REVIEW

CURRENT
OPINION An approach to anisocoria
Jordan R. Gross, Collin M. McClelland, and Michael S. Lee

Purpose of review
Anisocoria is a finding seen on a daily basis in nearly every eye clinic. Although often benign, it can also
represent the sole sign of a life-threatening disease making an up-to-date understanding of pathophysiology
and diagnosis essential for anyone practicing medicine.
Recent findings
Many aspects of the traditional approach to anisocoria still hold true today, but advancements in imaging
technology and changing trends in pharmacologic diagnosis and localization have led many to rethink that
approach. In addition, the differential diagnosis for anisocoria continuously expands with identification and
improved understanding of causal disease processes.
Summary
The present article discusses an approach to the classic anisocoria diagnostic algorithm modified by current
knowledge from the most recent literature.
Keywords
anisocoria, apraclonidine, autoimmune autonomic ganglionopathy, Horner syndrome, third nerve palsy

INTRODUCTION The efferent parasympathetic pathway (Fig. 1

The average ophthalmologist will see multiple
patients with physiologic anisocoria on a typical
clinic day. Although most patients are unaware
of it, some come specifically for evaluation. Ani-
socoria can represent vision or life-threatening
disorders, and the ophthalmologist must dis-
tinguish between benign anisocoria and dangerous
disease while simultaneously avoiding unnecessary
and costly evaluations. Essential to this task is
a sound knowledge of the causes of anisocoria,
their pathophysiology, and efficient, effective
diagnostic strategies. This review is not exhaustive,
but instead focuses on a practical approach to
anisocoria including differential diagnosis, tech-
niques to narrow or confirm a diagnosis in the
clinic, imaging modalities, and management of
specific disease processes.
NEUROANATOMY RELEVANT TO
ANISOCORIA
Anisocoria, unless caused by a mechanical abnor-
mality affecting the iris dilator or sphincter muscles,
is a neurologic phenomenon because of an imbal-
ance of the efferent autonomics. The parasympa-
thetic pathway causes miosis via activation of the
iris sphincter, and the sympathetic pathway causes
mydriasis through activation of the iris dilator.
[1]) arises from bilateral Edinger–Westphal nuclei
that each receive bilateral input from the pretectal
nuclei. Parasympathetic fibers then exit anteriorly
from the midbrain as a portion of the third cranial
nerve. From there the fibers follow the inferior
division of the oculomotor nerve until synapsing
in the ciliary ganglion between the optic nerve and
lateral rectus. The postganglionic fibers then travel
to the iris sphincter (and ciliary body) as the short
ciliary nerves.
The sympathetic pathway (Fig. 2 [1]) is a three-
neuron chain with the first-order neuron arising
from the hypothalamus and traveling to and
synapsing in the ciliospinal center of Budge at the
C8-T2 level within the intermediolateral cell col-
umn of the spinal cord. The second-order neuron
then travels through the sympathetic chain, passing
the adjacent lung apex, before synapsing with the
third (postganglionic) neuron at the superior cervi-
cal ganglion. From there the third-order neuron
Department of Ophthalmology and Visual Neurosciences, University of
Minnesota, Minneapolis, Minnesota, USA
Correspondence to Michael S. Lee, MD, 420 Delaware St SE, MMC
493, Minneapolis, MN 55455, USA. Tel: +1 612 625 3553;
Fax: +1 612 626 3119; e-mail: mikelee@umn.edu
Curr Opin Ophthalmol 2016, 27:486–492
DOI:10.1097/ICU.0000000000000316

www.co-ophthalmology.com Volume 27  Number 6  November 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

 An approach to anisocoria Gross et al.

KEY POINTS
Sympathetic
 Pilocarpine testing in cases of an abnormal dilated pathway
Hypothalamus
pupil is not as reliable as once thought and should be
used adjunctively in unclear cases. To Müller muscle

 Apraclonidine testing to confirm Horner syndrome is

useful and now favored over cocaine for its ease of use
and availability.

