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Anisocoria
Eric R Eggenberger, DO, MS, Vice-Chairman, Professor, Department of Neurology and Ophthalmology, Michigan State University Updated: Feb 23, 2007

Introduction
Background
Anisocoria, or unequal pupil sizes, is a common condition. The varied causes have implications ranging from life threatening to completely benign.

Pathophysiology
Various pathophysiological processes can cause anisocoria. However, pupil size depends upon the effects of the autonomic nervous system and the iris muscle. The parasympathetic system constricts the iris, while sympathetic channels dilate the iris. The sympathetic system begins in the hypothalamus, descends through the brain stem (including the lateral medulla) and into the cervical cord to synapse in the ciliospinal center of Budge-Waller at the C8-T1 level. The second-order neuron then exits the C8-T1 nerve root, travels over the lung apex, and ascends to the superior cervical ganglia with the carotid artery. The third-order neuron leaves the superior cervical ganglia to ascend with the internal carotid artery through the cavernous sinus, where fibers destined for the pupil dilator and the Mueller muscle of the eyelid travel with the trigeminal nerve. Fibers destined to modulate sweating of the face travel with the external carotid artery. The parasympathetic fibers begin in the Edinger-Westphal subnucleus of cranial nerve III in the midbrain. Parasympathetic fibers destined for the iris sphincter travel with the oculomotor (cranial III) nerve.

Frequency
United States Anisocoria is common, although no overall prevalence statistics are available. The incidence and prevalence data for anisocoria depend on the specific pathophysiology.

Mortality/Morbidity

Mortality and morbidity rates associated with anisocoria depend entirely upon the specific pathophysiology.

Several causes of anisocoria are life threatening, including Horner syndrome with carotid dissection or third nerve palsy due to aneurysmal expansion or rupture. Other causes of anisocoria are completely benign (eg, simple or physiologic anisocoria), although the evaluation of these disorders may produce morbidity inadvertently.

Clinical
History
The history of anisocoria is dependent on the specific pathophysiology.

The pupil size difference itself seldom produces specific symptoms. Associated features (with an underlying condition) may produce symptoms that lead to evaluation (eg, diplopia, photophobia, pain). Less commonly, anisocoria may be discovered incidentally by an observer.

Physical
Key aspects of the physical examination (eg, pupil size in light, pupil size in the dark, pupil reactivity) help to localize the problem. Additional historical features such as pain, diplopia, or ptosis help generate a differential diagnosis.

Pupil size (in mm) should be assessed in both light and dark. Transillumination by shining a light obliquely from below the patient's face and a handheld pupil gauge (found on most near-vision cards) assist in accurate assessment. The abbreviation PERRLA (pupils equal, round, reactive to light and accommodation) is best avoided. "A" for accommodation actually refers to the lens thickening in response to a near target and cannot be observed by the unaided eye. Onset of anisocoria o Old patient photographs often help to date anisocoria that is unaccompanied by other symptoms. o The use of a magnifying lens (eg, 20-diopter indirect ophthalmoscopy lens) or a slit lamp greatly assists this endeavor. Pupil reactivity o Pupil reactivity is graded subjectively on a scale of 0 (no reaction) to 4 (very brisk reaction), primarily to allow quantification of right and left asymmetry. o Similar to muscle stretch reflexes, symmetry is often more important than the absolute number grade. Associated features o The presence of associated features should be checked carefully, as these are often key features in diagnosis. As in the evaluation of diplopia, several of the "Ps" are relevantpupils, ptosis, proptosis, pain, poor movement.

Diplopia and ptosis may indicate the presence of a third nerve palsy. Pain often is associated with an expanding or ruptured intracranial aneurysm causing a compressive third nerve palsy or carotid dissections. Proptosis often indicates a space-occupying lesion within the orbit.

Causes
The causes of anisocoria are diverse and varied; refer to the flowchart at the end of this article to deduce the specific cause (see Image 1). For specific discussions of several of these topics see the articles Oculomotor Nerve Palsy and Horner Syndrome.

