiologic anisocoria or a
Horner syndrome, but the differential also
includes pharmacologic miosis, mechanical anisocoria, and aberrant regeneration
of the oculomotor nerve (Table 15-4).
Physiologic Anisocoria
Also known as simple or essential or
benign anisocoria, this is the most

TABLE 15-3
Agent

Example of distortion of pupil shape

caused by sectoral palsy of the iris
sphincter. In this patient with a tonic pupil,
the area of normally innervated sphincter lies between
the 11-oclock and 4-oclock positions and demonstrates
thickening of the pupillary ruff and puckering of the iris
stroma, changes consistent with sphincter contraction. The
paralyzed sector is between the 4-oclock and 8-oclock
positions. Note the looseness of the adjacent iris stroma
and the flattening of the radius of pupil curvature.

FIGURE 15-6

common cause of a difference in pupillary size. About 20% of the general

population demonstrates a readily visible anisocoria of 0.4 mm or more at
any given moment (Lam et al, 1996).
Physiologic anisocoria typically measures 1.0 mm or less, although the magnitude of anisocoria in an individual
varies from day to day. The anisocoria
is fairly equal in dim-light and brightlight conditions. The most important
aspect of physiologic anisocoria is that
both pupils constrict normally to light

227

Pharmacologic Testing for Cholinergic Denervation Supersensitivity

Drug Action

Pilocarpine Pilocarpine is a direct

cholinergic agonist; in dilute
0.125%
concentration, it is generally
or less
too weak to constrict a
normal pupil.

Test Procedure

Positive Result

Example

Put two drops of

diluted pilocarpine
in both eyes. Wait
45 minutes.

See Case 15-4

Larger pupil becomes
smaller pupil. Or
suspected pupil constricts
more than normal pupil.

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

" ANISOCORIA

Case 15-4

228

A 50-year-old woman developed a

headache behind her right eye and blurred
near vision. The next day she noticed that
her right pupil was larger than her left
pupil. She was otherwise healthy. On
examination 2 months after symptom
onset the larger right pupil had no
observable reaction to direct or consensual
light stimulation (in darkness, the right
pupil was 6.0 mm, left pupil was 4.5 mm;
and in bright light, right pupil was 6.0 mm,
left pupil was 3.0 mm). The right pupil,
however, constricted to a near effort
(Figure 15-7B). Eye movements were full,
and she was orthophoric in all fields of
gaze. No ptosis was present.
High-magnification slit-lamp examination
of the right eye showed paralysis of most
of the iris sphincter except for two focal
segments that remained briskly reactive to
light stimulation. Following instillation of
pilocarpine diluted to 0.125%, the right
pupil was constricted whereas the left pupil
was unchanged (Figure 15-7C). A diagnosis
of idiopathic tonic pupil (Adie pupil) was
made, and, after discussion, the patient was
reassured and sent home.
Comment. Tonic pupils may occur from a
variety of local processes affecting the
ciliary ganglion or short ciliary nerves, such
as orbital trauma (accidental or iatrogenic),
tumor, ischemia, or infection. Tonic pupils
may also occur as a manifestation of a more
widespread autonomic process, such as
diabetic or alcoholic peripheral neuropathy,
and in these cases both pupils are affected.
Most cases of tonic pupil, however, occur
as a spontaneous unilateral condition,
usually in women between the ages of
20 and 50 years; it is this idiopathic form
that has been termed an Adie tonic pupil.
When diminished muscle stretch reflexes
are an associated finding, the condition
is called Adie or Holmes-Adie syndrome.
Neuroimaging is not indicated for the
patient with a typical Adie pupil.

Patient with an Adie pupil on the right side.

A, The right pupil is dilated and unreactive
to light. B, The right pupil constricts to near
effort (light-near dissociation). C, Following instillation of
dilute pilocarpine to both eyes, the right pupil is constricted.
The left pupil is unchanged from the top frame.