 Imaging of the entire sympathetic pathway in Horner

syndrome has become common practice, whereas Abducens
localization with hydroxyamphetamine has fallen out nerve
Long ciliary
of favor. nerve
3rd-order
neuron
 An ever-increasing knowledge of the causes and
pathophysiology of anisocoria have expanded the Superior
differential, requiring consideration of more recently cervical To face-sweat glands
described disorders such as autonomic autoimmune 1st-order
ganglionopathy and trigeminal neuron 2nd-order
autonomic cephalalgias. neuron

Subclavian artery

travels with the internal carotid artery until reach- Ciliospinal

center of
ing the cavernous sinus where it then follows the Budge-waller
sixth cranial nerve briefly before following cranial
nerve V1 first as the nasociliary nerve and finally as
the long ciliary nerves to reach the iris dilator. Lung

FIGURE 2. Sympathetic pathway. Anatomy of the sympathetic

pathway showing first-order central neuron, second-order
Parasympathetic
pathway intermediate neuron, and third-order neuron pathways. Note the
proximity of the pulmonary apex to the sympathetic chain. Note
also the intimate relationship of the sympathetic fibers to CN VI
Optic nerve within the cavernous sinus. Reproduced with permission [1].
Short ciliary nerve
Ciliary ganglion

ANISOCORIA: INITIAL CLINICAL

CN III
Optic tract
Edinger-westphal
nucleus
Pretectal nucleus Posterior commissure
FIGURE 1. Parasympathetic pathway. From the optic nerve,
the signal splits in the chiasm and travels along the optic
tracts. It leaves the tract before the lateral geniculate body to
synapse in the pretectal nuclei. The pretectal nuclei send
bilateral input to the Edinger-Westphal nuclei. The signal
then travels along the third nerves before synapsing in the
ciliary ganglion. From there, it travels to the iris sphincter
and ciliary body via the short ciliary nerves. CN
III ¼ oculomotor nerve. Reproduced with permission [1].
EVALUATION
The initial assessment of anisocoria aims to exclude
mechanical causes such as posterior synechiae, iris
sphincter tears, and surgical injury. Physiologic ani-
Red nucleus socoria represents the most common cause of pupil
asymmetry with 15–30% of the general population
Lateral geniculate body
exhibiting this phenomenon [2,3]. Physiologic
anisocoria should be longstanding, neurologically
isolated, less than 1 mm in size discrepancy, and
stable in light and dark conditions. Old photographs
readily available with the pervasiveness of personal
electronic devices and social media can be diagnos-
tically helpful and reassuring.
When anisocoria is not physiologic or mechan-
ical, we begin with the diagnostic algorithm
depicted in Fig. 3. Initially, we must determine
which pupil is abnormal. Anisocoria greater in the
light signifies an abnormal large pupil, whereas
anisocoria greater in the dark indicates an abnormal

1040-8738 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-ophthalmology.com 487

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Neuro-ophthalmology

Anisocoria algorithm

Anisocoria

Equal anisocoria
Greater anisocoria in light light/dark, <1 mm, Greater anisocoria in dark
 isolated, chronic 
Large pupil abnormal  Small pupil abnormal
Physiologic anisocoria

Ptosis and/or motility
Full motility, no ptosis
abnormality
Segmental
Third nerve palsy constriction,
light/near dissociation
Apraclonidine or cocaine
Dilation of abnormal
No dilation of abnormal
pupil/reversal of
pupil (apraclonidine)
anisocoria (apraclonidine)
or
Dilute pilocarpine or
<0.8 mm residual
≥0.8 mm residual
anisocoria (cocaine)
anisocoria (cocaine)

Constriction?
Tonic pupil Horner syndrome
Yes No

Wait 48 hours if choosing Localize clinically and

MRI/MRA
Non-dilute pilocarpine to localize with determine urgency of
brain, orbits
hydroxyamphetamine imaging

Constriction No constriction
Consider CTA to Adults Children
exclude smaller MRI/MRA MRI
aneurysms if MR Reconsider third nerve Pharmacologic brain, neck, upper brain, neck, chest,
negative palsy mydriasis chest abdomen, pelvis

FIGURE 3. Anisocoria algorithm. Solid arrows indicate our typical approach to diagnosis. Dotted arrows indicate optional
workup. CTA, computed tomography angiography; MRA, magnetic resonance angiography. Original work.