Horner syndrome o Two conditions produce normally reactive pupils with anisocoria greater in darknessHorner syndrome and physiologic anisocoria. In the English-language literature, Horner syndrome refers to sympathetic paresis that affects the eye. Features include ptosis, miosis, and anhidrosis; however, the exact presentation varies with the site of the lesion. The causes vary from life-threatening to benign conditions. o The sympathetic pathway begins in the hypothalamus, travels down the brain stem (where it is most often disrupted in the lateral medulla), through the cervical spinal cord to the level of the ciliospinal center of Budge-Waller at C8-T1, then over the lung apex, ultimately ascending with the carotid artery into the cavernous sinus to the pupil dilators and the Muller muscle of the lid. The sudomotor sweat fibers supplying the face exit onto the external carotid and its branches. The sympathetic nerve pathway has 3 divisions: first order (hypothalamus to C8-T1), second order (C8-T1 to superior cervical ganglia), and third order (superior cervical ganglia to the pupil dilators and lid). o Ptosis typically measures 1-2 mm; miosis often measures less than 2 mm and is greatest in the dark. The sympathetic fibers serve to dilate the pupil under conditions of dark or in response to psychosensory stimulation (ie, startle or pain). o Dilation lag refers to the slowed dilation of the affected pupil in response to dark. It can be assessed by viewing the pupils through several cycles of light and dark stimulation. o The anisocoria itself is asymptomatic, and the minimal ptosis often goes unnoticed. The associated features often prompt medical attention, or the condition may be discovered incidentally by an observer. o Pharmacologic testing of Horner syndrome is helpful. Application of a 4-10% cocaine ophthalmic solution can determine whether Horner syndrome is present. However, it will not specify the site or cause. Cocaine prevents reuptake of norepinephrine and dilates a normal pupil but not a sympathectomized pupil. After instilling 1-2 drops of 4-10% solution (painful for several minutes), postdrop anisocoria of greater than 0.8 mm correlates with greater than 1000:1 odds that the patient has Horner syndrome. The drops require approximately 3045 min for greatest effect, and more than 2 drops may be toxic to the cornea. The test also results in positive urine drug screens for cocaine for several days.

Hydroxyamphetamine (Paredrine) stimulates norepinephrine release from an intact third-order sympathetic neuron. If the third-order neuron is intact and functional, hydroxyamphetamine will dilate the pupil. Conversely, if the third-order neuron is dysfunctional, the medication will not produce this effect. Because hydroxyamphetamine dilates the pupil if the first- or secondorder ocular sympathetic neurons are dysfunctional, it is not a useful screening drug to detect Horner syndrome (see cocaine test already discussed). Accordingly, hydroxyamphetamine helps answer the question as to whether the third-order sympathetic neuron is intact. Thus, the viability of the third-order neuron can be determined. The test is interpreted by calculating the difference between the degree of anisocoria before and after medication. If, after hydroxyamphetamine instillation, the anisocoria increases by 1.2 mm or more compared to before medication, the lesion is postganglionic with greater than 90% probability. Hydroxyamphetamine may be obtained from several pharmacies, including Leiter's (San Jose, CA; phone 800-292-6773) and Thayer's (Orlando, FL; phone 800-848-4809). o Although the causes of Horner syndrome are variable, several conditions are relatively common. First-order Horner syndrome often is caused by stroke, most commonly Wallenberg lateral medullary syndrome. Cervical spine disease may cause either a first- or second-order Horner syndrome depending on the pathophysiology (eg, disk disease or intrinsic cord disease such as syrinx, tumor, or inflammation). Lung apex lesions (eg, tumor) may produce a second-order Horner syndrome. Carotid artery dissection often produces pain and is accompanied by Horner syndrome in many patients (see Images 2-3). Cavernous sinus disease may produce a third-order Horner syndrome, often accompanied by other symptoms such as diplopia. Oculomotor nerve palsy o Third nerve (oculomotor nerve) palsy affecting parasympathetic innervation to the pupil is associated with compressive pathophysiology (unlike diabetic or ischemic third nerve palsy, which typically spares the pupil). o The pupil in third nerve palsy is poorly reactive and mydriatic compared to the contralateral pupil (see Image 4). o The isolated dilated pupil without ocular dysmotility or ptosis rarely represents a third nerve palsy. It is more likely related to a tonic or a pharmacologically affected pupil. Pharmacologic pupil o The pharmacologically dilated pupil is larger than in most other causes of anisocoria (often measuring 8-9 mm).
o

