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Horner Syndrome: A Clinical Review
Timothy J. Martin*
Department of Ophthalmology, Wake Forest University School of Medicine, Wiston-Salem, North Carolina 27157, United States
ABSTRACT: Horner syndrome results from an interruption
of the oculosympathetic pathway. Patients with Horner
syndrome present with a slightly droopy upper lid and a
smaller pupil on the affected side; less commonly, there is a
deficiency of sweating over the brow or face on the affected
side. This condition does not usually cause vision problems or
other significant symptoms, but is important as a warning sign
that the oculosympathetic pathway has been interrupted,
potentially with serious and even life-threatening processes.
The oculosympathetic pathway has a long and circuitous
course, beginning in the brain and traveling down the spinal
cord to exit in the chest, then up the neck and into the orbit. Therefore, this syndrome with unimpressive clinical findings and
insignificant symptoms may be a sign of serious pathology in the head, chest, or neck. This clinical review discusses how to
identify the signs, confirm the diagnosis, and evaluate the many causes of Horner syndrome.
KEYWORDS: Horner syndrome, ptosis, oculosympathetic pathway, anisocoria
■ INTRODUCTION
Horner syndrome describes the clinical findings (signs and sym-
ptoms) that result from an interruption of sympathetic inner-
vation to the eye (oculosympathetic paresis). The classic triad
in Horner syndrome is unilateral ptosis, miosis, and anhidrosis,
but the ptosis (slight narrowing of the ocular fissure) and
miosis (smaller pupil on the affected side) are far more com-
monly recognized than anhidrosis (lack of perspiration on the
forehead or face). Horner syndrome is not likely to cause any
functional visual disturbance but is of great importance clin-
ically as a “red flag” warning that the oculosympathetic pathway
has been interrupted. This pathway is a three-neuron chain that
originates in the hypothalamus in the brainstem, travels down
the spinal cord to the lower cervical and upper thoracic levels,
then traverses the upper chest cavity and apex of the lung,
traveling with the carotid artery into the cavernous sinus, tra-
versing the orbit to innervate the pupillary sphincter; it also
branches to innervate accessory muscles for eyelid retraction.
This long, circuitous route covers a lot of anatomy, and a patient
with a lesion anywhere along its course can present with Horner
syndrome. Therefore, this syndrome with minimal symptoms
and often subtle findings is of great importance in the diagnosis
of potentially life-threatening lesions in the head, neck, and
chest!1
Horner syndrome bears the name of Johann Friedrich
Horner (1831−1886), a Swiss ophthalmologist who published
a case report in 1869 describing a 40 year old woman with
unilateral miosis, ptosis, and facial anhidrosis. However, there
were case reports of the syndrome that predated Horner’s by
many years: a report by Edward Selleck Hare in 1838 and another
by Silas Weir Mitchell in 1864. The French ophthalmologist
Claude Bernard was the first to identify the triad of findings as the
manifestations of an oculosympathetic paresis in animal studies
© 2017 American Chemical Society
in 1852.2 Therefore, this condition is sometimes called Claude
Bernard−Horner syndrome, especially in the French literature.3,4
Signs and Symptoms. Patients with Horner syndrome
typically present with a small upper eyelid ptosis (1−2 mm)
and an anisocoria with the smaller pupil on the affected side.
Ipsilateral anhidrosis of the forehead or face is a far less reliable
sign, as it is not clinically evident (or not present at all) most of
the time. Similar to the upper eyelid, the lower eyelid can be
slightly more closed as well, narrowing the palpebral fissure,
which makes the eye look enophthalmic even though true
enophthalmos is not present. Transient conjunctival injec-
tion and relative hypotony have been reported in the acute
setting.5
Miosis. In Horner syndrome, the pupil in the affected eye
is smaller than that in the opposite eye due to the loss of
sympathetic tone of the pupillary dilator. A difference in the
size of one pupil compared to that of the other is called anis-
ocoria. In a normal state, the two pupils are the same size.
The size of the pupillary aperture of the iris is controlled by
autonomic innervation to two opposing sets of muscles in the
iris. The pupillary sphincter is a circular muscle in the iris that
frames the pupil; it is innervated by the parasympathetic auto-
nomic system, and activation makes the pupil smaller. The
pupillary dilator consists of radial muscle fibers that dilate the
pupil when activated and is innervated by the sympathetic
autonomic system; the pupils become large with sympathetic
“fight or flight” response. Ultimately, the size of the pupil is
determined by the balance of these opposing systems. There
are many factors that influence sympathetic and parasympathetic
Received: October 25, 2017
Accepted: November 30, 2017
Published: December 20, 2017
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input to the pupil, including the amount of light entering the

eyes, the state of accommodative tone (looking at someth-
ing close versus far away), but also emotional factors, systemic
medications, and disease states. In general, the autonomic
innervation controlling the pupil is equal in both eyes, so both
pupils are normally the same size as each other, even as they
change dynamically throughout the day. In the case of Horner
syndrome, there is a loss of sympathetic tone to the pupillary
dilator in one eye. Therefore, the pupil in the affected eye is
smaller than the pupil in the opposite eye, as parasympathetic
tone to the pupillary sphincter is relatively unopposed.