small pupil. One should also observe the briskness of
constriction and dilation, rule out a relative afferent
pupillary defect, assess pupillary response to near,
and evaluate for any ptosis or abnormalities in
extraocular motility and alignment.
THIRD NERVE PALSY
A pupil-sparing third nerve palsy (TNP) will not
appear as anisocoria. A pupil-involving TNP will
show a mid-dilated pupil that does not react to light
or convergence. In some cases, the pupil appears
larger but reacts and is deemed ‘relative pupil spar-
ing’. A couple of case reports exist where a TNP
presented as an isolated mydriatic pupil [4,5]. In
general, one should not consider an isolated efferent
pupillary defect as a TNP, but the clinician should
carefully evaluate for subtle ptosis or hyperdevia-
tions in eccentric vertical gaze in patients with a
dilated, unreactive pupil.
The most concerning cause of a TNP with aniso-
coria is posterior communicating artery aneurysm.
&
Lyons et al. [6 ] recently stated pupil-involving TNPs
in children, however, are typically not associated
with compressive lesions based on their prior small
case series. In our experience, nearly all aneurysmal
TNPs are painful, and this symptom may help guide
the diagnostic workup. Although CTA can detect
smaller aneurysms (threshold 1–2 mm), most clini-
cally relevant aneurysms are 4 mm and can be
detected with magnetic resonance angiography
(MRA; threshold 3–5 mm) or CTA [7]. We favor
emergent MRI/MRA in this scenario because MRI
can better detect other causative pathologies. If the
initial MRI is negative, then we consider CTA when
aneurysm suspicion remains high. Aneurysms may
be missed when the radiologist is not informed
that a TNP is present or the radiologist lacks formal
neuroradiology fellowship training [7].
TONIC PUPIL
Tonic pupil, or Adie pupil, is another commonly
encountered cause of anisocoria. It classically

488 www.co-ophthalmology.com Volume 27  Number 6  November 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