FIGURE 15-7

and dilate equally in darkness. Rarely,

physiologic anisocoria can change sides.
In other words, the larger pupil appears

sometimes on the right side and sometimes on the left side. This has been called
seesaw anisocoria. After instillation of

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 15-4

"

Causes of
Anisocoria
Greater in
Dim Light

Mechanical Anisocoria

can cause a small mechanically restricted

pupil. Like pharmacologic miosis, a pupil
that is mechanically tied down cannot
TABLE 15-5

Iris adhesions, eg, prior

inflammation
Pigment dispersion syndrome

"

"

"

Central Lesion

Neurologic Anisocoria

Hypothalamic tumor

Horner syndrome

Brainstem infarct
(eg, Wallenberg syndrome)

Aberrant regeneration of
oculomotor nerve

Demyelinating disease

Pharmacologic Anisocoria

Cervical cord trauma, tumor,

or syrinx

Glaucoma medications

"

Topical anti-inflammatory

"

Common Causes
of Horner
Syndrome

Preganglionic Lesion
Cervicothoracic cord lesion

Physiologic Anisocoria

Paravertebral tumor
Epidural anesthesia
Sympathetic chain tumor
(eg, schwannoma)

topical cocaine, both pupils dilate so the

anisocoria often disappears after cocaine.
No ocular or neurologic abnormalities are
related to physiologic anisocoria.
Pharmacologic Miosis
The use of pilocarpine or other topical
medications for glaucoma may result in
a small pupil. Often the miotic pupil
constricts poorly or barely at all to light.
This is simply because the pharmacologic
agent creates so small a pupil that it
has reached the mechanical limit. The
pharmacologic agent is usually a cholinergic parasympathetic agonist that directly stimulates the iris sphincter.
Although the dilator muscle remains
intact, it is not strong enough to overcome a maximally contracted sphincter
muscle. Thus, a pharmacologically miotic
pupil fails to dilate in darkness and to
topical dilating drops, including sympathomimetic and anticholinergic agents.
Mechanical Anisocoria
Posterior synechiae after bouts of iritis
or chronic pigment dispersion syndrome

Lower brachial plexus trauma

Pulmonary apex lesion
(eg, Pancoast syndrome)
Mediastinal tumor
Iatrogenic (eg, chest tube,
central line)
Anterior neck tumor or trauma

"

Postganglionic Lesion
Superior cervical ganglion
tumor (eg, paraganglioma)
Jugular vein trauma
(eg, internal jugular
catheterization)
Parapharyngeal surgery
Internal carotid artery
dissection
Cluster headache
Skull base pathology
(eg, bony fracture,
nasopharyngeal carcinoma)
Cavernous sinus meningioma
Carotid-cavernous fistula

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

229

" ANISOCORIA

KEY POINT

A mechanically
restricted miotic
pupil does not
dilate well in
darkness or to
topical cocaine
and thus may be
confused for a
Horner syndrome.
However, a
Horner pupil
dilates easily to
direct
sympathomimetic
agonists such as
phenylephrine,
whereas a
mechanically
restricted pupil
remains miotic.

Two patients with a left Horner syndrome.

A, The patient demonstrates obvious upper
eyelid ptosis and lower eyelid ptosis (seen
as a rising up of the lower eyelid resting position), but her
anisocoria is barely visible in room light. B, This patient has
mild left upper eyelid ptosis but a more pronounced
anisocoria in room light.

FIGURE 15-8

dilate in response to any topical sympathomimetics or anticholinergics.

Horner Syndrome
Horner syndrome is caused by interruption of sympathetic innervation to

the head and eye and results in miosis,

ptosis, and facial anhidrosis on the side
of the lesion (Table 15-5). Weakness
of the superior and inferior tarsal muscles results in upper and lower eyelid
ptosis, which together cause a decrease

230

Pupillographic tracing of a patient with a Horner syndrome who demonstrates

pupillary dilation lag. Time in seconds is given at the top of the graph. The
bar indicates a 1-second light flash, which is followed by 15 seconds of
darkness. Following transient pupilloconstriction, the normal pupil dilates promptly and is
nearly redilated back to baseline within 4 to 5 seconds. The Horner pupil has, in comparison,
dilated little by 5 seconds and takes about 15 seconds to redilate completely. The bottom
line shows the changing magnitude of anisocoria over time in darkness.