The degree of anisocoria in Horner syndrome is greater in
darkness than in bright light; in fact, anisocoria can be missed
altogether if the pupils are only observed in bright light.6 This
is because parasympathetic tone (to the pupillary constrictor) is
maximized and sympathetic tone is minimized in bright light;
thus, the difference in pupil size is not as noticeable. However,
in darkness, the pupillary dilator is activated, and the anisocoria
becomes greater as the affected side fails to dilate as well as the
opposite side. It is important to note that the pupil will dilate in
darkness, even in Horner syndrome, as much of the dilation
in darkness comes from relaxation of the powerful pupillary
sphincter, allowing the mechanical elastic forces of the iris to
open the pupil. This passive dilation of the pupil is much slower
than the dilation of the pupil when the sympathetic system
activates the dilator muscles. This is why the pupil in Horner
syndrome is said to have a “dilation lag”: minimal anisocoria in
bright light, a larger degree of anisocoria when the lights are
turned off for the first 5 s and then less anisocoria after 10−15 s
as passive dilation in the affected eye gradually catches up with
the size of the pupil in the normal eye. This is best observed by
evaluating pupil size first in bright light and then in darkness as
the room lights are suddenly turned off (the pupils are observed
in relative darkness by illuminating the patient’s eyes with a
penlight tangentially from below).7 The dilation lag can also be
recorded by taking photographs of the pupils in darkness after
five seconds and then again at 15 s.8 Digital pupillography can
also be used to plot the pupillary dilation in darkness, produc-
ing a characteristic dilation lag pattern.9 The dynamic nature of
the dilation lag needs to be understood by the clinician, as it is
critical that the pupils be observed as they are in the process of
dilating, particularly in the first 5−15 s after the lights are turned
off (Figure 1). The dilation lag is very characteristic of Horner
syndrome10 but may not always be present.6,11
The anisocoria can be further exaggerated by giving the
patient a “scare” a few seconds after the lights are turned off. Figure 1. A 22 year old with right Horner syndrome. Photograph in
A loud noise or other stimulus that causes a systemic sympathetic room light shows anisocoria with the right pupil smaller than the left and
discharge will exaggerate dilation in the unaffected eye, maximiz- subtle ptosis of the right upper eyelid; also note the lower lid sits higher
ing anisocoria. Pinching the patient (not recommended!) has the on the globe (“upside-down ptosis”) (A). In bright light, the anisocoria is
same effect.12 These noxious stimuli techniques are more of an minimized (B) and is greatest after ∼5 s in the dark (C) with lessening of
intriguing side note than a clinically practical tool. the anisocoria at 15 s as the right pupil “catches up” (D). Forty-five
minutes after apraclonidine eye drops were instilled in both eyes, the
In summary, the pupillary abnormality Horner syndrome is anisocoria is reversed due to supersensitivity of the pupillary dilator in the
an anisocoria with a smaller pupil on the affected side. This is right eye from Horner syndrome (E). Note that the ptosis is also
best identified by comparing the degree of anisocoria in bright reversed in this case due to similar supersensitivity of the sympathetically
light and in darkness with the greatest degree of anisocoria innervated eyelid retractors; however, the ptosis reversal alone is not
expected 5−7 s after the lights are turned off because of a defi- reliable enough to act as an indicator of a positive test.
ciency of sympathetic tone to the dilator muscle in the affected
eye. Note that an anisocoria that is greater in bright light than wider (as expected because wide open eyes are a part of the “fight
in darkness implicates that the larger of the two pupils is abnor- or flight” sympathetic response). With a deficiency in oculo-
mal, suggesting a parasympathetic deficiency, as occurs with a sympathetic tone in Horner syndrome, there is the opposite
third cranial nerve palsy or Adie tonic pupil. effect, a narrowing of the palpebral fissure on the affected side.
Ptosis. Increased sympathetic tone to the eyelids causes a The primary elevator of the eyelid is the levator palpebrae
slight retraction of the eyelids making the palpebral fissure muscle, which is innervated by the third cranial nerve. How-
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ACS Chemical Neuroscience
ever, a small amount of eyelid elevation is produced by Mueller’s
muscle, a small sympathetically innervated eyelid retractor that
contributes ∼1−2 mm of lift to the upper eyelid.13 Therefore,
with an oculosympathetic paresis, there is a 1−2 mm ptosis of
the upper eyelid, narrowing the ocular fissure. A ptosis greater
than 1−2 mm cannot be fully explained by Horner syndrome.
There is a similar rudimentary muscle in the lower lid; thus,
the lower lid may be slightly elevated in Horner syndrome
(sometimes called “upside-down ptosis”).14 This may only be
evident by comparing the position of the lower lid to the limbus
between the two eyes. The end result of a loss of sympathetic
tone to the eye is a narrowing of the ocular fissure. The narrowed
fissure can give the appearance of enophthalmos, though there is
no true measurable enophthalmos in Horner syndrome.15
The ptosis in Horner syndrome may be variable and subtle;
one study noted that ptosis was absent in 12% of patients.16
Sudomotor and Vasomotor Deficiency. The oculosym-
pathetic system also carries sudomotor fibers (for perspiration)
to the face. Interruption of this pathway can cause a deficiency
in sweating (anhidrosis) on the affected side. Most of the face is
innervated by sudomotor fibers that travel with the common
carotid via the external carotid; however, fibers that travel with
the internal carotid supply a small area on the forehead and side
of the nose. Therefore, lesions involving the superior cervical
ganglion or more proximal pathway can result in ipsilateral
facial anhidrosis (Figure 2), but more distal lesions along the
Figure 2. A 45 year old man presenting with right Horner syndrome.