presents as a large pupil in young women with
or without visual symptoms. The pupil exhibits
light-near dissociation and will slowly dilate follow-
ing accommodative constriction. Pupil constriction
is frequently described as sectoral or vermiform [8].
Tonic pupil is typically unilateral at onset. Over a
period of years the involved pupil may become miotic
[9]. The diagnosis is generally clinical, but confirma-
tory pharmacologic testing can be performed
(see Pharmacologically Dilated or Miotic Pupil).
The study is often benign and idiopathic; how-
ever, autonomic disorders, ischemia, or virtually
any orbital process can be causative [10–16]. We
do not routinely perform laboratory or imaging
workup for unilateral cases and instead rely on
clinical context to guide further evaluation. MRI
of the orbits may be indicated if history or exam
suggest an orbital process. Systemic processes
should be strongly considered in bilateral cases
(see Autoimmune Autonomic Ganglionopathy).
PHARMACOLOGICALLY DILATED OR
MIOTIC PUPIL
The pharmacologically dilated (or less commonly
miotic) pupil occurs in two scenarios: accidental
versus intentional exposure to an agent that affects
pupillomotor function. The latter may or may not
have a secondary gain component. Known dilation
culprits include scopolamine patches, inhaled ipra-
tropium, nasal vasoconstrictors, glycopyrrolate
antiperspirants, and herbals such as Jimson weed,
Angel’s trumpet, and blue nightshade [17–23].
Smaller pupils are seen with exposure to pilocarpine,
prostaglandins, opioids, clonidine, and organo-
phosphate insecticides [24,25].
After excluding mechanical causes of an abnor-
mally dilated pupil with a careful history and slit
lamp exam, application of dilute (0.05–0.15%) and
nondilute (1–2%) pilocarpine can be considered.
Pilocarpine is a muscarinic agonist that directly acts
on the neuromuscular junction of the pupil
constrictor. In the case of a tonic pupil (duration > 2
2 weeks), the constrictor responds to denervation by
upregulating the number of receptors on the muscle
leading to a state in which it is hypersensitive and
will constrict with dilute pilocarpine. Evidence that
this test may not be as useful as once thought is
found in a small retrospective study that found no
difference in the response to dilute pilocarpine
between tonic pupils and those of pupil-involved
third nerve palsies [26]. Nondilute pilocarpine
should be instilled if there is no constriction
30–45 min following dilute pilocarpine adminis-
tration. Failure to constrict with nondilute pilocar-
pine indicates a pharmacologically dilated pupil.
1040-8738 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
An approach to anisocoria Gross et al.
HORNER SYNDROME
When the clinician is faced with an abnormal small
pupil, Horner syndrome needs to be ruled out
because it may be a harbinger of serious disease.
The classic triad of unilateral miosis, ptosis, and
anhidrosis can be subtle or incomplete. Dilation
lag of the miotic pupil in dark can be a helpful
adjunct finding [27]. This is typically detected with
measurements at 5 and 15 s following dark exposure.
The anisocoria is greatest at 5 s and significantly
less at 15 s. There is no abnormality in pupillary
constriction to light or near. In congenital cases,
and rarely in long-standing Horner syndrome, iris
heterochromia can be observed due to a lack of the
normal sympathetic input necessary for melanocyte
development [28].
PHARMACOLOGIC TESTING OF THE
ABNORMAL MIOTIC PUPIL IN
ANISOCORIA
When a Horner syndrome is suspected based on
clinical findings, although not required, it can be
confirmed with either 4–10% cocaine or 0.5–1%
apraclonidine testing. Instillation of cocaine should
be performed in both eyes initially and again 5 min
later. Cocaine blocks norepinephrine reuptake by
the presynaptic nerve terminal normally resulting
in pupil dilation 45–60 min later. In Horner
syndrome, the affected pupil will minimally dilate
or fail to dilate due to a lack of norepinephrine
release. Postdrop anisocoria of 0.8 mm or more is
considered positive [29]. A positive apraclonidine
test appears very different. Thirty to forty-five
minutes after drop instillation in both eyes the
abnormal eyelid will rise and the pupil will dilate,
sometimes ‘reversing’ the anisocoria, whereas the
normal pupil will remain unaffected or become
slightly smaller. Apraclonidine is an alpha-adrener-
gic agonist and its use in Horner syndrome relies on
denervation hypersensitivity much like dilute pilo-
carpine in tonic pupil. Because of this, it is less
reliable than cocaine in an acute Horner syndrome
and therefore requires a word of caution regarding a
negative result. The shortest reported time between
onset of symptoms and a positive apraclonidine test
is 36 h, but how long supersensitivity takes to
&&
develop is variable [30 ,31]. We have seen a case
where the apraclonidine test was negative 7 days
following carotid dissection. We do not use apra-
clonidine in children under 2 years old because it
may cause central nervous system and respiratory
