Anisocoria 

Updated: Dec 27, 2018
Author: Eric R Eggenberger, DO, MS, FAAN; Chief Editor: Edsel Ing, MD, MPH, FRCSC 

Overview

Background

Anisocoria, or unequal pupil sizes, is a common condition. The varied causes have implications ranging from life-threatening to completely benign, and a clinically guided history and examination is the first step in establishing a diagnosis.

Pathophysiology

Pupil size depends on the effects of the autonomic nervous system and the iris muscle, and numerous pathophysiological processes can cause anisocoria.

From the autonomic nerve standpoint, the parasympathetic system constricts the iris, while the anatomically distinct 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 as a plexus around 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 through the superior orbital fissure to their orbital targets. 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 travel with the oculomotor (cranial III) nerve, traverse the cavernous sinus, and enter the orbit via the superior orbital fissure to synapse in the ciliary ganglia. The short ciliary nerves then innervate the iris sphincter and muscles of accommodation.

Epidemiology

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 and population. The presence of physiologic anisocoria has been estimated at 20% of the normal population, so some degree of pupil difference may be expected in at least 1 in 5 clinic patients.

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 due to carotid dissection or third nerve palsy due to an aneurysm or uncal herniation.

Other causes of anisocoria are completely benign (eg, simple or physiologic anisocoria), although the unnecessary evaluation of these disorders may produce morbidity inadvertently.

 

Presentation

History

Isolated anisocoria is usually asymptomatic and incidentally discovered. Occasionally, anisocoria may be associated with visual symptoms (eg, unilateral photosensitivity with mydriasis, decreased accommodation with Horner syndrome) or have associated features that lead to evaluation (eg, diplopia, photophobia, pain, ptosis, blur).

Onset of anisocoria: Old patient photographs often help to date anisocoria that is unaccompanied by other symptoms.

A careful history can establish the etiology of anisocoria in some cases. Contact with a diverse variety of agents such as eye drops, scopolamine patches, asthma inhalers, or pet flea collars with anticholinesterase can cause anisocoria. Intraocular surgery can sometimes alter pupil size or reaction.

Causes of headache with anisocoria include Horner syndrome and trigeminal autonomic cephalgias, including cluster headache.

Physical

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

Pupil size (in mm) should be assessed in both light and dark with the patient fixating in the distance. Illumination of the pupil 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 author suggests that the abbreviation PERRLA (pupils equal, round, reactive to light and accommodation) be avoided. "A" for accommodation actually refers to the lens thickening in response to a near target and cannot be observed by the unaided eye.[1]

Pupil documentation should include the millimeter size of the pupils in light, the size in dark, light and dark reactivity of the pupils, shape, and iris color and comment on the presence or absence of a relative afferent pupillary defect (RAPD).

The use of a magnifying lens (eg, 20-diopter indirect ophthalmoscopy lens), slit lamp, autorefractor,[2] or pupillometer greatly assists in pupil examination.

Pupil reactivity

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.

Similar to muscle stretch reflexes, symmetry is often more important than the absolute number grade.

When assessing pupil light reaction, be careful to shine the light along the visual axis (this can be problematic if significant ocular misalignment exists).

Contraction anisocoria is a phenomenon in which the pupil of a directly illuminated eye constricts more than the pupil of the contralateral eye. A study using infrared binocular pupillography in 44 healthy girls and boys aged 6-16 years found that illuminating the right eye led to larger contraction anisocoria than stimulating the left eye, and that right-side lateralization of contraction anisocoria was much greater in the boys than in the girls; the anisocoria produced was well less than 0.5 mm and not of clinical relevance.[3]

An iris notch may suggest trauma and sphincter rupture as contributing to impaired constriction. Pseudoexfoliation, iris neovascularization, or posterior synechiae may hamper dilation.

Associated features

The presence of associated features should be checked carefully, as these are often key to the diagnosis. As in the evaluation of diplopia, several of the "Ps" and "Ds" are relevant: pupils, ptosis, proptosis, pain, paresis, paresthesia, diplopia, dysarthria, dysphagia, and dysesthesia.

Diplopia and ptosis along with anisocoria 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 but is also very typical of microvascular (ischemic or "diabetic") ocular motor neuropathies. Proptosis often indicates a space-occupying lesion within the orbit.

Causes

The causes of anisocoria are diverse and varied. Traditionally, physiologic anisocoria shows equal asymmetry in light and dark conditions. The following flowchart to deduce the specific cause.[4] See the diagram below.

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

For specific discussions of several of these topics, see the articles Oculomotor Nerve Palsy and Horner Syndrome.

Horner syndrome

Two conditions commonly produce normally reactive pupils with anisocoria equal or greater in darkness: Horner syndrome and physiologic anisocoria. In the English-language literature, Horner syndrome refers to sympathetic paresis that affects the eye (also known as oculosympathetic paresis, Claude Bernard-Horner syndrome). 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.

