Anisocoria.17

ANISOCORIAAki Kawasaki

ABSTRACT

Pupillary size and movement are controlled by the autonomic nervous system,which innervates two muscles of the iris, the radial dilator (sympathetically inner-vated), and the circular sphincter (parasympathetically innervated). In the normalstate, the distribution of efferent pupillomotor signal to the iris is symmetric be-tween the two eyes so that pupil size is generally equal under varying lightingconditions. Similarly, reflex pupillary movements, eg, constriction and dilation, areidentical between the two eyes. Asymmetry in the pupillomotor neural output ortheir muscular forces results in impaired pupillary movement on one side andunequal pupil size between the right and left eyes. This chapter reviews theevaluation of anisocoria, both transient and persistent, in assuming that only oneside (pupil) is faulty and focuses on the neurologic causes of pupillary dysfunction.

Continuum Lifelong Learning Neurol 2009;15(4):218–235.

TRANSIENT ANISOCORIA

Transient unilateral mydriasis is a clini-cal sign that often raises the anxietylevel of the consulting clinician be-cause a dilated pupil may herald thepresence of a potentially devastatingneurologic condition. While this state-ment is true, benign explanations alsoexist. In sorting out the different causesof transientmydriasis, the patient’s back-ground medical history, mental status,and ocular motility findings can rapidlyassert whether the situation at hand isan emergency. The emergency diagno-ses to consider and their circumstancesare described in this chapter.

Brain Herniation

In a patient with an intracranial masslesion or acute expanding pathology,such as edema or hemorrhage, uni-lateral pupillary dilation may indicateimpending transtentorial herniation. Insuch a setting, the patient usually hasdeclining consciousness and develop-

ing focal neurologic deficits, includingophthalmoplegia. In an awake, alert,and neurologically intact patient whoreports transient mydriasis, brain her-niation is not a tenable consideration.

Seizure

Seizure-related mydriasis is associatedwith an abrupt change in mental statusas well as involuntary contraversivehead or eye movements. It is an ex-tremely rare occurrence.

Cerebral Aneurysm

Because of their peripheral locationwithin the interpeduncular portion ofthe oculomotor nerve, the pupil fi-bers are particularly prone to dysfunc-tion from compressive lesions. A dilatedpoorly reactive pupil may be an earlysign of a symptomatic intracranial an-eurysm, but the pupillary dysfunctionis not a transient abnormality and,moreover, is nearly always accompa-nied by eyelid or eye muscle weakness.

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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 topicalpilocarpine, topical cocaine, and topical apraclonidine in the clinical evaluation of anisocoria.

KEY POINT

A Transient

anisocoria,

if recurrent,

in a patient

with a normal

examination is

most often

benign.

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 neuro-logic deficits, a transient or episodicdilation of one pupil that recoverscompletely between episodes is notdue to an aneurysm.

Assuming that the patient who hasexperienced transient anisocoria isalert and without focal neurologic de-ficits at the time of examination, adetailed descriptive account of accom-panying symptoms or signs, such asvisual blur, pain, ptosis, impaired eyemovement, and conjunctival injection,is the first step, and often the only clue,to determining the mechanism of thetransient anisocoria. In an ideal world,patients would have had the presenceof mind to observe (or even pho-tograph) their anisocoria in ambientroom light and again with a flashlightshining on the eyes. This providesinformation regarding the responsive-ness of the pupils to light stimulation.An anisocoria that is notable when ex-tra light is added, eg, flashlight orsunlight, suggests that the mydriaticpupil is the abnormal one, since it failsto constrict as well as the contralateralpupil. Conversely, if the patient noticesanisocoria mostly in dim lighting con-ditions, then the smaller pupil likelyhas a dilating problem and marks theabnormal side. What then are possiblecauses of a transient anisocoria in anotherwise well patient?

Physiologic Anisocoria

Physiologic anisocoria is presumed tooccur from small and fluctuating differ-ences in the supranuclear modulatinginput to the paired parasympatheticEdinger-Westphal nuclei. Most patientswith physiologic anisocoria demon-strate persistent anisocoria, but thedegree of pupillary inequality can fluc-tuate from day to day and at times isso minimal as to go undetected by di-rect observation. In occasional patients,physiologic anisocoria is truly an epi-sodic phenomenon, and, more rarely,

it may even alternate sides, ie, theside of the larger pupil switches. Fur-ther discussion of physiologic anisoco-ria is found in the section ‘‘AnisocoriaGreater in Dim Light.’’

Intermittent SubacuteAngle-Closure Glaucoma

Angle-closure glaucoma may be a pri-mary disorder caused by a structurallynarrow anterior chamber angle or asecondary condition resulting from in-flammation, trauma, or ischemia. Whenthe anterior chamber angle closes, thenormal outflow of aqueous humor isacutely blocked, and intraocular pres-sure increases rapidly. Conjunctival in-jection and corneal edema developbecause of hypoxia and secondary cor-neal decompensation, producing vi-sual blur and haloes. The patient maynotice that the affected eye is red andtender to touch. The pupil is mildlydilated and fixed. Factors that may pre-cipitate angle closure include assuminga prone position, dark or dim lighting,prolonged near work, stress, sneez-ing, pharmacologic mydriasis, and cer-tain anesthetic agents. Patients, as inCase 15-1, can have repeated self-limited episodes of subacute angleclosure before a full-blown attack.In subacute cases, the angle reopensspontaneously and symptoms and signsresolve. An ophthalmic examination isrequired to visualize the narrow anglethat is predisposed to closure. Failureto recognize this cause of intermit-tent mydriasis can lead to persistent vi-sual loss.