depression. A recent comparison between 4%
cocaine and 0.5% apraclonidine in 10 patients age
1.2 to 16 years old found both to be well tolerated
and effective in diagnosis, but the numbers are small
www.co-ophthalmology.com 489
Neuro-ophthalmology
Table 1. Causes of Horner syndrome
First-order neuron Thalamic/hypothalamic/brainstem lesions
Wallenberg syndrome (lateral medulla)
Cervical spinal cord lesions
Syringomyelia
Klippel–Feil syndrome
Second-order neuron Lung and mediastinal tumors
Neuroblastoma
Benign sympathetic chain tumors
Jugular vein thrombosis
Thyroid lesions
Cervical lymphadenopathy and tumors
Local trauma
Iatrogenic
Third-order neuron Carotid artery dissection
Carotid artery sclerosis
Carotid agenesis
Cavernous sinus lesions
Trigeminal autonomic cephalalgias
Autoimmune autonomic ganglionopathy
Causes of Horner syndrome categorized by the neuron affected [16].
[32]. Apraclonidine’s value is in its availability,
whereas cocaine is more regulated and difficult to
obtain. Positive test results are also easier to inter-
pret with apraclonidine. There are case reports of
over-the-counter weak adrenergic agonists, or ‘get
the red out’ drops, masking ptosis and miosis in
patients with Horner syndrome, and in chronic
cases without an identified cause we will actually
suggest symptomatic management with these drops
if the patient desires [33,34 ].
&&
Neither cocaine nor apraclonidine aid in Horner
syndrome lesion localization, but 1% hydroxyam-
phetamine can help distinguish between a third-
order neuron and a first-/second-order neuron
lesion. Hydroxyamphetamine causes release of nor-
epinephrine into the neuromuscular junction, and
therefore bilateral pupil dilation, when the first- or
second-order neuron is involved. If the Horner pupil
fails to dilate, then a third-order neuron lesion is
indicated [29]. Pharmacologic localization is prob-
lematic because one must wait 48 h following
cocaine or apraclonidine, it has high false positive
and negative rates, and hydroxyamphetamine drops
are difficult to obtain [35,36]. For these reasons most
neuro-ophthalmologists, including our group, do
not use hydroxyamphetamine to localize.
MANAGEMENT OF HORNER SYNDROME
Table 1 lists common causes of Horner syndrome
broken down by which neuron is affected.
490 www.co-ophthalmology.com
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Localization in the clinic may, in some instances,
help tailor or prioritize the imaging that needs to be
completed. In ruling out carotid dissection, MRA
combined with MRI neck is preferred to CTA and
Doppler ultrasound unless the presentation is acute
in which case a CTA may be favored due to avail-
ability and speed. MRI of the brain and upper spinal
cord is preferred in cases where a first-order neuron
lesion is suspected based on brainstem or spinal cord
findings on exam. CT or MRI of the chest including
the lower neck is appropriate if there is a strong
suspicion for lung tumor.
Although pharmacologic testing, history, and
exam may suggest a lesion of a particular neuron,
recent publications seem to favor complete imaging
of the sympathetic pathway, which is our practice as
&
well [37 ,38]. We favor an MRI and MRA of the neck
with the MRI images extending from the hypothala-
mus to the upper chest in adults. Because of the risk
of neuroblastoma in children, we perform MRI of
the entire sympathetic chain into the abdomen and
& &
pelvis [39,40 ,41 ]. Although some experts advocate
for testing urine catecholamines in children, these
are not sensitive, and we do not routinely test for
them. Children with Horner syndrome at birth have
been reported to harbor neuroblastoma, so we image
nearly all Horner syndrome unless it has been
present > 1 year in an otherwise asymptomatic indi-
vidual [42]. Studies have shown that in both adult
and pediatric Horner Syndrome a causative lesion is
& &
often not identified [37 ,40 ,43]. Therefore, we do
not perform further workup if the MRI is normal.
TRIGEMINAL AUTONOMIC CEPHALALGIAS
Trigeminal autonomic cephalalgias are a group
of primary headache disorders characterized by uni-
lateral head pain with ipsilateral autonomic symp-
toms, most commonly lacrimation and rhinorrhea.
They are rare relative to the more common migraine
and tension type headaches. The group includes
cluster headache, paroxysmal hemicrania, hemicra-
nia continua, and short-lasting unilateral neuralgi-
form headache attacks with conjunctival injection
and tearing syndrome (SUNCT). Ptosis and/or mio-
sis (i.e. Horner syndrome) is a common finding and
makes up a portion of the diagnostic criteria for all
four, although is not required [44]. It is reported in
16–84% of cluster headache cases and can persist, to
a lesser degree, indefinitely with more prominent
findings during repeat attacks [45].
The disorders differ and are therefore classified
by frequency and duration of attacks. They each
have well described treatments if diagnosed appro-
priately. Like Horner syndrome, imaging should be
pursued in the initial workup to exclude other
Volume 27  Number 6  November 2016