The sympathetic pathway begins in the hypothalamus, travels down the brain stem (where it is 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).

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).

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.

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.

Pharmacologic testing of Horner syndrome is helpful for diagnosis confirmation and to assist in localization. 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 30-45 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.

Testing with cocaine can give equivocal results, and it can be difficult to obtain and safely store as a controlled substance. Apraclonidine 1% or 0.5% has been proposed as a substitute.[5, 6] In patients with Horner syndrome, reversal of anisocoria usually occurs after bilateral instillation of apraclonidine via the drug's weak alpha-1 activity acting on a denervated supersensitive pupil. However, false-negative results have been reported in this setting.[7]

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 second-order ocular sympathetic neurons are dysfunctional, it is not a useful screening drug to detect Horner syndrome (see cocaine and apraclonidine, discussed above).

Accordingly, hydroxyamphetamine helps answer the question "Is the 3rd order sympathetic neuron intact?"

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 local or national pharmacies, including Leiter's (San Jose, CA; phone 800-292-6773). Although the causes of Horner syndrome are variable, several conditions are relatively common.

Apraclonidine 0.5% is more readily available than cocaine or hydroxyamphetamine. The apraclonidine is instilled in both eyes, and, after 30 minutes, the Horner pupil should be dilated (reversal of anisocoria).

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 and location (eg, disk disease or intrinsic cord disease such as syrinx, tumor, or inflammation).

Lung apex lesions (eg, Pancoast tumor) may produce a second-order Horner syndrome.

Carotid artery dissection often produces pain and is accompanied by Horner syndrome in many patients. See the images below.

Horner syndrome secondary to carotid dissection. N Horner syndrome secondary to carotid dissection. Note that degree of anisocoria is relatively mild in room light. Also, see the image below of the same patient.
Horner syndrome due to carotid dissection. Note th Horner syndrome due to carotid dissection. Note the increase in degree of anisocoria under dark conditions.

Cavernous sinus disease may produce a third-order Horner syndrome, often accompanied by other symptoms related to cranial nerve III, IV, V, or VI palsy such as diplopia.

Horner syndrome is a component of trigeminal autonomic cephalgia in some cases. There may be short-lasting unilateral neuralgiform headache with injection of the conjunctiva and tearing (SUNCT).

Oculomotor nerve palsy

Third nerve (oculomotor nerve) palsy affecting parasympathetic innervation to the pupil is often associated with compressive pathophysiology (unlike diabetic or ischemic third nerve palsy, which typically spares the pupil, and generally produces ≤1 mm anisocoria in the one third of ischemic oculomotor nerve palsies that do affect the pupil).

The pupil in third nerve palsy is poorly reactive and mydriatic compared with the contralateral pupil, as shown below; accordingly, anisocoria is maximal in light.

Typical pupil in third nerve palsy, with mydriasis 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.

An isolated dilated pupil without ocular dysmotility or ptosis rarely ("never") represents a third nerve palsy (it is important to check extreme of gaze for subtle misalignment suggestive of partial oculomotor nerve palsy). It is more likely related to a tonic, a mechanically, or a pharmacologically affected pupil.

The pupil may constrict upon adduction owing to aberrant regeneration. The physician should test for pupil-gaze synkinesis with the patient looking in the distance while moving the suspect eye into adduction.

Pharmacologic pupil

The pharmacologically dilated pupil is larger than in most other causes of anisocoria with mydriasis (often measuring 8-9 mm initially).

The pupil fails to respond to light stimuli, near stimuli, or 1% pilocarpine solution; mechanical iris disruption can also account for such findings and can be distinguished with slit lamp examination.

The remainder of the examination findings (ie, motility, eyelids, fundus, trigeminal function) should be normal, except near acuity (which is normalized with the use of a plus reading lens).

Instillation of atropine-like 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[8] , exposure to toxic plants such as Datura [Angel's Trumpet][9] ).

Mechanical

Mechanical damage to the iris muscle itself resulting from trauma, surgical intervention (eg, cataract extraction), iris synechiae (uveitis), and iridocorneal endothelial syndrome may produce anisocoria.

Acute angle closure is an important cause of mechanical iris dysfunction and poor pupil reactivity. An acute rise in intraocular pressure may cause the iris to mechanically occlude the trabecular meshwork (or drainage channels) in the anterior chamber’s angle. Acute presentation often includes pain, corneal edema, raised intraocular pressure, and a light-fixed midposition pupil. Angle-closure glaucoma is more frequent in hyperopes and certain races such as Asians and Inuits. The presentation may be confused with aneurysmal oculomotor nerve palsy owing to the pain and fixed pupil, but corneal edema and normal motility with angle closure help separate these entities. Treatment is directed at emergent lowering of intraocular pressure.