He had a right paraspinal cervical abscess as a late complication of
previous spine surgery producing a right preganglionic Horner syn-
drome. This clinical photograph was taken at a time when the patient
had fever and was diaphoretic, revealing right hemifacial anhidrosis.
third-order neuron will only result in anhidrosis of a small patch
of skin on the forehead above the brow. Theoretically, Horner
syndrome from lesions in the brainstem or spinal cord could
even produce hemibody anhidrosis. However, anhidrosis is
almost never evident in the environmentally controlled clinical
setting and only rarely recognized by patients. Because of this
difference in facial perspiration, women may sometimes note a
difference when makeup is applied on one side of the face
versus the other. In the past, elaborate methods have been
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Review
suggested for identifying this finding clinically, such as sliding
a plastic prism bar across the skin of the brow on one side
versus the other (it will slide more smoothly where there is no
perspiration),17 or applying a powder to the face or body that
will change color depending on degree of skin moisture.18
In the acute setting, loss of vasomotor control from sym-
pathetic denervation can cause facial flushing, conjunctival
hyperemia, tearing, and even nasal stuffiness with consequent
dilation of the vasculature. Later, the skin may be paler than the
normal side with vasoconstriction caused by denervation super-
sensitivity of the vasculature to normally circulating adrenergic
elements.7
The Harlequin sign is a striking manifestation of loss of
sympathetic vasomotor innervation with hemifacial flushing
that respects the vertical midline, typically in infants with an
oculosympathetic paresis.19
Neuroanatomy and Clinical Implications. As noted in
the Introduction, the oculosympathetic “chain” is a three-neuron
pathway: The first-order neurons are in the hypothalamus with
axons traveling through the brainstem and spinal cord to synapse
in the lower cervical/upper thoracic spinal cord. Second-order
axons originate from this spinal nucleus and travel through the
upper chest cavity to synapse in the superior cervical ganglion;
then, third-order axons originating in the superior cervical gan-
glion travel along the carotid artery system to reach the orbit and
eye. Horner syndrome can result from lesions anywhere along
this pathway, which is logically divided into central or first-order,
preganglionic (proximal to the superior cervical ganglion) or
second-order, and postganglionic or third-order neuron regions
(Figure 3). One study demonstrated that 65% of patients
presenting with Horner syndrome were found to have an
identifiable cause with 13% of these having a central lesion, 44%
with a preganglionic lesion, and 43% with a postganglionic lesion.16
First-Order (Central) Horner Syndrome. The cell bodies
of first-order neurons reside in the hypothalamus. From there,
axons descend through the brainstem and down the spinal cord
to synapse in the ciliospinal center of Budge−Waller located at
the level of C8 to T2. Therefore, lesions in the brainstem and
cervical cord can present with a first-order neuron Horner syn-
drome often called a “central” Horner syndrome (Table 1).20
This is rarely a cause of isolated Horner syndrome given the
proximity of this pathway to important brainstem structures,
though there are exceptions.21
Hypothalamic/thalamic lesions (tumor, infarct, hemorrhage)
can cause ipsilateral Horner syndrome associated with con-
tralateral hemiparesis and hypesthesia22−24 Lesions of the
dorsal midbrain can result in the combination of an ipsilateral
Horner syndrome with a contralateral fourth cranial nerve palsy
because the fourth cranial nerve fibers cross to the contralateral
side as they exit the brainstem.25 Lesions affecting the pons can
produce Horner syndrome associated with an ipsilateral or
bilateral abducens palsy.26
The most commonly recognized central Horner syndrome
occurs in the setting of a lateral medullary plate syndrome from
infarction (rarely demyelination), producing a constellation of
symptoms called Wallenberg syndrome: Horner syndrome,
ipsilateral ataxia, and contralateral hypalgesia; nystagmus, facial
weakness, dysphagia, and vertigo may also be present.27
Finally, cervical or upper thoracic spinal cord lesions (trauma,
demyelination, tumor, syrinx, or vascular causes) can cause
an isolated Horner syndrome28 but most often are associated
with long tract signs or spinal cord syndromes such as Brown−
Séquard syndrome.7
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Figure 3. Oculosympathetic pathway. Reproduced with permission from Martin, T.J.; Corbett, J.J. Practical Neuroophthalmology; McGraw Hill,
2013. This illustration was originally redrawn with permission from Weinstein, J.M.; The pupil. In Slamovits, T.L., Burde, R., associate eds.; Neuro-
ophthalmology, vol. 6. In Podos, S.M., Yanoff, M., eds.; Textbook of ophthalmology, St. Louis, 1991, Mosby.

Second-Order (Preganglionic) Horner Syndrome.
Second-order neuron lesions are sometimes referred to as
“preganglionic” because they are proximal to the superior
orbital ganglion. In one study, up to 25% of preganglionic
Horner syndrome were the result of malignancy.29 Another
study showed that 28% of preganglionic Horner syndrome may
have no identifiable etiology.5 Second-order neurons originate
in the ciliospinal center of Budge−Waller, a spinal nucleus
extending from C8 to T2. They exit the spinal cord as a part
of the paraspinal sympathetic plexus. The axons form a
sympathetic nerve, traveling under the aorta, draping over the
apex of the lung before passing through the stellate ganglion
and up the carotid sheath, synapsing in the superior cervical
ganglion at the level of the carotid bifurcation. For this reason,
lesions in the upper chest cavity can result in Horner syndrome
(Figure 4). The classic example is the Pancoast tumor, an apical
lung tumor resulting in Horner syndrome and sometimes also
producing ipsilateral shoulder pain and signs and symptoms
associated with thoracic outlet syndrome.30
Trauma, including injury to the brachial plexus or soft tissue
of the neck, or pneumothorax can also cause Horner syndrome.