Paroxysmal Dischargeof Irritated CervicalSympathetic Nerves

This phenomenon is a rare cause ofepisodic unilateral mydriasis describedin occasional patients with injury tothe cervical spine, upper cord, andbrachial plexus. Typically, other signs

219

Continuum Lifelong Learning Neurol 2009;15(4)

KEY POINTS

A Cerebral

aneurysm is

not a cause of

isolated,

transient,

unilateral

mydriasis.

A Determining

whether

anisocoria is more

notable in bright

light or in dim

light helps to

identify the

abnormal pupil.

A 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.


of sympathetic hyperactivity, notablyeyelid retraction, conjunctival blanch-ing, and facial hyperhidrosis, are pres-ent in addition to pupillary dilation.Visual blur is not a common feature.The pupil light reflex is normal, in-dicating intact oculo-parasympatheticfunction. Some patients later developa permanent oculosympathetic deficit(ie, Horner syndrome) on the sameside, presumably related to progressivedamage to the nerves.

Tadpole-shaped pupil is a relatedentity. Episodes of pupillary distortionwith peaking on one side results fromfocal spasmof the iris dilatormuscle andrepresents a benign entity (Thompsonet al, 1983).

Toxic Exposure

A dilated pupil can result from inad-vertent contact with plants containingbelladonna alkaloids, such as jimson-weed (thornapple), angel’s trumpet,deadly nightshade, and black henbane.These plants are cultivated as ornamen-tal shrubs, used as medicinal herbs, orfound growing wild along roadsides

and in fields, eg, cornpicker’s mydriasis.The degree of pupil dilation and loss ofreactivity to light varies, depending onthe amount of plant alkaloid exposure.Accommodative paresis accompaniesthe mydriasis so the diminished nearvision in one eye is a very helpful find-ing in young patients. In all cases, themydriasis resolves in 1 to 7 days. Ad-ditional discussion of pharmacologiccauses of anisocoria is found in the‘‘Pharmacologic Mydriasis and Pharma-cologic Miosis’’ section.

Migraine Attack

Anisocoria during a migraine attack isa well-described association, but themechanism is not fully established andmay vary between patients or be multi-factorial. In some patients, migrainousvasospasm causing local and reversibleischemia of the ciliary ganglion leads to adilated, poorly reactive pupil and ac-commodative palsy. In others, sympa-thetic dysregulation, occurring either asincreased or decreased activity, whichmay be unilateral or bilateral and asym-metric, has been described (Demarinis

220

Case 15-1A 62-year-old retired teacher was referred for recurrent episodes ofheadache, visual blur, and mydriasis on the right side. She describedthe headache as a dull pain around the right eye, which frequentlyappeared at night; the visual disturbance was a fuzziness with haloesaround lights. Symptoms always resolved by the following morning,and between episodes she felt fine and noticed no visual or pupillaryabnormalities. At the insistence of her husband, the patient soughtmedical advice. Her general and neurologic examinations were normal.Neuroimaging was normal. A tentative diagnosis of subacute angle-closureglaucoma was made, and following referral to an ophthalmologist, thediagnosis was confirmed.

Comment. Subacute angle-closure glaucoma causes unilateral eye,face, or head pain accompanied by blurred vision, typically lasting 30 to60 minutes. During an attack, the affected eye often becomes red as aresult of conjunctival injection, leading to confusion with cluster headache.The pupil is poorly reactive, and some patients notice the resultinganisocoria. The specific historical clues to this ocular diagnosis are the linkto low light (night occurrence with resultant pupil dilation) and seeinghalos (suggesting corneal edema) in the painful eye with mydriasis.


KEY POINT

A Disorders of the

cervical spine

and cord can

cause transient

mydriasis

and other

intermittent

symptoms related

to paroxysms

of excessive

sympathetic

discharge.

"ANISOCORIA


et al, 1998). It has also been suggestedthat some cases of anisocoria duringmigraine simply represent an exag-geration of an underlying physiologicanisocoria.

Benign Episodic Mydriasis

Also called a springing pupil, benignepisodic mydriasis is a descriptive termfor recurrent episodes of isolated unilat-eral mydriasis occurring in young adults,usually migrainous women (Case 15-2)(Jacobson 1995, Woods et al, 1984). Themydriasis typically appears in the sameeye but can alternate sides andmay occureither during a migraine or independentof headache. The duration of mydriasisis usually several hours, but it may per-sist for days. When examined during anepisode, some patients have a normalpupil light reflex, whereas others show apoor reaction to light with impaired ac-commodation. Some patients note visualblur, and others have orbital pain or a redeye. Benign episodic mydriasis probablyrepresents a heterogeneous group of dis-orders, including migraine-associated ani-socoria and physiologic anisocoria, withdifferent mechanisms that result in tran-sient and episodic anisocoria. It is called

benign because it is not associated withany systemic or neurologic condition.