causes unless the case is typical and lacking neuro-
logic deficits. Consultation with an experienced
neurologist or neuro-ophthalmologist is recom-
mended to guide treatment and confirm the diag-
nosis in atypical cases.
AUTOIMMUNE AUTONOMIC
GANGLIONOPATHY
Autoimmune autonomic ganglionopathy (AAG) is
a rare, more recently recognized entity with auto-
antibodies [ganglionic acetylcholine receptor anti-
body (gAChR-Ab)] targeting autonomic ganglia
& & && &
[46 ,48 ,49 ,51 ]. Both sympathetic and parasym-
pathetic systems can be affected; however, the para-
sympathetic ganglion seems to be affected more
frequently in regard to pupillary abnormalities. In
one study 40% of patients had pupil abnormalities.
&
Anisocoria has been observed [51 ]. In addition, a
small case series recently described an abnormality
called pupillary fatigue that is characteristic of AAG.
It is characterized by premature re-dilation after a 2 s
duration light stimulus in which an AAG pupil will
actually begin dilating nearly a full second prior to
light extinction [50].
GAchr-Ab are commercially available, but a
positive antibody test is not required for diagnosis
nor is it specific for AAG, although a higher titer is
&&
suggestive [47,49 ]. Patients can have any symp-
toms of dysautonomia, but orthostatic hypotension
&&
and anhidrosis are most commonly seen [49 ]. AAG
can affect all ages and it can present with concerning
features such as encephalitis or with coexisting
& &&
malignancy [47,48 ,49 ]. It can spontaneously
resolve, but damage to neurons may persist so
& &
immunotherapy is often indicated [46 ,47,51 ].
Consultation with an experienced neuro-ophthal-
mologist and/or immunoneurologist is recom-
mended if AAG is suspected.
CONCLUSION
Anisocoria is a common finding in the eye clinic.
The diagnostic approach to anisocoria has remained
relatively unchanged over time. However, there
have been several notable changes to the list of
possible causes, trends in diagnostic techniques,
and management. The present review has provided
a practical approach to anisocoria used in our clinic
that we believe provides good balance between
patient safety, accurate diagnosis, and responsible
use of healthcare resources.
Acknowledgements
None.
1040-8738 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
An approach to anisocoria Gross et al.
Financial support and sponsorship
This work was supported by the Department of Ophthal-
mology and Visual Neurosciences, University of Minne-
sota, Minneapolis, MN, USA.
Conflicts of interest
There are no conflicts of interests.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Kline LB. Pupil. In: Section 5. Neuro-ophthalmology of basic and clinical
science course. 2012–2013 Edition. San Francisco, CA: American Academy
of Ophthalmology; 2012. Illustration by Christine Gralapp.
2. Lam BL, Thompson HS, Corbett JJ. The prevalence of simple anisocoria. Am J
Ophthalmol 1987; 104:69–73.
3. Loewenfeld IE. ‘Simple central’ anisocoria: a common condition, seldom
recognized. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol
1977; 83:832–839.
4. Albayram S, Ozer H, Sarici A, et al. Unilateral mydriasis without ophthalmo-
plegia—a sign of neurovascular compression? Case report. Neurosurgery
2006; 58:E582–E583; discussion E-3.
5. Werner M, Bhatti MT, Vaishnav H, et al. Isolated anisocoria from an endo-
dermal cyst of the third cranial nerve mimicking an Adie’s tonic pupil. J Pediatr
Ophthalmol Strabismus 2005; 42:176–179.
6. Lyons CJ, Godoy F, E AL. Cranial nerve palsies in childhood. Eye (Lond)
& 2015; 29:246–251.
The authors discuss cranial nerve palsies in children and how they differ from those
in adults. The increased propensity towards aberrant regeneration and rarity of
acutely life threatening compressive lesions are emphasized as considerations in
clinical practice.
7. Elmalem VI, Hudgins PA, Bruce BB, et al. Underdiagnosis of posterior
communicating artery aneurysm in noninvasive brain vascular studies. J
Neuroophthalmol 2011; 31:103–109.
8. Thompson HS. Segmental palsy of the iris sphincter in Adie’s syndrome. Arch
Ophthalmol 1978; 96:1615–1620.
9. Thompson HS. Adie’s syndrome: some new observations. Trans Am Ophthal-
mol Soc 1977; 75:587–626.
10. Bowie EM, Givre SJ. Tonic pupil and sarcoidosis. Am J Ophthalmol 2003;
135:417–419.
11. Currie J, Lessell S. Tonic pupil with giant cell arteritis. Br J Ophthalmol 1984;