Surgical procedures involving upper chest (including central
180
lines and anesthetic procedures) or the neck, such as cervical
spine surgery or thyroid surgery, can be an iatrogenic cause of
Horner syndrome.
Third-Order (Postganglionic) Horner Syndrome.
Third-order neurons have their cell bodies in the superior
cervical ganglion located at the bifurcation of the carotid artery
near the angle of the jaw. Axons travel to their final destination
not as a single nerve but as a net or plexus (rete) that surrounds
the common carotid artery and then the internal carotid artery
to reach the eye (or the external carotid artery to supply the
face). This plexus of oculosympathetic nerves travels with the
carotid artery into the cavernous sinus. Within the cavernous
sinus, the plexus coalesces to form a well-defined nerve that
travels with the sixth cranial nerve through the middle of the
cavernous sinus (unlike cranial nerves III, IV, and V1 that travel
relatively protected in the wall of the cavernous sinus). Sym-
pathetic fibers then travel with the first division of the fifth
cranial nerve through the superior orbital fissure into the orbit.
Sympathetic fibers destined to innervate the pupillary dilator
travel through the ciliary ganglion (without synapsing), via the
long ciliary nerves that penetrate the sclera near the optic nerve,
and then through the suprachoroidal space to segmentally
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Table 1. Anatomic Location and Pathological Processes in Horner Syndrome

anatomic location types of lesions associated symptoms
first-order (central) hypothalamus infarction, hemorrhage, tumor contralateral hemiparesis and/or hypesthesia
mesencephalon contralateral trochlear nerve palsy
pons as above, also demyelination ipsilateral or bilateral abducens palsy
medulla as above, more specifically infarction, arterial dissection, cardiac embolism, rarely Wallenberg syndrome
demyelination
spinal cord trauma, infarction, vascular malformation, demyelination, tumor, inflammatory or radicular signs, Brown−Séquard syndrome,
infectious myelitis, syrinx, syringomyelia, cervical disc herniation alternating Horner syndrome
second-order thoracic cavity breast and lung cancer, mediastinal masses, chest surgery, thoracic aortic
(preganglionic) aneurysm, central vascular access, trauma
apical lung lesions: non-small-cell lung carcinoma, other tumors, metastatic Pancoast syndrome
disease, infection
cervical neuroblastoma, schwannoma, neuroectodermal tumor, vagal paraganglioma,
sympathetic mediastinal tumors, cysts
chain
neck trauma, abscess, tumor, lymphadenopathy, thyroid neoplasm, thyroidectomy,
radical neck surgery, central vascular access, cervical rib
third-order superior cervical trauma, jugular venous ectasia, surgical neck dissection
(postganglionic) ganglion
penetrating intraoral injury, intraoral surgery, tonsillectomy
carotid artery traumatic or spontaneous dissection, aneurysm, fibromuscular dysplasia, Ehlers− facial pain, stroke, ocular ischemia, cerebral
Danlos syndrome, Marfan syndrome, arteritis ischemic symptoms
cavernous sinus cavernous carotid aneurysm, tumor, thrombosis Abducens and other ocular motor palsy
skull base mass lesion, basilar skull fracture cranial nerve deficits, trigeminal pain and sensory
loss
orbit/superior herpes zoster, nasopharyngeal carcinoma
orbital fissure
other or unknown cluster headache severe transient unilateral headache with tearing,
conjunctival injection, nasal stuffiness
trigeminal autonomic cephalgias ipsilateral trigeminal neuralgia
microvascular ischemia, giant cell arteritis, autonomic neuropathies

innervate the dilator muscles of the iris. Therefore, pathology in
the neck, skull base, and orbit can cause “postganglionic” (third-
order) Horner syndrome. As noted previously, the sudomotor
fibers that supply the majority of the face travel with the external
carotid with only a small portion traveling with the internal
carotid to supply a patch of skin above the brow (and side of the
nose). Therefore, when anhidrosis is identifiable in postganglionic
Horner syndrome, the only affected area is a small patch above
the brow. On the other hand, pathology affecting the superior
cervical ganglion or more proximal may cause hemifacial
anhidrosis, though this is rarely recognized clinically (see Figure 2).