ANISOCORIA GREATER INBRIGHT LIGHT

When observing the pupils in a patientseated quietly in room light, small spon-taneous oscillations of the pupil aresometimes noted. This phenomenon,known as hippus, is a normal finding.The baseline pupil size in room light isgreatest (7.0 mm to 7.5 mm) during theteenage years and then gradually de-creases with increasing age. Asymme-try of pupil size measuring 0.4 mmor more is visible to the unaided eyeand is considered anisocoria. If anisoco-ria is present, the first step is to checkthe pupil light reflex of each eye. Dimthe room light and ask the patient tofixate a distant target. This prevents anyunwanted pupillary constriction relatedto accommodation, ie, the near reflexconsisting of miosis, convergence, andaccommodation (lens thickening to fa-cilitate near focus). Shine a bright focallight (a disposable commercial penlightis usually not bright enough) directlyonto one pupil for 3 seconds and notethe amplitude and velocity of the pupil

221Case 15-2A 21-year-old woman recently developed severe and recurring headaches.A friend pointed out that her pupils were not the same size. Whenthe patient examined herself in a mirror later that same day, her pupilsappeared isocoric. One week later, the patient noticed that her rightpupil was much larger than her left pupil. Fearing a brain tumor, shesought urgent medical consultation. Examination revealed no anisocoria;specifically, her pupils measured 2.5 mm in bright light and 7.0 mm indarkness, with a brisk pupillary light reflex in each eye. Vision, eyelidfunction, and ocular motility were normal. A diagnosis of springingpupil 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 anisocoriawho has no systemic or neurologic condition known to affect pupilsand who demonstrates no abnormalities on ophthalmic and neurologicexamination.


KEY POINT

A Benign episodic

mydriasis is a

diagnosis of

exclusion based

on a clinical

description and

a normal

examination

between

episodes.


constriction of the illuminated eye. Ifone pupil reacts less vigorously and/orwith less amplitude to both direct andconsensual light stimulation, this is thefaulty pupil. When pupilloconstriction issubnormal in one eye, the magnitudeof anisocoria is obviously greater un-der bright light compared to dim light,and the larger pupil is clearly the ab-normal one (Figure 15-1). In general,the causes of a large poorly reactive pu-pil can be distilled down to mechanicalanisocoria, oculomotor nerve palsy, tonicpupil, and pharmacologic mydriasis(Table 15-1). These are discussed inthe following paragraphs.

Mechanical Anisocoria

The termmechanical anisocoria is usedwhen impaired pupil movement re-sults from defects in the iris framework,in particular, damage to iris sphinctermuscle. The sphincter cannot constrictnormally anddoes not respondnormally

222


TABLE 15-1 Causes ofAnisocoriaGreater in BrightLight

" Mechanical Anisocoria

Ocular trauma(eg, sphincter tear)

Iridectomy

Angle-closure glaucoma

Iris tumor or mass

" Neurologic Anisocoria

Oculomotor nerve palsy

Postganglionicparasympathetic nervepalsy (eg, tonic pupil)

" Pharmacologic Anisocoria

Topical anticholinergics

Topical sympathomimetics

Aerosolized bronchodilators

KEY POINTS

A In the evaluation

of anisocoria,

remember to

inquire about

any previous

infection,

inflammation,

trauma, or

surgery involving

the eyes,

including laser

procedures.

A 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.

FIGURE 15-1 Example of a patient who has an anisocoriathat is more notable in bright light. A,The patient is seated in a dark room,

and the pupils are viewed with tangential illumination. Thepupils are dilated and slightly unequal in size. B, The roomlight is turned on, and extra illumination with a brightflashlight is added. The patient’s anisocoria is much moreobvious now and the left pupil likely the faulty one as itis not constricting well.

"ANISOCORIA


to topical pharmacologic agents. Insevere cases of sphincter damage, thepupil may be widely mydriatic and lightfixed and near fixed. Ocular conditionsthat can lead to structural iris defectsare trauma, infection, intraocular sur-gery, inflammation (prior uveitis), lasertreatment, angle-closure glaucoma, andpseudoexfoliation. A thorough historyand, if possible, slit-lamp examinationis adequate for identifying most causesof mechanical anisocoria. Clues that irisdamage is the cause of anisocoria includedistortion of the pupillary shape, iristransilluminationdefects, synechiae, intra-ocular inflammation, and pigment disper-sion (Figure 15-2).

Neurologic Anisocoria

The neurologic basis for a large, poorlyreactive pupil is interruption within theoculo-parasympathetic pathway, whichmediates pupillary constriction and lensaccommodation. This is a two-neuronpathway (Figure 15-3). The first, orpreganglionic, neuron originates in theEdinger-Westphal subnuclei of the oc-

ulomotor nuclear complex in the dor-sal midbrain. Parasympathetic axons jointhe motor axons to form the oculomo-tor nerve, which exits the ventral aspectof the midbrain. Passing through theanterior cavernous sinus into the or-bit, the preganglionic parasympatheticfibers synapse in the ciliary ganglionin the orbit. The ciliary ganglion is thesite of the second, or postganglionic,

223

FIGURE 15-3 Schematic illustration of the two-neuronoculo-parasympathetic pathway.

Reprinted with permission from Kashii S, ed. Clinical neuro-ophthalmology.Tokyo: Kanehara and Co., Ltd, 2007:130.

FIGURE 15-2 Example of a mechanically deformed anddilated pupil due to metastatic melanomato the iris.



neuron. Postganglionic parasympatheticfibers are carried in the short ciliarynerves, which pierce the back of theglobe and travel anteriorly in the sclerato reach the iris sphincter and the cili-ary muscle. The neurotransmitter at thepostganglionic synapse is acetylcholine.