The pupil fails to respond to light stimuli, near stimuli, or 1% pilocarpine solution. o The remainder of the examination findings (ie, motility, eyelids, fundus) should be normal, except near acuity (which is normalized with the use of plus lens reading glasses). o Instillation of atropinelike drugs may be either accidental or intentional, and potential sources of such exposure should be sought (eg, old eye drops in the house, exposure to medications such as inhalers). Mechanical o Mechanical damage to the iris muscle itself resulting from trauma, surgical intervention (eg, cataract extraction), or inflammation within the eye (uveitis) may produce anisocoria. o Slit-lamp examination, often a helpful diagnostic tool, demonstrates iris thinning or defects, or evidence of previous or current inflammation. Tonic pupil o Tonic pupils respond poorly to light but briskly to a near target. This condition constitutes one of the near-light dissociation syndromes. The classic tonic pupil is the Adie pupil. Adie pupil responds tonically to near stimulation (the pupil takes longer to redilate after near fixation effort). o Slit-lamp examination is helpful, often demonstrating iris sector palsy (only a portion of the iris reacts to light) or vermiform iris movements (radially oriented iris movements). The pupil may be supersensitive to weak (1/8% - 1/16%) pilocarpine solution, which would not constrict a normal pupil. Transient anisocoria: This has been documented as an intermittent feature in several conditions. More often, it reflects benign causes such as migraine headache, especially if no other associated features are present.
o

Differential Diagnoses
Basilar Artery Thrombosis Brainstem Gliomas Cardioembolic Stroke Cavernous Sinus Syndromes Cerebral Aneurysms Cervical Spondylosis: Diagnosis and Management Cluster Headache Dissection Syndromes Migraine Headache Migraine Headache: Neuro-Ophthalmic Perspective Migraine Headache: Pediatric Perspective Migraine Variants Multiple Sclerosis Neuro-ophthalmic Examination Neuro-ophthalmic History Neuro-ophthalmic Manifestations of Vascular Eye Diseases Raeder Paratrigeminal Syndrome

Other Problems to Be Considered

Cervical spine disease Cervical spine disk disease Horner syndrome

Lung disease at apex (eg, tumor) Neoplasm in brain, skull, or orbit Third nerve (oculomotor) palsy Uveitis Wallenberg lateral medullary syndrome Carotid disease and stroke

Workup
Laboratory Studies

Depends upon the specific etiology

Imaging Studies

The use of imaging studies depends entirely upon the underlying cause of anisocoria. o Horner syndrome due to lateral medullary syndrome usually can be confirmed by MRI of the head. o Carotid dissection may be confirmed with magnetic resonance angiography (MRA), contrast angiography, or Doppler ultrasound, depending on the segment involved, the level of suspicion, and the availability of imaging modalities. Third nerve palsies with pupillary involvement should be presumed compressive in origin. An enlarging or leaking berry aneurysm, if suggested by the presentation, is the compressive lesion that requires most immediate diagnosis. The choice of imaging type is dependent on the suspected pathophysiology: a cerebral aneurysm would be best imaged with angiography, while skull-based neoplasms are best demonstrated by MRI.

Procedures

Depends upon the specific etiology

Histologic Findings
Depends upon the specific etiology

Treatment
Medical Care
Depends upon the underlying pathophysiology

Surgical Care

Depends upon the specific etiology

Consultations
Depends upon the underlying cause. Compressive third nerve palsies may require neurosurgical intervention, while ophthalmologists may be helpful in other causes of anisocoria.