One of the most common causes of postganglionic Horner
syndrome is carotid dissection with Horner syndrome occurring
in 20 to 30% of patients with this condition.31,32 Carotid dis-
section can occur as a result of trauma (including chiropractic
manipulation)33,34 but can also occur spontaneously. In carotid
dissection, tears in the intimal wall allow blood to enter into the
wall of the carotid artery.35 This results in a narrowing of the
lumen and occlusion of carotid branches but also an increase in
the diameter of the carotid artery, stretching and breaking the
plexus of sympathetic nerves. The resulting Horner syndrome
is usually accompanied by pain (in the neck, eye, ear, teeth, or
head) and other neurologic findings.31,36 Other causes of post-
ganglionic Horner syndrome include cluster headaches (both
transient with episodes and chronic after repeated episodes)37
or less commonly tumors of the skull base (often accompanied
by facial pain or anesthesia from trigeminal involvement).38
Cavernous sinus lesions, such as cavernous sinus carotid aneu-
rysms, classically cause ipsilateral Horner syndrome associated
with a sixth nerve palsy due to the close association of oculo-
sympathetic fibers with the sixth cranial nerve running through
the cavernous sinus.39,40
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Horner Syndrome in Children. Although Horner
syndrome identified during the first year of life is most often
idiopathic (70% in one study),41 the fact that it can be associated
with potentially fatal neuroblastoma means that Horner syndrome
in children is a serious matter. It is important to distinguish
between congenital and acquired Horner syndrome. More than
half of infants with acquired Horner syndrome during the first
year of life had an associated underlying potentially fatal disorder
in one study.42 Horner syndrome at birth is often idiopathic or
associated with birth trauma (often accompanied by brachial plexus
injury);42 however, congenital Horner syndrome can also be a sign
of intrauterine neuroblastoma.43 Early diagnosis is important as
survival declines if the diagnosis is made after the first year of life.44
In addition to ptosis and anisocoria, patients who had
Horner syndrome at birth (or acquired during early childhood)
can have a lighter-colored iris on the affected side (iris hetero-
chromia) because sympathetic innervation plays an important
role in the development of iris melanocytes, which ultimately
determine iris color.42 Harlequin sign is a striking presentation
of Horner syndrome in infancy with contralateral facial flushing
with absolute respect of the vertical midline.19
One study demonstrated that in a group of pediatric patients
with Horner syndrome, 40% were congenital, 42% were acquired
after a surgical procedure in the thorax, neck, or central nervous
system, and 15% were acquired from causes that included neuro-
blastoma, spinal cord tumors, rhabdomyosarcoma embryonal
cell carcinoma, vascular malformations, intrathoracic aneurysm,
and trauma.42
Children with Horner syndrome without obvious surgical
or traumatic cause require a thorough investigation for a mass
lesion including MRI of brain, neck, and chest with and without
contrast and urinary catecholamine testing.45
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Figure 4. This 65 year old patient presented with a left Horner
syndrome from a left upper mediastinal mass (arrow, A) shown to be a
schwannoma following resection. The Horner syndrome persisted
following resection. Note the 2 mm ptosis of the left upper lid and
anisocoria with a smaller pupil on the left side (B). Forty-five min after
instilling apraclonidine eye drops, the anisocoria reversed with prompt
dilation of the left pupil, confirming the presence of oculosympathetic
paresis (Horner syndrome) (C). Hydroxyamphetamine testing was
not performed, but one would anticipate that both pupils would dilate
well because the third-order neuron is intact in this example of
preganglionic Horner syndrome.
Differential Diagnosis. There are many causes of anisocoria
and many causes of ptosis. Occasionally, these two findings occur
together for other reasons (pseudo-Horner syndrome). There-
fore, a working knowledge of the differential diagnosis of these
two entities is important to arrive at a correct diagnosis.
When the pupils are different sizes (anisocoria), the first step
is to determine which pupil is the abnormal one: Is the larger
pupil too big or is the smaller pupil too small? This is deter-
mined by looking at the degree of anisocoria in bright light and
in darkness. Obviously, if the large pupil is implicated as the
abnormal one (anisocoria greatest in bright light), then Horner
syndrome is not a consideration and attention should be turned
to disorders of the parasympathetic system, such as Adie tonic
pupil or third cranial nerve palsy.
Horner syndrome is a consideration when the smaller pupil
is identified as abnormal (anisocoria greatest in darkness when
compared to light). However, there are other entities that can
cause an abnormally small pupil. Essential anisocoria is a small
anisocoria (usually less than 0.5 mm) not associated with dis-
ease that can be identified in 15−30% of the normal popula-
tion;46 the anisocoria is usually about the same in darkness
and in light, unlike pathologic states.5 Some topical eye drops,
contamination of the tear film with systemic medications, and
local ocular disease such as uveitis, eye trauma, and diabetic eye
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Review
disease can also create a small pupil in the setting of anisocoria.
Many of these entities can be identified on the slit lamp
examination or are evident in the patient’s history.
Horner syndrome is actually an uncommon cause of ptosis;
aging changes in the eyelid causing a mechanical drooping
(levator dehiscence) is the most common cause of ptosis in
older patients. This can also occur in young patients who wear
contact lenses, particularly hard contact lenses. Ocular myasthe-
nia gravis and other neuromuscular conditions can also produce
ptosis.
Clinical Evaluation of Horner Syndrome. The first,
and perhaps most important, aspect of evaluating suspected
Horner syndrome is a careful history. The history often reveals
an obvious cause, such as trauma or neck/chest surgery, or will
show that the Horner syndrome had been present for many
years and therefore may not require an extensive investigation.
The history may also reveal other symptoms that would help
localize the lesion causing the Horner syndrome. A careful
examination is obviously also critical, as other causes of anisocoria
or ptosis may need to be considered rather than Horner
syndrome, and concomitant signs (for example, a sixth nerve
paresis) may help localize a potential lesion. After this, pharma-
cologic testing can be helpful to confirm Horner syndrome, as
discussed extensively below. Next, all this information needs to
be combined to decide if additional investigation is necessary,
and if so decide on the best imaging strategy to evaluate the
suspected cause of Horner syndrome.
Though there is some disagreement on the exact interval,
many clinicians will elect not to evaluate Horner syndrome if it
has been present for greater than two years. For this reason,
evaluating old pictures, particularly those with sufficient resolu-
tion to see the pupils clearly, may avert an extensive and expen-
sive investigation. So-called “FAT scan” (family album tomo-
graphy) can be greatly beneficial and easier to obtain in this
digital age. Usually, a driver’s license is not sufficient to see the
pupils, though is helpful in showing ptosis. The best pictures
are usually graduation or school pictures.