Oculomotor nerve palsy. The pre-ganglionic oculo-parasympathetic fibersrun peripherally alongside their con-frere ocular motor fibers within the

oculomotor nerve. Injury to the oculo-motor nerve that damages the pupilfibers will almost always involve one ormore of the motor fibers as well. Onlywith very rare exception is an isolatedpupil abnormality the sole manifes-tation of an oculomotor nerve palsy.Thus, in a patient with a large, poorlyreactive pupil, it is important to ask aboutdiplopia and look very closely for eyelidandmotility deficits (Bartlesonet al, 1986)

224

Case 15-3A 38-year-old healthy accountant had developed a severe, unremitting,left temporal headache that often kept him awake at night. Within1 week, he noted vertical diplopia especially when reading. Hisexamination showed normal vision, eyelids, and orbits. Sensory functionwas intact. He had a mild anisocoria and the pupil light reflex on theleft side was mildly sluggish. Ocular ductions and versions were full, butin downgaze, the patient reported diplopia. Cross-cover testing revealeda small left hypertropia in downgaze.

Comment. Thispatient has anacute, painful,partial oculomotornerve palsywith pupillaryinvolvement onthe left side(Figure 15-4). Theonly finding toindicate that hedoes not have anisolated anisocoriais a small ocularmisalignmentin downgaze.Followinghospitalizationand appropriateinvestigations, adiagnosis of Tolosa-Hunt syndrome(idiopathicinflammation ofthe cavernoussinus) is made.Treatment with oralsteroids results incomplete recovery.

FIGURE 15-4 Patient with an acute painful leftoculomotor nerve palsy with pupillaryinvolvement. A, The eyes are aligned in

primary position, the eyelids are symmetric, and a smallanisocoria is noticeable in room light. B, Ocular ductionsappear full (downgaze shown), but a small left hypertropiais revealed by cross-cover testing.


KEY POINT

A A subtle

oculomotor nerve

palsy might

appear as isolated

anisocoria, but

careful

examination

almost always

reveals

accompanying

motor deficits.

"ANISOCORIA


(Case 15-3). In some cases, the ocularmotor deficit is very subtle and notevident by testing ocular ductions alone.Cross-cover testing in all gaze positions orformal orthoptic testing is mandatory toreveal such subtlemotility deficits. Formalmeasurements of eyelid position andlevator function should be noted.

Pupillary dysfunction in the settingof an acute oculomotor nerve palsyraises the possibility of compressive pa-thology and is considered a neurologicemergency. Diagnoses to consider in-clude aneurysm, pituitary apoplexy, cav-ernous sinus inflammation, skull baselesion, and meningeal infection, amongothers (Kupersmith et al, 2006). On theother hand, acute unilateral mydriasisas an isolated finding represents pe-ripheral pathology at the level of theorbit or the eye in nearly all cases.

Tonic pupil. A tonic pupil repre-sents a lesion in the postganglionicparasympathetic pathway, ie, damageto the ciliary ganglion in the orbit orthe short ciliary nerves (Figure 15-5).In the acute stage of denervation, theiris sphincter and ciliary muscle areparalyzed. Patients report a dilatedpupil, photophobia, brow ache, and,in young patients, blur at near. Thedenervation injury, however, is typicallyincomplete, so only the involved sec-tors of iris sphincter are paralyzed; thisis sometimes visible as a focal flatten-ing of the pupil margin (Table 15-2,Figure 15-6). Dynamic observation ofsectoral sphincter palsy requires highmagnification with a slit lamp (Kardonet al, 1998). It is a powerful clinicalfinding because, in the absence of struc-tural iris damage, it is diagnostic ofpostganglionic oculo-parasympatheticdamage and effectively rules out ocu-lomotor nerve palsy and pharmaco-logic mydriasis.

Like many denervated end organs,the iris sphincter develops a supersen-sitivity to cholinergic agonists within afew weeks (earliest is 5 to 7 days) fol-

lowing injury. Dilute pilocarpine (0.125%or less) is the most commonly usedpharmacologic agent for testing for cho-linergic denervation supersensitivity ofthe iris sphincter. The proposed crite-rion for a positive response is either (1)the affected pupil constricts 0.5 mmmore than the unaffected pupil or (2)the suspected pupil, which was largerthan the normal pupil before instilla-tion of pilocarpine, becomes the smallerpupil after instillation (Table 15-3,Case 15-4). Despite its popular useamong clinicians, this pharmacologictest is neither specific nor particularlysensitive for tonic pupil. The presenceof cholinergic supersensitivity is alsofound in a dilated pupil with pregangli-onic denervation, ie, oculomotor nervepalsy ( Jacobson and Vierkant 1998).The absence of cholinergic supersen-sitivity does not rule out tonic pupil


FIGURE 15-5 Site of lesion causing Adie pupil. Theciliary ganglion and/or postganglionicfibers are damaged. There are separate

postganglionic fibers for pupil constriction and foraccommodation.

Reprinted with permission from Levin LA, Arnold A, eds.Neuro-ophthalmology: the practical guide. New York: Thieme, 2005.

KEY POINT

A For practical

purposes, isolated

unilateral

mydriasis is not

due to an

oculomotor

nerve palsy.

225


because only about 80% of cases de-monstrate this finding.