FIGURE 15-9

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

of the palpebral fissure and the appearance of enophthalmos (Figure 15-8).

It is important to remember that the
classic triad of clinical findings is often
incomplete. Ptosis is absent in 12% to
13% of patients with Horner syndrome.
Facial anhidrosis is seldom reported by
patients. Anisocoria is the most reliable,
and sometimes only, manifestation of
an oculosympathetic defect. The clinical
feature that differentiates Horner syndrome from physiologic anisocoria is
dilation lag of the smaller pupil in darkness. When the room light is abruptly
turned off, the pupil with an oculosympathetic defect shows slow and delayed
dilation over 15 to 20 seconds compared
TABLE 15-6

with the normal pupil, which promptly

redilates back to baseline within 3 to 5
seconds (Figure 15-9). This finding is
diagnostic for Horner syndrome but is
demonstrable in only about 50% of
patients. Therefore, practical diagnosis
of Horner syndrome and distinction
from physiologic anisocoria usually
requires a pharmacologic test. Currently, two agents are used for this purpose: cocaine and apraclonidine.
Cocaine blocks the reuptake of
norepinephrine released at neuromuscular junctions of the iris dilator muscle,
thereby increasing the amount of norepinephrine available to stimulate the
muscle. Following instillation of cocaine

Pharmacologic Testing for the Diagnosis of Horner Syndrome

Agent

Drug Action

Cocaine
(4% or 10%)

Cocaine inhibits
reuptake of
norepinephrine
in postsynaptic
junction
(acts as indirect
sympathomimetic)

Test
Procedure
Put two drops
of cocaine in
each eye; wait
45 minutes

Positive Result

Example

Postcocaine
anisocoria of
1.0 mm or more
(smaller pupil is
Horner pupil)

Before cocaine

After cocaine (right Horner

syndrome confirmed)

231
Apraclonidine
(0.5% or 1%)

Apraclonidines
secondary
property is weak
agonist action at
postsynaptic
1-adrenergic
receptors
(ie, dilute direct
sympathomimetic)

Put one drop of

apraclonidine
in each eye;
wait 45 minutes

Postapraclonidine
reversal of
anisocoria (larger
pupil is Horner
pupil)

Before apraclonidine

After apraclonidine (right

Horner syndrome confirmed)

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

" ANISOCORIA

into the conjunctival sac, the normal

response is pupillary dilation usually
accompanied by conjunctival blanching
and eyelid retraction. A sympathetically
denervated eye does not respond to
cocaine, and the anisocoria is typically
enhanced by cocaine. The magnitude
of postcocaine anisocoria is the measured end point, with 1.0 mm or more
considered diagnostic of a Horner syndrome (Table 15-6) (Kardon et al,
1990).
Apraclonidine is a new drug used for
lowering intraocular pressure through its
2-adrenergic action. However, apraclonidine also has a weak 1-agonist
activity, which can stimulate a denervated
iris dilator muscle because of adrenergic denervation supersensitivity.
Following topical instillation of apraclonidine, a reversal of anisocori is

232

FIGURE 15-10

Schematic illustration of the three-neuron

oculosympathetic pathway.

Reprinted with permission from Liu GT, Volpe NJ, Galetta SL.
Neuro-ophthalmology: diagnosis and management. Philadelphia:
WB Saunders, 2000. Copyright # 2000, Elsevier.