Pharmacologic Testing. The diagnosis of Horner syn-
drome may be convincing based on clinical examination and
history alone, but often, the diagnosis is uncertain. Pharmaco-
logic testing can be performed in the clinic by placing eye drops
into the eyes to confirm the presence of Horner syndrome.
Apraclonidine is now the most commonly used agent, largely
supplanting cocaine eye drops as the pharmacologic test of
choice for Horner syndrome in adults. Hydroxyamphetamine
drops can be used to distinguish third-order neuron lesions
from first- and second-order lesions but are used infrequently as
the entire oculosympathetic pathway is usually imaged when
Horner syndrome is being evaluated.
Activation of the oculosympathetic end organs in the eye
(the pupillary dilator and Mueller’s muscle in the eyelid) occurs
when norepinephrine is released by the terminal axon into the
synaptic cleft, which then binds to receptors on the post-
synaptic cell membrane to initiate activation of the muscle
(pupil dilator or eyelid retractor). The amount of norepinephr-
ine in the synapse is increased by release from the presynaptic
bulb in response to neuronal activation. Norepinephrine is also
continuously reabsorbed and recycled by the presynaptic cleft.
In Horner syndrome, when there is no oculosympathetic activa-
tion, there is no release of norepinephrine into the synaptic
cleft. The postsynaptic membrane responds to this lack of
stimulation by upregulation, actually increasing the postsynaptic
receptors for norepinephrine (α-1 receptors). Pharmacologic
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agents used to tests for Horner syndrome exploit these mecha-
nisms to produce clinical tests that can confirm the presence of
an oculosympathetic paresis or localize the lesion within the
oculosympathetic chain.1
Apraclonidine. Apraclonidine is an α-2 adrenergic agonist
with weak α-1 activity. Clinically, it is an agent used to lower
intraocular pressure due to its α-2 agonist properties. Normally,
it has a negligible effect on pupil size; however, in patients with
Horner syndrome, it reliably dilates the pupil because of super-
sensitivity of the iris dilator muscle from upregulation of α-1
postsynaptic receptors. This clinically useful property was ser-
endipitously discovered when patients with Horner syndrome
were used to evaluate the intraocular pressure-lowering prop-
erties of apraclonidine. Patients with Horner syndrome were
specifically chosen because any pressure-lowering effect would
be entirely from local effects of the drug rather than any sec-
ondary systemic absorption and a sympathetic-mediated effect.
It was quickly realized that this unanticipated dilating effect
in an eye with Horner syndrome could provide a useful phar-
macologic diagnostic test,47 and indeed, this has proven to be
the case. A number of clinical studies show that apraclo-
nidine is both sensitive and specific for diagnosing Horner
syndrome,48−51 largely supplanting cocaine, which has histor-
ically been the diagnostic eye drop of choice (see Figure 4).
Apraclonidine has many advantages over cocaine eye drops: The
end point is obvious as it creates a reversal of the anisocoria
(unlike cocaine in which a positive test is when cocaine fails to
dilate the affected pupil); apraclonidine is readily commercially
available and does not have the stringent storage and use
regulations of cocaine.
The test is performed by placing 0.5% apraclonidine in both
eyes. The test is considered positive for the presence of Horner
syndrome if the anisocoria reverses: the smaller pupil in the eye
suspected of having the oculosympathetic paresis becomes
larger than the opposite eye at the end of 45 min (Box 1).
One potential drawback to this test is that it requires super-
sensitivity to be present, which means that an oculosympathetic
paresis has been present for a sufficient time for upregulation of
postsynaptic receptors to occur. Therefore, the test is not useful
in a suspected acute Horner syndrome but is generally thought
to be reliable after 2 weeks from onset of symptoms.52 Because
there are a few reported cases in which the test was positive
even within a few days,21,53 it is reasonable to try apraclonidine
testing in the acute period. A positive test should be considered
diagnostic, but a negative test in the acute period has no mean-
ing and cocaine testing should be performed.6
There are safety concerns with regard to the use of apraclo-
nidine eye drops in infants, including drowsiness and even
unresponsiveness,54 consistent with the known effects of other
adrenergic receptor agonists.55 Though with limited numbers,
other reports suggest apraclonidine 0.5% is safe in children
younger than 10 years old.22 However, given the current reports
in the literature, there is a general consensus that cocaine is the
preferred choice for pharmacologic testing of Horner syndrome
in infants and young children.45,56
Cocaine. Until the past decade, cocaine eye drops were the
agent of choice for diagnosing Horner syndrome.57,58 Cocaine
blocks the uptake of norepinephrine by the presynaptic mem-
brane. Therefore, it increases the concentration of norepineph-
rine in the synaptic cleft and causes pupillary dilation in the
normal eye. This is because in the normal eye there is always
some baseline sympathetic tone and therefore some release of
norepinephrine from the presynaptic cleft, balanced by the
183
Review
Box 1. Pharmacologic Testing for Horner Syndrome
Apraclonidine (Iopidine) 0.5% is readily available commer-
cially and is frequently used in the ophthalmologist office as a
pressure lowering agent prior to laser procedures such as YAG
capsulotomy. It has emerged as the preferred agent for
confirming Horner syndrome but should not be used in infants
and young children because of reported respiratory depression.
Because it depends on the development of denervation super-
sensitivity, this test may produce a false negative result if
performed within 2 weeks after the onset of Horner syndrome.