Following acute denervation, theshort ciliary nerves tend to regrow andseek their end organs (Loewenfeld andThompson, 1981). During this reinner-vation stage, resprouting accommodativefibers reconnect to the ciliary muscle,leading to improvement of near visionwith time. A relative abundance ofaccommodative fibers results in aberrantreinnervation of the iris sphincter as well.Thus, the pupil near reflex is alsorestored, but the constriction move-ment, as well as the redilation after anear effort, is slow and delayed, ie, tonic.Because the number of surviving pupil-loconstrictor fibers is sparse, the pupil-

lary light reflex never improves and insome cases gets worse. The combinationof a poor pupil light reflex with a betterpupil near response is termed light-near dissociation.

After several months to years, thebaseline size of an idiopathic tonic pupilbegins to decrease due to tonic firing inthe accommodative fibers innervatingthe sphincter. It is not unusual for achronic tonic pupil to be the smallerpupil in room light and the larger pupilin dim light because tonicity prevents itfrom full constriction and full dilation. Achronic tonic pupil still demonstratesthe classic features of a poor lightresponse, sectoral sphincter palsy, andlight-near dissociation.

Pharmacologic mydriasis. Topi-cal mydriatic agents can be divided intotwo categories: (1) parasympatheticinhibitors (anticholinergic substances)and (2) sympathomimetics. Productscontaining atropinelike anticholinergicsubstances include scopolamine patch,certain insecticides, plant-based bella-donna alkaloids such as Jimson weed,and anticholinergic inhalants used totreat respiratory disease. A pupil di-lated by an anticholinergic substance,eg, an atropinized pupil, is enormouslylarge, on the order of 8 mm to 9 mm,and nonreactive to light and near stim-ulation. It is distinguished from anacutely denervated pupil by the ab-sence of sectoral palsy and unrespon-siveness to full-strength (1% or 2%)pilocarpine eyedrops. An atropinizedpupil will not constrict to full-strengthpilocarpine, whereas a neurologicallydenervated pupil, such as a tonic pupilor oculomotor nerve palsy, constrictsvigorously to full-strength pilocarpineand, in most cases, also constricts todilute (0.125%) pilocarpine because ofdenervation supersensitivity.

Sympathomimetics are adrenergic-like substances that cause pupillary di-lation by excessively stimulating thedilator muscle, but they do not paralyze

226


A The clinical

features of an

Adie tonic pupil

evolve over time.

A 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 andFeatures of anIdiopathic Tonic(Adie) Pupil

TimeCourse Features

Day 1 Acute unilateralmydriasis appears

Pupil does notconstrict to light or tonear effort

Sectoral palsy of irissphincter is visible

Week 1 Denervationsupersensitivitydevelops

Week 8 Pupil remainsunresponsive to light

Pupil shows a slowsustained constrictionto near effort

Pupil redilation afternear constriction isalso slow

Week 16 Baseline pupil size (inroom light) decreases

Other features remain

KEY POINTS

A The presence of

cholinergic

supersensitivity

is not definitive

evidence of an

Adie pupil but

must be

considered with

the other

clinical findings.

A Sectoral palsy of

the iris sphincter

is the earliest

and most

specific feature

of anAdie pupil.

"ANISOCORIA


the sphincter muscle. Thus, the pupilretains a light reflex although it has lessamplitude compared with the normalpupil and will constrict quite well to full-strength pilocarpine. Mydriasis from asympathomimetic agent can be sus-pected from conjunctival blanchingand eyelid retraction in the eye withthe larger pupil. Examples include epi-nephrine, phenylephrine, ephedrine,hydroxyamphetamine, cocaine, oculardecongestants, and adrenergic inha-lants. Even in patients using eyedropsin both eyes, asymmetric absorption canlead to anisocoria.

ANISOCORIA GREATER INDIM LIGHT

If the pupillary light reflex is normal inboth eyes, then it can be assumed that theoculo-parasympathetic system and irissphincter are intact. The next step is toexamine and compare the magnitude ofanisocoria in darkness between the twoeyes. This is easily done by turning offthe room light and holding a penlight orhandheld flashlight at the patient’s chinto illuminate the eyes indirectly. Anisoco-ria that is greater in dim light is mostcommonly a physiologic anisocoria or aHorner syndrome,but thedifferential alsoincludes pharmacologic miosis, mechan-ical anisocoria, and aberrant regenerationof the oculomotor nerve (Table 15-4).

Physiologic Anisocoria

Also known as simple or essential orbenign anisocoria, this is the most

common cause of a difference in pu-pillary size. About 20% of the generalpopulation demonstrates a readily vis-ible anisocoria of 0.4 mm or more atany given moment (Lam et al, 1996).Physiologic anisocoria typically mea-sures 1.0 mm or less, although the mag-nitude of anisocoria in an individualvaries from day to day. The anisocoriais fairly equal in dim-light and bright-light conditions. The most importantaspect of physiologic anisocoria is thatboth pupils constrict normally to light

227


FIGURE 15-6 Example of distortion of pupil shapecaused by sectoral palsy of the irissphincter. In this patient with a tonic pupil,

the area of normally innervated sphincter lies betweenthe 11-o’clock and 4-o’clock positions and demonstratesthickening of the pupillary ruff and puckering of the irisstroma, changes consistent with sphincter contraction. Theparalyzed sector is between the 4-o’clock and 8-o’clockpositions. Note the looseness of the adjacent iris stromaand the flattening of the radius of pupil curvature.