Activity
Depends upon the specific etiology

Medication
Drugs used in the diagnosis of anisocoria include cocaine, hydroxyamphetamine, and pilocarpine (0.1-1%).

Topical anesthetic agents

This agent is used for diagnostic testing to detect Horner syndrome.

Cocaine 4-10% (ophthalmic solution) Prevents norepinephrine reuptake and accordingly dilates eye with intact sympathetic nervous system supply. Decreases membrane permeability to sodium ions, which, in turn, inhibits depolarization and blocks conduction of nerve impulses. Dosing
Adult

1-2 gtt 4-10% OU

Pediatric

1 gtt 4% OU Interactions Increases toxicity of MAOIs Contraindications Documented hypersensitivity

Precautions
Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in hypertension, severe cardiovascular disease, thyrotoxicosis; avoid use in traumatized mucosa and sepsis at region of intended application; do not inject; corneal toxicity may result from overuse; urine drug screen will be positive for cocaine at least 24 h after use

Cholinergic agents
This agent is used for diagnostic testing related to tonic pupil (0.1% concentration) or pharmacologic dilation-induced anisocoria (1% concentration).

Pilocarpine 0.1 % (Isopto) Does not normally constrict pupil; however, with tonic pupil, produces miosis due to cholinergic supersensitivity. Constricts normal pupil or mydriatic pupil due to oculomotor palsy; however, after pharmacologic dilation (eg, atropinelike agents), pilocarpine has no miotic effects. Dosing
Adult

1-2 gtt OU
Pediatric

1 gtt OU Interactions May be ineffective when used concomitantly with NSAIDs Contraindications Documented hypersensitivity; acute inflammatory disease of anterior chamber; acute iritis; pupillary block glaucoma Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in acute cardiac failure, peptic ulcer, hyperthyroidism, GI spasm, bronchial asthma, Parkinson disease, recent MI, urinary tract obstruction, and hypertension or hypotension; miosis may cause difficulty with dark adaptation and night driving

Sympathomimetic agents
Hydroxyamphetamine is useful diagnostically to test integrity of the third-order sympathetic neuron.

Hydroxyamphetamine (Paredrine) Dilates pupil if third-order sympathetic neuron intact, and fails to dilate pupil if third-order neuron impaired. Dosing
Adult

1-2 gtt OU
Pediatric

1 gtt OU Interactions Beta-blockers may cause systemic adverse effects; exaggerated adrenergic effects may result as long as 21 d after MAOIs (supervise and adjust dosage carefully) Contraindications Documented hypersensitivity; narrow-angle glaucoma; anatomically narrow (occludable) angle without glaucoma Precautions
Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in hypertension, diabetes, hyperthyroidism, cardiovascular abnormalities, arteriosclerosis; rebound congestion may occur with frequent or extended use; rebound miosis may occur in older persons 1 day after phenylephrine treatment; reinstillation may produce reduction in mydriasis

Follow-up
Further Inpatient Care

Follow-up, treatment, prognosis, and educational issues depend upon the underlying diagnosis.

Further Outpatient Care

Depends upon the specific etiology

Inpatient & Outpatient Medications

Depends upon the specific etiology

Transfer

Depends upon the specific etiology

Complications

Depends upon the specific etiology

Prognosis

Depends upon the specific etiology

Patient Education

Depends upon the specific etiology

Miscellaneous
Medicolegal Pitfalls

Misdiagnosis of potentially life-threatening conditions o The most immediate concern is the oculomotor nerve palsy related to compression. Acute compression can take the form of uncal herniation in hemispheric mass lesions. However, other signs and symptoms of elevated intracranial pressure, including altered sensorium and cognition, are invariably present by the time third nerve palsy occurs in uncal herniation. Aneurysmal compression of the oculomotor nerve may also produce mydriasis in addition to other aspects of oculomotor nerve palsy. o Carotid dissection is associated with pain in almost all cases. This pain often involves the ipsilateral neck, face, and periorbital region. The majority of carotid dissections produce an ipsilateral Horner syndrome. Because carotid dissection can produce hemispheric infarctions, this diagnosis should be considered in any patient with a painful Horner syndrome.