A positive test is indicated by reversal of the anisocoria, pro-
viding an unambiguous end point.
Cocaine hydrochloride 10% ophthalmic eye drops were the
standard for confirming Horner syndrome prior to apracloni-
dine and remains the preferred agent in infants and young
children. This test should be valid even in the acute phase of
Horner syndrome. However, because this agent is a controlled
substance, there are many obstacles with compounding and
storage. Patients should be notified that cocaine eye drops can
produce a positive urine drug screen. A positive cocaine test
for Horner syndrome is indicated by the failure of the affected
pupil to dilate with anisocoria of at least 1 mm remaining at
the end of the test.
Hydroxyamphetamine 1% solution is no longer commer-
cially available and thus must be compounded by a pharmacy.
After Horner syndrome has been confirmed, this agent can
be used to distinguish pre- from postganglionic Horner syn-
drome, as it reliably dilates any pupil with an intact third-order
neuron (even a preganglionic Horner syndrome pupil) but will
not dilate a pupil with loss of the third-order neuron. If this
test is to be performed after apraclonidine or cocaine testing,
one should wait at least 48 h. Therefore, the failure of a pupil
with Horner syndrome to dilate with hydroxyamphetamine
indicates a postganglionic Horner syndrome.
These topical pharmacologic tests are most accurate if they
are performed in eyes that have not had instrumentation (such
as applanation tonometry) or other eye drops at the time of
the evaluation. The tests are performed by placing a single
drop of the pharmacologic agent in the inferior cul-desac
in each eye with care to instill the same amount in each eye.
A second application is performed after several minutes. Sys-
temic absorption can be minimized by having the patient close
his/her eyes for several minutes after the drop is instilled. After
45 min, the end point is evaluated.
External photography showing the pupils and eyelids is
the best way to document the pretest baseline and the test
result; serving as a record for interpretation and for medical
documentation.
reuptake of norepinephrine. Therefore, blocking the reuptake
increases the amount of norepinephrine in the synaptic cleft,
activating the end organ (dilating the pupil, raising the eyelid).
However, in a patient with Horner syndrome with no oculo-
sympathetic outflow, there is no (or far less) norepinephrine
present in the synaptic cleft. Therefore, blocking the uptake of
norepinephrine with cocaine would have no effect on pupil size.
Therefore, this test relies on comparing the dilation response to
cocaine eye drops in an affected eye versus the normal eye.
Cocaine 10% is placed in both eyes, and the test is considered
positive for Horner syndrome if the affected eye does not dilate
as well as the normal eye. Clinical tests have shown that a
practical threshold for considering a test positive is a remaining
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anisocoria of at least 0.8 mm after 45 min59 or negative if the
suspected pupil dilates more than 2 mm.6 Several potential
problems are immediately evident. First, a positive end point is
not much different from the starting point; for example, mecha-
nical issues that keep a pupil from dilating (such as posterior
synechiae or neovascularization of the iris), or eye drops with-
out active cocaine for whatever reason, can produce a false
positive test. In addition, the compounding, storage, and use of
a controlled substance such as cocaine are difficult from a
practical perspective. It also has a short shelf life, and metab-
olites can remain in the urine for up to 2 days causing potential
problems for patients who may have to have a drug screening
test.60 Therefore, given the limitations noted above, it is no
surprise that apraclonidine has essentially replaced this histor-
ically important test in adults (but not infants, where cocaine is
deemed safer).
Hydroxyamphetamine. Hydroxyamphetamine dilates a
normal pupil as it forces presynaptic norepinephrine into the
synaptic cleft regardless of sympathetic activation.61 Hydroxy-
amphetamine will even dilate a patient with Horner syndrome
but only if the third-order neuron is intact. Dilation of a pupil
affected with an oculosympathetic paresis with hydroxyamphet-
amine 0.5% demonstrates that the lesion is a first- or second-
order neuron process because the third-order neuron is shown
to be intact. Failure to dilate with hydroxyamphetamine demon-
strates that the third-order neuron is not intact, as there is no
norepinephrine present at the terminal synapse, and is therefore
diagnostic of a postganglionic Horner syndrome.62,63 It is impor-
tant to note that a false-negative test can occur if hydroxyamphet-
amine testing is performed too soon after the third-order neuron
is affected (within 2−3 weeks of symptom onset), before atrophy
of the presynaptic bulb has occurred.64 Furthermore, trans-
ynaptic degeneration of the third-order neuron can occur even
from preganglionic lesions in congenital Horner syndrome (or
if acquired in the first year of life), which may falsely implicate a
third-order (postganglionic) lesion in infants.65 Hydroxyam-
phetamine testing should not be performed within 48 h of
apraclonidine or cocaine eye drop tests.