TABLE 15-3 Pharmacologic Testing for Cholinergic Denervation Supersensitivity

Agent Drug Action Test Procedure Positive Result Example

Pilocarpine0.125%or less

Pilocarpine is a directcholinergic agonist; in diluteconcentration, it is generallytoo weak to constrict anormal pupil.

Put two drops ofdiluted pilocarpinein both eyes. Wait45 minutes.

Larger pupil becomessmaller pupil. Orsuspected pupil constrictsmore than normal pupil.

See Case 15-4


and dilate equally in darkness. Rarely,physiologic anisocoria can change sides.In other words, the larger pupil appears

sometimes on the right side and some-timeson the left side. This has been calledseesaw anisocoria. After instillation of

228


Case 15-4A 50-year-old woman developed aheadache behind her right eye and blurrednear vision. The next day she noticed thather right pupil was larger than her leftpupil. She was otherwise healthy. Onexamination 2 months after symptomonset the larger right pupil had noobservable reaction to direct or consensuallight stimulation (in darkness, the rightpupil 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 ofgaze. No ptosis was present.

High-magnification slit-lamp examinationof the right eye showed paralysis of mostof the iris sphincter except for two focalsegments that remained briskly reactive tolight stimulation. Following instillation ofpilocarpine diluted to 0.125%, the rightpupil was constricted whereas the left pupilwas unchanged (Figure 15-7C). A diagnosisof idiopathic tonic pupil (Adie pupil) wasmade, and, after discussion, the patient wasreassured and sent home.

Comment. Tonic pupils may occur from avariety of local processes affecting theciliary ganglion or short ciliary nerves, suchas orbital trauma (accidental or iatrogenic),tumor, ischemia, or infection. Tonic pupilsmay also occur as a manifestation of a morewidespread autonomic process, such asdiabetic or alcoholic peripheral neuropathy,and in these cases both pupils are affected.Most cases of tonic pupil, however, occuras a spontaneous unilateral condition,usually in women between the ages of20 and 50 years; it is this idiopathic formthat has been termed an Adie tonic pupil.When diminished muscle stretch reflexesare an associated finding, the conditionis called Adie or Holmes-Adie syndrome.Neuroimaging is not indicated for thepatient with a typical Adie pupil.

FIGURE 15-7 Patient with an Adie pupil on the right side.A, The right pupil is dilated and unreactiveto light. B, The right pupil constricts to near

effort (light-near dissociation). C, Following instillation ofdilute pilocarpine to both eyes, the right pupil is constricted.The left pupil is unchanged from the top frame.

"ANISOCORIA


topical cocaine, both pupils dilate so theanisocoria often disappears after cocaine.Noocular or neurologic abnormalities arerelated to physiologic anisocoria.

Pharmacologic Miosis

The use of pilocarpine or other topicalmedications for glaucoma may result ina small pupil. Often the miotic pupilconstricts poorly or barely at all to light.This is simply because thepharmacologicagent creates so small a pupil that ithas reached the mechanical limit. Thepharmacologic agent is usually a cholin-ergic parasympathetic agonist that di-rectly stimulates the iris sphincter.Although the dilator muscle remainsintact, it is not strong enough to over-come a maximally contracted sphinctermuscle. Thus, a pharmacologicallymioticpupil fails to dilate in darkness and totopical dilating drops, including sympa-thomimetic and anticholinergic agents.

Mechanical Anisocoria

Posterior synechiae after bouts of iritisor chronic pigment dispersion syndrome

can cause a small mechanically restrictedpupil. Like pharmacologic miosis, a pupilthat is mechanically tied down cannot

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TABLE 15-4 Causes ofAnisocoriaGreater inDim Light

" Mechanical Anisocoria

Iris adhesions, eg, priorinflammation

Pigment dispersion syndrome

" Neurologic Anisocoria

Horner syndrome

Aberrant regeneration ofoculomotor nerve

" Pharmacologic Anisocoria

Glaucoma medications

Topical anti-inflammatory

" Physiologic Anisocoria

TABLE 15-5 Common Causesof HornerSyndrome

" Central Lesion

Hypothalamic tumor

Brainstem infarct(eg, Wallenberg syndrome)

Demyelinating disease

Cervical cord trauma, tumor,or syrinx

" Preganglionic Lesion

Cervicothoracic cord lesion

Paravertebral tumor

Epidural anesthesia

Sympathetic chain tumor(eg, schwannoma)

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 gangliontumor (eg, paraganglioma)

Jugular vein trauma(eg, internal jugularcatheterization)

Parapharyngeal surgery

Internal carotid arterydissection

Cluster headache

Skull base pathology(eg, bony fracture,nasopharyngeal carcinoma)

Cavernous sinus meningioma

Carotid-cavernous fistula


dilate in response to any topical sympa-thomimetics or anticholinergics.

Horner Syndrome

Horner syndrome is caused by inter-ruption of sympathetic innervation to

the head and eye and results in miosis,ptosis, and facial anhidrosis on the sideof the lesion (Table 15-5). Weaknessof the superior and inferior tarsal mus-cles results in upper and lower eyelidptosis, which together cause a decrease

230

FIGURE 15-8 Two patients with a left Horner syndrome.A, The patient demonstrates obvious uppereyelid ptosis and lower eyelid ptosis (seen

as a rising up of the lower eyelid resting position), but heranisocoria is barely visible in room light. B, This patient hasmild left upper eyelid ptosis but a more pronouncedanisocoria in room light.