68:135–138.
12. Bennett JL, Pelak VA, Mourelatos Z, et al. Acute sensorimotor polyneuropathy
with tonic pupils and an abduction deficit: an unusual presentation of poly-
arteritis nodosa. Surv Ophthalmol 1999; 43:341–344.
13. Brooks-Kayal AR, Liu GT, Menacker SJ, et al. Tonic pupil and orbital glial-
neural hamartoma in infancy. Am J Ophthalmol 1995; 119:809–811.
14. Toth C, Fletcher WA. Autonomic disorders and the eye. J Neuroophthalmol
2005; 25:1–4.
15. Wirtz PW, de Keizer RJ, de Visser M, et al. Tonic pupils in Lambert-Eaton
myasthenic syndrome. Muscle Nerve 2001; 24:444–445.
16. Wilhelm H. Disorders of the pupil. Handb Clin Neurol 2011; 102:427–466.
17. Moeller JJ, Maxner CE. The dilated pupil: an update. Curr Neurol Neurosci Rep
2007; 7:417–422.
18. Openshaw H. Unilateral mydriasis from ipratropium in transplant patients.
Neurology 2006; 67:914.
19. Firestone D, Sloane C. Not your everyday anisocoria: Angel’s trumpet ocular
toxicity. J Emerg Med 2007; 33:21–24.
20. Izadi S, Choudhary A, Newman W. Mydriasis and accommodative failure from
exposure to topical glycopyrrolate used in hyperhidrosis. J Neuroophthalmol
2006; 26:232–233.
21. Thompson HS. Cornpicker’s pupil: Jimson weed mydriasis. J Iowa Med Soc
1971; 61:475–477.
22. Rubinfeld RS, Currie JN. Accidental mydriasis from blue nightshade ‘lipstick’. J
Clin Neuroophthalmol 1987; 7:34–37.
23. Thiele EA, Riviello JJ. Scopolamine patch-induced unilateral mydriasis. Pe-
diatrics 1995; 96 (3 Pt 1):525.
24. Slattery A, Liebelt E, Gaines LA. Common ocular effects reported to a poison
control center after systemic absorption of drugs in therapeutic and toxic
doses. Curr Opin Ophthalmol 2014; 25:519–523.
25. Dinslage S, Diestelhorst M, Kuhner H, Krieglstein GK. The effect of latano-
prost 0.005% on pupillary reaction of the human eye. Ophthalmologe 2000;
97:396–401.
www.co-ophthalmology.com 491
Neuro-ophthalmology
26. Jacobson DM, Vierkant RA. Comparison of cholinergic supersensitivity in third
nerve palsy and Adie’s syndrome. J Neuroophthalmol 1998; 18:171–175.
27. Pilley SF, Thompson HS. Pupillary ‘dilatation lag’ in Horner’s syndrome. Br J
Ophthalmol 1975; 59:731–735.
28. Jaffe N, Cassady R, Petersen R, Traggis D. Heterochromia and Horner
syndrome associated with cervical and mediastinal neuroblastoma. J Pediatr
1975; 87:75–77.
29. Antonio-Santos AA, Santo RN, Eggenberger ER. Pharmacological testing of
anisocoria. Expert Opin Pharmacother 2005; 6:2007–2013.
30. Kauh CY, Bursztyn LL. Positive apraclonidine test in Horner syndrome caused
&& by thalamic hemorrhage. J Neuroophthalmol 2015; 35:287–288.
Apraclonidine testing in Horner syndrome relies on denervation hypersensitivity,
which develops over a variable period of time from the initial insult, but has been
reported in this and another case as soon as 36 h from onset of symptoms. This is a
very important consideration in interpreting results of this test.
31. Lebas M, Seror J, Debroucker T. Positive apraclonidine test 36 h after acute
onset of Horner syndrome in dorsolateral pontomedullary stroke. J Neu-
roophthalmol 2010; 30:12–17.
32. Chen PL, Chen JT, Lu DW, et al. Comparing efficacies of 0.5% apraclonidine
with 4% cocaine in the diagnosis of horner syndrome in pediatric patients. J
Ocul Pharmacol Ther 2006; 22:182–187.
33. Lee MS, Harrison AR, Kardon RH. Patient use of Visine (tetrahydrozoline)
masks Horner syndrome. Br J Ophthalmol 2008; 92:149–150.
34. Pemberton JD, MacIntosh PW, Zeglam A, Fay A. Naphazoline as a confounder
&& in the diagnosis of carotid artery dissection. Ophthal Plast Reconstr Surg
2015; 31:e33–e35.
Patient use of over-the-counter weak adrenergic agents (so-called ‘get the red out’
drops) should be considered in cases suspicious for Horner syndrome with an
incomplete triad as these agents can mask the signs.
35. Cremer SA, Thompson HS, Digre KB, Kardon RH. Hydroxyamphetamine
mydriasis in Horner’s syndrome. Am J Ophthalmol 1990; 110:71–76.
36. Van der Wiel HL, Van Gijn J. Localization of Horner’s syndrome. Use and
limitations of the hydroxyamphetamine test. J Neurol Sci 1983; 59:229–
235.
37. Chen Y, Morgan ML, Barros Palau AE, et al. Evaluation and neuroimaging of
& the Horner syndrome. Can J Ophthalmol 2015; 50:107–111.
The authors discuss their preferences for pharmacologic confirmation of Horner
syndrome without pharmacologic localization and imaging the entire oculosympa-