the current criterion for a positive

result that diagnoses a Horner syndrome (Table 15-6) (Brown et al,
2003). The advantage of apraclonidine
is its ready availability in most ophthalmology clinics.
The sympathetic pathway to the eye
is an ipsilateral, three-neuron pathway
(Figure 15-10). In brief, the first-order
neuron (central neuron) originates in
the hypothalamus and descends the
brainstem to synapse in the lower cervical upper thoracic spinal cord (C8-T2).
The second-order neuron (preganglionic
neuron) exits the spinal cord and passes
across the apex of the lung and under
the subclavian artery to ascend the neck
and synapse in the superior cervical
ganglion. The third-order neuron (postganglionic neuron) supplies vasomotor
and sudomotor function to the head and
neck as well as pupillodilator and tarsal
muscle (Mu
ller muscle) function in the
eye. At the carotid bifurcation, the vasomotor and sweating fibers travel primarily with the external carotid artery,
whereas the oculosympathetic fibers
travel with the internal carotid artery
as a plexus around its wall. At the
orbital apex, the oculosympathetic fibers follow the nasociliary nerve to the
eye.
The differential diagnosis of a Horner
syndrome is influenced by the location of the lesion. In general, a central
Horner syndrome is usually stroke
related (eg, Wallenberg lateral medullary syndrome), so other symptoms and
signs of brainstem dysfunction are
usually present. A preganglionic Horner
syndrome is known for its association
with neoplasms of the pulmonary apex,
mediastinum, or neck in 20% to 50%
of cases. A postganglionic Horner syndrome is often accompanied by pain
or headache for which considerations
should include carotid artery dissection,
tumors spreading along the skull base,
lesions in the cavernous sinus, and
cluster headache.
Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Localization of the lesion using topical 1% hydroxyamphetamine and examination clues helps to direct the
imaging studies. Following instillation
of hydroxyamphetamine, if both pupils dilate, the Horner syndrome is
central or preganglionic; if brainstem
signs are present, then a head MRI with
contrast is sufficient. If brainstem signs
are absent, a head, neck, and chest CT

or magnetic resonance scan is an appropriate consideration depending on

localization. If the Horner pupil does
not dilate to hydroxyamphetamine, it is
a postganglionic lesion. A painful postganglionic Horner syndrome warrants
investigation for a carotid dissection,
particularly if accompanied by focal
neurologic deficits, visual loss, dysphagia, or dysgeusia. In patients with

Case 15-5
A 34-year-old woman developed an acute
left periorbital headache and left ptosis.
Further questioning revealed that she had
spent the day before at an amusement park
with some friends. Examination revealed
a subtle decrease in her left palpebral
fissure due to upper and lower eyelid ptosis
(Figure 15-11). Subtle anisocoria was most
apparent in dim light. Pupillary dilation lag
was present on the left side, and cocaine
testing showed failure of the left pupil to
dilate. A diagnosis of left Horner syndrome
was made, and an emergent MRI revealed
a dissection of the left internal carotid
artery. The patient was hospitalized for
appropriate management.
Comment. An acute and painful Horner
syndrome should be considered to result
from an acute carotid dissection until
proven otherwise (Biousse et al, 1998). Pain
is the most common symptom of carotid
dissection. The location of the pain is usually
a focal area on the face or head ipsilateral
to the side of the dissection. Other sites of
pain include the neck, jaw, pharynx, and
ear. Tinnitus or pulsatile sounds are also
frequent symptoms, and this triad of
findings (pain, Horner syndrome, tinnitus)
is highly suggestive of an acute carotid
dissection. Traumatic dissections are usually
caused by severe blunt head or neck injury,
such as motor vehicle accident, fist fighting,
or manipulative neck therapy. In other
cases, the precipitating event may have
been trivial trauma, including coughing,
sneezing, jerking the head to one side,
painting a ceiling, or riding a roller
coaster, as in this patient.

233

Patient with a left Horner syndrome due

to carotid artery dissection, presumably
related to riding a roller coaster. A, The
patient has mild left upper eyelid ptosis and anisocoria.
B, Axial T2 MRI at the skull base shows a crescent-shaped
hyperintensity adjacent to the left internal carotid artery
(arrow), a characteristic appearance of dissection.