FIGURE 15-9 Pupillographic tracing of a patient with a Horner syndrome who demonstratespupillary dilation lag. Time in seconds is given at the top of the graph. Thebar indicates a 1-second light flash, which is followed by 15 seconds of

darkness. Following transient pupilloconstriction, the normal pupil dilates promptly and isnearly 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 bottomline shows the changing magnitude of anisocoria over time in darkness.

KEY POINT

A 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.


"ANISOCORIA


of the palpebral fissure and the appear-ance of enophthalmos (Figure 15-8).It is important to remember that theclassic triad of clinical findings is oftenincomplete. Ptosis is absent in 12% to13% of patients with Horner syndrome.Facial anhidrosis is seldom reported bypatients. Anisocoria is the most reliable,and sometimes only, manifestation ofan oculosympathetic defect. The clinicalfeature that differentiates Horner syn-drome from physiologic anisocoria isdilation lag of the smaller pupil in dark-ness. When the room light is abruptlyturned off, the pupil with an oculosym-pathetic defect shows slow and delayeddilation over 15 to 20 seconds compared

with the normal pupil, which promptlyredilates back to baseline within 3 to 5seconds (Figure 15-9). This finding isdiagnostic for Horner syndrome but isdemonstrable in only about 50% ofpatients. Therefore, practical diagnosisof Horner syndrome and distinctionfrom physiologic anisocoria usuallyrequires a pharmacologic test. Current-ly, two agents are used for this pur-pose: cocaine and apraclonidine.

Cocaine blocks the reuptake ofnorepinephrine released at neuromus-cular junctions of the iris dilator muscle,thereby increasing the amount of nor-epinephrine available to stimulate themuscle. Following instillation of cocaine

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TABLE 15-6 Pharmacologic Testing for the Diagnosis of Horner Syndrome

Agent Drug ActionTestProcedure Positive Result Example

Cocaine(4% or 10%)

Cocaine inhibitsreuptake ofnorepinephrinein postsynapticjunction(acts as indirectsympathomimetic)

Put two dropsof cocaine ineach eye; wait45 minutes

Postcocaineanisocoria of1.0 mm or more(smaller pupil isHorner pupil)

Before cocaine

After cocaine (right Hornersyndrome confirmed)

Apraclonidine(0.5% or 1%)

Apraclonidine’ssecondaryproperty is weakagonist action atpostsynaptic�1-adrenergicreceptors(ie, dilute directsympathomimetic)

Put one drop ofapraclonidinein each eye;wait 45 minutes

Postapraclonidinereversal ofanisocoria (largerpupil is Hornerpupil)

Before apraclonidine

After apraclonidine (rightHorner syndrome confirmed)



into the conjunctival sac, the normalresponse is pupillary dilation usuallyaccompanied by conjunctival blanchingand eyelid retraction. A sympatheticallydenervated eye does not respond tococaine, and the anisocoria is typicallyenhanced by cocaine. The magnitudeof postcocaine anisocoria is the mea-sured end point, with 1.0 mm or moreconsidered diagnostic of a Horner syn-drome (Table 15-6) (Kardon et al,1990).

Apraclonidine is a new drug used forlowering intraocular pressure through its�2-adrenergic action. However, apra-clonidine also has a weak �1-agonistactivity, which can stimulate a denervatediris dilator muscle because of ad-renergic denervation supersensitivity.Following topical instillation of apra-clonidine, a reversal of anisocori is

the current criterion for a ‘‘positive’’result that diagnoses a Horner syn-drome (Table 15-6) (Brown et al,2003). The advantage of apraclonidineis its ready availability in most oph-thalmology clinics.

The sympathetic pathway to the eyeis an ipsilateral, three-neuron pathway(Figure 15-10). In brief, the first-orderneuron (central neuron) originates inthe hypothalamus and descends thebrainstem to synapse in the lower cer-vical upper thoracic spinal cord (C8-T2).The second-order neuron (preganglionicneuron) exits the spinal cord and passesacross the apex of the lung and underthe subclavian artery to ascend the neckand synapse in the superior cervicalganglion. The third-order neuron (post-ganglionic neuron) supplies vasomotorand sudomotor function to the head andneck as well as pupillodilator and tarsalmuscle (Muller muscle) function in theeye. At the carotid bifurcation, the vaso-motor and sweating fibers travel pri-marily with the external carotid artery,whereas the oculosympathetic fiberstravel with the internal carotid arteryas a plexus around its wall. At theorbital apex, the oculosympathetic fi-bers follow the nasociliary nerve to theeye.

The differential diagnosis of a Hornersyndrome is influenced by the loca-tion of the lesion. In general, a centralHorner syndrome is usually strokerelated (eg, Wallenberg lateral medul-lary syndrome), so other symptoms andsigns of brainstem dysfunction areusually present. A preganglionic Hornersyndrome is known for its associationwith neoplasms of the pulmonary apex,mediastinum, or neck in 20% to 50%of cases. A postganglionic Horner syn-drome is often accompanied by painor headache for which considerationsshould include carotid artery dissection,tumors spreading along the skull base,lesions in the cavernous sinus, andcluster headache.

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FIGURE 15-10 Schematic illustration of the three-neuronoculosympathetic pathway.