thetic pathway in all patients with MRI/MRA (or CT/CTA depending on patient
characteristics and/or facility availability). They note that this protocol is cost-
effective and easier for the clinician.
38. Davagnanam I, Fraser CL, Miszkiel K, et al. Adult Horner’s syndrome: a
combined clinical, pharmacological, and imaging algorithm. Eye (Lond)
2013; 27:291–298.
39. Gibbs J, Appleton RE, Martin J, Findlay G. Congenital Horner syndrome
associated with noncervical neuroblastoma. Dev Med Child Neurol 1992;
34:642–644.
40. Kadom N, Rosman NP, Jubouri S, et al. Neuroimaging experience in pediatric
& Horner syndrome. Pediatr Radiol 2015; 45:1535–1543.
This study reports on the causes of Horner syndrome in children and advocates for
complete imaging of the oculosympathetic pathway with MRI with or without MRA.
It does not discuss imaging of the abdomen/pelvis to exclude neuroblastoma.
492 www.co-ophthalmology.com
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
41. Cahill JA, Ross J. Eye on children: acute work-up for pediatric Horner’s
& syndrome. case presentation and review of the literature. J Emerg Med
2015; 48:58–62.
This study is written for emergency medicine providers and discusses the various
etiologies of Horner syndrome in children and the variety of recommended imaging
protocols reported in the literature. It advocates for urgent imaging in general, and
admission for expedited evaluation of children in which neuroblastoma is suspected.
42. Zafeiriou DI, Economou M, Koliouskas D, et al. Congenital Horner’s syndrome
associated with cervical neuroblastoma. Eur J Paediatr Neurol 2006; 10:90–
92.
43. Maloney WF, Younge BR, Moyer NJ. Evaluation of the causes and accuracy of
pharmacologic localization in Horner’s syndrome. Am J Ophthalmol 1980;
90:394–402.
44. May A. Diagnosis and clinical features of trigemino-autonomic headaches.
Headache 2013; 53:1470–1478.
45. Rozen TD. Trigeminal autonomic cephalalgias. Neurol Clin 2009; 27:537–556.
46. Gupta A, Harris S, Vernino S, Naina HV. Rituximab-based therapy and long-
& term control of autoimmune autonomic ganglionopathy. Clin Auton Res 2015;
25:255–258.
This reports on a patient with AAG initially treated with mycofenolate and pre-
dnisone with incomplete reduction of gAChR-Ab who was then treated for
lymphoma with combination chemotherapy including rituximab and subsequent
levels of gAChR-Ab were undetectable. It reports rituximab as a potential therapy in
severe or intractable cases of AAG.
47. Koike H, Watanabe H, Sobue G. The spectrum of immune-mediated auto-
nomic neuropathies: insights from the clinicopathological features. J Neurol
Neurosurg Psychiatry 2013; 84:98–106.
48. Kuki I, Kawawaki H, Okazaki S, et al. Autoimmune autonomic ganglionopathy
& in a pediatric patient presenting with acute encephalitis. Brain Dev 2016;
38:605–608.
This case report importantly reminds one that AAG can affect children and can
present with a severe clinical picture as in this 13-year-old with orthostatic
hypotension and rapidly progressive disturbance of consciousness.
49. Li Y, Jammoul A, Mente K, et al. Clinical experience of seropositive ganglionic
&& acetylcholine receptor antibody in a tertiary neurology referral center. Muscle
Nerve 2015; 52:386–391.
This paper discusses evidence of the gAChR-Ab role in the pathophysiology of
AAG and its clinical utility in diagnosis, as a marker of treatment effect and as a
predictive indicator of malignancy risk. While it can be helpful, its value is limited in
all of these areas.
50. Muppidi S, Scribner M, Gibbons CH, et al. A unique manifestation of pupillary
fatigue in autoimmune autonomic ganglionopathy. Arch Neurol 2012;
69:644–648.
51. Nakane S, Higuchi O, Koga M, et al. Clinical features of autoimmune
& autonomic ganglionopathy and the detection of subunit-specific autoantibo-
dies to the ganglionic acetylcholine receptor in Japanese patients. PLoS One
2015; 10:e0118312.
This study reports on the development of a new assay to detect gAChR-Ab.
Importantly, it quantifies the prevalence of pupil abnormalities in AAG patients,
notes that the parasympathetic arm of the autonomics is more commonly affected
than the sympathetic in regard to pupil abnormalities, and reports anisocoria as one
of those abnormalities, confirming the possibility of asymmetry.
Volume 27  Number 6  November 2016