FIGURE 15-11

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

" ANISOCORIA

an acute and painful Horner syndrome, pharmacologic localization with

hydroxyamphetamine is often bypassed
in order to expedite the imaging study
(Case 15-5).
Most dissections are diagnosed with
noninvasive methods. On noncontrast
axial MRI images at the skull base, a
dissection characteristically appears as
a T1 bright crescent of methemoglobin around the carotid artery. Luminal
narrowing is better documented with
angiography (magnetic resonance, CT,
or conventional contrast angiography). Treatment is aimed at preventing
stroke. If a dissection is diagnosed in its
acute phase, eg, within 1 to 2 weeks of
symptom onset, heparin anticoagulation is often recommended to reduce
emboli formation. After approximately
1 month, the risk of stroke is low (1%)
and antiplatelet therapy alone is generally adequate.
Congenital Horner syndrome is usually caused by birth trauma to the
brachial plexus. Horner syndrome acquired in early childhood raises the
possibility of neuroblastoma arising in

the sympathetic chain of the chest.

Clinical analysis of the urine for determination of catecholamine excretion
as well as imaging of the neck, chest,
and abdomen may also be warranted.

Aberrant Regeneration of the

Oculomotor Nerve
In the primary position, the affected
pupil has a poor light reflex due to
damaged parasympathetic pupil fibers that have never recovered.
However, when the patient supraducts, infraducts, or adducts the eye,
the pupil synchronously constricts.
This is a synkinesis and occurs because regenerating fibers originally
destined to the motor muscles are
misguided to the iris sphincter. Over
time the sphincter is increasingly
reinnervated by these aberrant motor
fibers and the resting size of the pupil becomes smaller, as occurs with a
chronic tonic pupil; this aberrant oculomotor pattern is always accompanied by other third-nerve motor
dysfunction.

REFERENCES
Bartleson JD, Trautmann JC, Sundt TM Jr. Minimal oculomotor nerve paresis secondary
to unruptured intracranial aneurysm. Arch Neurol 1986;43(10):10151020.

234

Biousse V, Touboul PJ, DAnglejan-Chatillon J, et al. Ophthalmologic manifestations

of internal carotid artery dissection. Am J Ophthalmol 1998;126(4):565577.
Brown SM, Aouchiche R, Freedman KA. The utility of 0.5% apraclonidine in the
diagnosis of Horner syndrome. Arch Ophthalmol 2003;121(8):12011203.
DeMarinis M, Assenza S, Carletto F. Oculosympathetic alternations in migraine patients.
Cephalalgia 1998;18(2):7784.
Jacobson DM. Benign episodic unilateral mydriasis: clinical characteristics.
Ophthalmology 1995;102(11):16231627.
Jacobson DM, Vierkant RA. Comparison of cholinergic supersensitivity in third nerve
palsy and Adies syndrome. J Neuroophthalmol 1998;18(3):171175.

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Kardon RH, Corbett JJ, Thompson HS. Segmental denervation and reinnervation of the
iris sphincter as shown by infrared videographic transillumination. Ophthalmology
1998;105(2):313321.
Kardon RH, Denison CE, Brown CK, Thompson HS. Critical evaluation of the cocaine test
in the diagnosis of Horners syndrome. Arch Ophthalmol 1990;108(3):384387.
Kupersmith MJ, Heller G, Cox TA. Magnetic resonance angiography and clinical
evaluation of third nerve palsies and posterior communicating artery aneurysms.
J Neurosurg 2006;105(2):228234.
Lam BL, Thompson HS, Walls RC. Effect of light on the prevalence of simple anisocoria.
Ophthalmology 1996;103(5):790793.
Loewenfeld IE, Thompson HS. Mechanism of tonic pupil. Ann Neurol 1981;10(3):
275276.
Thompson HS, Zackon DH, Czarnecki JS. Tadpoleshaped pupils caused by segmental
spasm of the iris dilator muscle. Am J Ophthalmol 1983;96(4):467477.
Woods D, OConnor PS, Fleming R. Episodic unilateral mydriasis and migraine.
Am J Ophthalmol 1984;98(2):229234.

235

Continuum Lifelong Learning Neurol 2009;15(4)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.