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

"ANISOCORIA


Localization of the lesion using topi-cal 1% hydroxyamphetamine and ex-amination clues helps to direct theimaging studies. Following instillationof hydroxyamphetamine, if both pu-pils dilate, the Horner syndrome iscentral or preganglionic; if brainstemsigns are present, then a head MRI withcontrast is sufficient. If brainstem signsare absent, a head, neck, and chest CT

or magnetic resonance scan is an ap-propriate consideration depending onlocalization. If the Horner pupil doesnot dilate to hydroxyamphetamine, it isa postganglionic lesion. A painful post-ganglionic Horner syndrome warrantsinvestigation for a carotid dissection,particularly if accompanied by focalneurologic deficits, visual loss, dyspha-gia, or dysgeusia. In patients with

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Case 15-5A 34-year-old woman developed an acuteleft periorbital headache and left ptosis.Further questioning revealed that she hadspent the day before at an amusement parkwith some friends. Examination revealeda subtle decrease in her left palpebralfissure due to upper and lower eyelid ptosis(Figure 15-11). Subtle anisocoria was mostapparent in dim light. Pupillary dilation lagwas present on the left side, and cocainetesting showed failure of the left pupil todilate. A diagnosis of left Horner syndromewas made, and an emergent MRI revealeda dissection of the left internal carotidartery. The patient was hospitalized forappropriate management.

Comment. An acute and painful Hornersyndrome should be considered to resultfrom an acute carotid dissection untilproven otherwise (Biousse et al, 1998). Painis the most common symptom of carotiddissection. The location of the pain is usuallya focal area on the face or head ipsilateralto the side of the dissection. Other sites ofpain include the neck, jaw, pharynx, andear. Tinnitus or pulsatile sounds are alsofrequent symptoms, and this triad offindings (pain, Horner syndrome, tinnitus)is highly suggestive of an acute carotiddissection. Traumatic dissections are usuallycaused by severe blunt head or neck injury,such as motor vehicle accident, fist fighting,or manipulative neck therapy. In othercases, the precipitating event may havebeen trivial trauma, including coughing,sneezing, jerking the head to one side,painting a ceiling, or riding a rollercoaster, as in this patient.

FIGURE 15-11 Patient with a left Horner syndrome dueto carotid artery dissection, presumablyrelated 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-shapedhyperintensity adjacent to the left internal carotid artery(arrow), a characteristic appearance of dissection.


an acute and painful Horner syn-drome, pharmacologic localization withhydroxyamphetamine is often bypassedin order to expedite the imaging study(Case 15-5).

Most dissections are diagnosed withnoninvasive methods. On noncontrastaxial MRI images at the skull base, adissection characteristically appears asa T1 bright crescent of methemoglo-bin around the carotid artery. Luminalnarrowing is better documented withangiography (magnetic resonance, CT,or conventional contrast angiogra-phy). Treatment is aimed at preventingstroke. If a dissection is diagnosed in itsacute phase, eg, within 1 to 2 weeks ofsymptom onset, heparin anticoagula-tion is often recommended to reduceemboli formation. After approximately1 month, the risk of stroke is low (1%)and antiplatelet therapy alone is gen-erally adequate.

Congenital Horner syndrome is usu-ally caused by birth trauma to thebrachial plexus. Horner syndrome ac-quired in early childhood raises thepossibility of neuroblastoma arising in

the sympathetic chain of the chest.Clinical analysis of the urine for de-termination of catecholamine excretionas well as imaging of the neck, chest,and abdomen may also be warranted.

Aberrant Regeneration of theOculomotor NerveIn the primary position, the affectedpupil has a poor light reflex due todamaged parasympathetic pupil fi-bers that have never recovered.However, when the patient supra-ducts, infraducts, or adducts the eye,the pupil synchronously constricts.This is a synkinesis and occurs be-cause regenerating fibers originallydestined to the motor muscles aremisguided to the iris sphincter. Overtime the sphincter is increasinglyreinnervated by these aberrant motorfibers and the resting size of the pu-pil becomes smaller, as occurs with achronic tonic pupil; this aberrant oc-ulomotor pattern is always accom-panied by other third-nerve motordysfunction.

REFERENCES

Bartleson JD, Trautmann JC, Sundt TM Jr. Minimal oculomotor nerve paresis secondaryto unruptured intracranial aneurysm. Arch Neurol 1986;43(10):1015–1020.

Biousse V, Touboul PJ, D’Anglejan-Chatillon J, et al. Ophthalmologic manifestationsof internal carotid artery dissection. Am J Ophthalmol 1998;126(4):565–577.

Brown SM, Aouchiche R, Freedman KA. The utility of 0.5% apraclonidine in thediagnosis of Horner syndrome. Arch Ophthalmol 2003;121(8):1201–1203.

DeMarinis M, Assenza S, Carletto F. Oculosympathetic alternations in migraine patients.Cephalalgia 1998;18(2):77–84.

Jacobson DM. Benign episodic unilateral mydriasis: clinical characteristics.Ophthalmology 1995;102(11):1623–1627.

Jacobson DM, Vierkant RA. Comparison of cholinergic supersensitivity in third nervepalsy and Adie’s syndrome. J Neuroophthalmol 1998;18(3):171–175.

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Kardon RH, Corbett JJ, Thompson HS. Segmental denervation and reinnervation of theiris sphincter as shown by infrared videographic transillumination. Ophthalmology1998;105(2):313–321.

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Lam BL, Thompson HS, Walls RC. Effect of light on the prevalence of simple anisocoria.Ophthalmology 1996;103(5):790–793.

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