There is no doubt that the hydroxyamphetamine test is an
elegant method for refining the location of a lesion causing
Horner syndrome. However, most clinicians insist on imaging
the entire oculosympathetic pathway when a workup is indi-
cated in Horner syndrome, so hydroxyamphetamine testing is
not routinely performed.66
In addition to hydroxyamphetamine, there is some discussion
in the literature that a first-order (central) Horner syndrome
will not develop pupillary supersensitivity to the same degree as
second- and third-order lesions. These authors advocate the
use of very dilute phenylephrine (1%) or epinephrine (2%) eye
drops to separate these groups67 but this method has not
proven to be clinically reliable.7,68
Pharmacologic Testing Overview. All things considered,
using the apraclonidine test to test for Horner syndrome is by
far the easiest and most reliable test in adults. As noted above, it
does not work in acute Horner syndrome, as it takes several
weeks for supersensitivity to develop. If the diagnosis is required
on an acute basis, cocaine testing may still have some utility
despite the potential drawbacks discussed above. Furthermore,
cocaine is preferred over apraclonidine for diagnosing Horner
syndrome in infants and young children due to potential side
effects of apraclonidine. Once Horner syndrome is confirmed,
hydroxyamphetamine eye drops can be used to distinguish
between pre- and postganglionic lesions. Hydroxyamphetamine
184
Review
testing has some academic interest but usually does not change
the general indication for evaluating the entire oculosympa-
thetic pathway with imaging; thus, this step is often omitted.
Radiologic Investigation of Horner Syndrome. Imaging
is the primary investigative tool in Horner syndrome. The first
question to be answered by the clinician is whether or not
further investigation with imaging is even warranted. Patients
with long-standing isolated Horner syndrome (greater than two
years), or patients with an obvious cause of Horner syndrome,
may not require further investigation.69 When imaging is
indicated, the next question is which study or studies to order,
particularly given the large anatomic area that could harbor a
lesion. Imaging recommendations for evaluating Horner syn-
drome in the literature range from “one size fits all” to elaborate
decision trees that precisely tailor the study. In practice, the
imaging method depends on additional localizing signs and
symptoms and if the presentation of Horner syndrome is acute
or chronic.70−72
Sometimes the patient has additional symptoms or signs that
localize the cause of Horner syndrome with a reasonable degree
of certainty. For example, a patient with Horner syndrome and
neurologic symptoms of Wallenberg syndrome should have an
MRI of the head with and without contrast. A patient with
acute Horner syndrome and pain in the neck and face should
have an immediate CTA or MRA/MRI of the neck and head
for suspicion of a carotid dissection. A patient with arm pain
and a smoking history should have a CT of the chest or other
study directed at a suspected lung apex tumor. If directed studies
are negative, then any remaining portion of the oculosympathetic
pathway not adequately addressed should be imaged.
However, most often patients present with an isolated Horner
syndrome without other convincing localizing signs or sym-
ptoms. In these cases, most clinicians advocate imaging the entire
oculosympathetic pathway (regardless of hydroxyamphetamine
localization, if performed). In one study of 88 patients with
isolated Horner syndrome, 20% had a causative lesion on neuro-
imaging with carotid dissection being the most common.32 The
imaging choice depends on whether the symptoms are acute or
chronic. In the acute setting, an urgent CTA study that includes
the circle of Willis and orbits down to the level of the aortic
arch is recommended. This study allows excellent imaging of
the vascular structures for the possibility of carotid dissection
or other vascular disorders but also allows for visualization of
the lung apices and soft tissues of the neck and orbit. This
protocol has a number of advantages, including covering the
entire pathway and minimal imaging time to reduce movement
artifact.7
Patients who present with nonacute Horner syndrome, with
no pain, no localizing signs, and without a history of trauma,
may not require urgent imaging.73 In this setting, a contrast-
enhanced MRI with or without MRA including the brain and
neck from the hypothalamus to the T2 level in the chest has
been advocated.66,70 MRI offers better imaging of the brainstem,
hypothalamus, cervical cord, and brachial plexus compared to
CT imaging.
Children with Horner syndrome require MRI to best
visualize the sympathetic chain with some experts saying that
the MRI scan should also extend into the abdomen and pelvis73
to fully investigate the possibility of neuroblastoma. Additional
recommended studies include spot urine catecholamines, VMA,
and homovanillic acid.45
Management/Treatment. Horner syndrome usually does
not result in loss of function. Having a smaller pupil does not
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ACS Chemical Neuroscience
typically create symptoms, though there may be some excep-
tions; for example, patients with a central cataract might experi-
ence greater glare and a decrease in vision when the resting
pupil is smaller. By definition, the ptosis in Horner syndrome is
only 1−2 mm, and thus it is unlikely to affect vision. Therefore,
patients with Horner syndrome are usually asymptomatic and
mainly concerned about their appearance rather than complain-
ing of loss of function.
It is readily evident with diagnostic testing that apraclonidine
not only acts on the pupil in an eye with Horner syndrome but
likewise can elevate the eyelid in an affected eye as the post-
synaptic receptors and Mueller’s muscle are also upregulated and
become supersensitive to apraclonidine. Apraclonidine eye drops
therefore may have utility as a therapeutic agent for temporary
cosmetic reversal of the ptosis in Horner syndrome.74 Over-the-
counter eye drops containing naphazoline (sympathomimetic
agent used as a vasoconstrictor for red eyes) can have a sim-
ilar effect.75,76 Surgical intervention with a levator resection or
other method of ptosis repair has a high success rate because
the ptosis is reliably small and stable.
■
CONCLUSIONS
Although the ptosis and miosis of Horner syndrome may not
result in significant symptoms, recognizing Horner syndrome is
critical, as these findings point to a lesion in the oculosym-
pathetic pathway. Though often benign or idiopathic, the cause
of Horner syndrome can be very threatening or even lethal, so
understanding how to recognize, diagnose, and appropriately
evaluate Horner syndrome is important to all clinicians.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: tmmartin@wakehealth.edu.
ORCID
Timothy J. Martin: 0000-0001-7194-5560
Notes
The author declares no competing financial interest.
■
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DOI: 10.1021/acschemneuro.7b00405
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