Special Concerns

Depends upon the specific etiology

Multimedia

Media file 1: Flowchart to assist in the diagnosis of anisocoria (modified with permission from Thompson and Pilley)

Media file 2: Horner syndrome secondary to carotid dissection. Note that degree of anisocoria is relatively mild in room light (see Image 3).

Media file 3: Horner syndrome due to carotid dissection (same patient as in Image 2). Note the increase in degree of anisocoria under dark conditions.

Media file 4: Typical pupil in third nerve palsy, with mydriasis. Note the inability to adduct the right eye. This patient has a skull-based meningioma that is compressing the right third nerve. At rest, complete ptosis is present in the right eye; however, lid elevation with attempted adduction of the right eye is noted, which is consistent with aberrant regeneration.

References
1. Cremer SA, Thompson HS, Digre KB, Kardon RH. Hydroxyamphetamine mydriasis in

Horner's syndrome. Am J Ophthalmol. Jul 15 1990;110(1):71-6. [Medline].

2. Harle DE, Wolffsohn JS, Evans BJ. The pupillary light reflex in migraine. Ophthalmic

Physiol Opt. May 2005;25(3):240-5. [Medline].

3. Kardon RH, Denison CE, Brown CK, Thompson HS. Critical evaluation of the cocaine

4.
5. 6.

7.

test in the diagnosis of Horner's syndrome. Arch Ophthalmol. Mar 1990;108(3):3847. [Medline]. Lowenfeld IE. The Pupil. Anatomy, Physiology, and Clinical Application. Iowa State Press;1993. Miller NR, Newman NJ, eds. Walsh & Hoyt's Clinical Neuro-ophthalmology. Vol 1. 5th ed. 1998. Moster ML, Galiani D, Garfinkle W. False negative hydroxyamphetamine test in horner syndrome caused by acute internal carotid artery dissection. J Neuroophthalmol. Mar 2003;23(1):22-3. [Medline]. Thompson S, Pilley SF. Unequal pupils. A flow chart for sorting out the anisocorias. Surv Ophthalmol. Jul-Aug 1976;21(1):45-8. [Medline].

Keywords
unequal pupil size, Horner's syndrome, Horner syndrome, third nerve palsy, carotid dissection, aneurysmal expansion, aneurysmal rupture, simple anisocoria, physiologic anisocoria, oculomotor nerve palsy, pharmacologic pupil, iris muscle damage, tonic pupil, transient anisocoria, pupil disorder

Contributor Information and Disclosures

Author Eric R Eggenberger, DO, MS, Vice-Chairman, Professor, Department of Neurology and Ophthalmology, Michigan State University Eric R Eggenberger, DO, MS is a member of the following medical societies: American Academy of Neurology, American Academy of Ophthalmology, American Osteopathic Association, and North American Neuro-Ophthalmology Society Disclosure: Nothing to disclose. Medical Editor James Goodwin, MD, Director of Neuro-Ophthalmology, Associate Professor, Departments of Neurology and Ophthalmology, University of Illinois College of Medicine James Goodwin, MD is a member of the following medical societies: American Academy of Neurology, Illinois State Medical Society, North American Neuro-Ophthalmology Society, and Royal Society of Medicine Disclosure: Nothing to disclose. Pharmacy Editor Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine Disclosure: Nothing to disclose.

Managing Editor Robert A Egan, MD, Director of Neuro-Ophthalmology, St Helena Hospital Robert A Egan, MD is a member of the following medical societies: American Academy of Neurology, American Heart Association, North American Neuro-Ophthalmology Society, and Oregon Medical Association Disclosure: Nothing to disclose. CME Editor Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology Disclosure: Nothing to disclose. Chief Editor Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology Disclosure: Nothing to disclose. Further Reading 1994-2009 by Medscape. All Rights Reserved (http://www.medscape.com/public/copyright)