Slit-lamp examination, often a helpful diagnostic tool, demonstrates iris thinning or defects, or evidence of previous or current inflammation.

Tonic pupil

Tonic pupils respond poorly to light but briskly to a near target, and they maintain this near-induced miosis for a prolonged period (tonic). This condition constitutes one of the near-light dissociation syndromes. Other near-light dissociation syndromes include the following:

  • Autonomic neuropathies (eg, DM)

  • Severe afferent system damage

  • Aberrant regeneration CN3

  • Parinaud dorsal midbrain syndrome

  • Argyll Robertson pupils

The classic tonic pupil is the Adie tonic pupil. Adie tonic pupil responds tonically to near stimulation (the pupil takes longer to redilate after near fixation).

Slit-lamp examination is helpful, often demonstrating iris sector palsy (only a portion of the iris reacts to light), vermiform iris movements (radially oriented iris movements or "purse-stringing"), and providing excellent magnification to observe near-light dissociation. The pupil may be supersensitive to weak (1/8-1/16%) pilocarpine solution, which will not constrict a normal pupil.

Transient anisocoria: This has been documented as an intermittent feature in several conditions. Most often, it reflects a benign condition and may be associated with migraine headache, especially if no other associated features are present, but it can represent transient parasympathetic or sympathetic dysfunction from other causes.

Autoimmune autonomic ganglionopathy is a rare cause of anisocoria.

 

DDx

 

Workup

Laboratory Studies

Lab studies depend upon the specific etiology.

Imaging Studies

The use of imaging studies depends entirely upon the underlying cause of anisocoria.

Horner syndrome due to lateral medullary syndrome usually can be confirmed by MRI of the head. Imaging of the entire sympathetic pathway is common in the workup of Horner syndrome.[10]

Carotid dissection may be confirmed with magnetic resonance imaging (MRI) or angiography (MRA), computerized tomography angiography (CTA), contrast angiography, or Doppler ultrasound, depending on the segment involved, the level of suspicion, and the availability of imaging modalities. A T1-weighted MRI with fat saturation through the carotid course is the imaging modality of choice.

Third nerve palsies with pupillary involvement should be presumed compressive in origin. An enlarging or leaking berry aneurysm, if suggested by the presentation, is often 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. Imaging decisions are best made in consultation with the local radiologist after a discussion including the region and lesion of interest.

Procedures

Procedures depend upon the specific etiology.

Histologic Findings

Depends upon the specific etiology

Other Tests

Pupillometers can be used to accurately measure pupil size under various lighting conditions.[11]

 

Treatment

Medical Care

Medical care depends upon the underlying pathophysiology.

If the patient has unequal accommodation, reading glasses or bifocals may be required.

If the patient has mydriasis and glare, dilute pilocarpine, sunglasses, or FL-41 lenses may be beneficial.

Surgical Care

Surgical care depends upon the specific etiology.

Consultations

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

Further Inpatient Care

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

 

Medication

Medication Summary

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

Topical anesthetic agents

Class Summary

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

Cocaine

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.

Cholinergic agents

Class Summary

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

Pilocarpine ophthalmic (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.

Sympathomimetic agents

Class Summary

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.

Alpha2-adrenergic agonist agent, ophthalmic

Class Summary

These agents decrease IOP by reducing aqueous humor production.

Apraclonidine (Iopidine)

Potent alpha-adrenergic agent selective for alpha2-receptors with minimal cross-reactivity to alpha1-receptors. Suppresses aqueous production. Reduces elevated, as well as normal, intraocular pressure (IOP) whether accompanied by glaucoma or not. Apraclonidine is relatively selective alpha-adrenergic agonist that does not have significant local anesthetic activity. Has minimal cardiovascular effects.

Due to the weak, direct alpha-1 and alpha-2 receptor agonist effect, apraclonidine may reverse the Horner anisocoria (no effect on normal pupil, but Horner syndrome-related denervation supersensitivity produces pupil dilation).

 

Questions & Answers

Overview

What is anisocoria?

What is the pathophysiology of anisocoria?

How common is anisocoria in the US?

What are the mortality and morbidity of anisocoria?

Presentation

How is the patient history characterized in anisocoria?

What are the key aspects of the physical exam in anisocoria?

How is pupil reactivity graded in the assessment of anisocoria?

What is contraction anisocoria?

How do the associated features of anisocoria contribute to the diagnosis?

What causes anisocoria?

What is Horner syndrome, and how is it related to anisocoria?

How is the pathophysiology of anisocoria in Horner syndrome?

How is pharmacologic testing used in anisocoria and Horner syndrome?

What causes Horner syndrome?

How does oculomotor nerve palsy manifest in Horner syndrome?

How is a pharmacologic pupil characterized in the presentation of anisocoria?

How does mechanical damage to the iris contribute to anisocoria?

How are tonic pupils characterized in the presentation of anisocoria?

What is transient anisocoria?

DDX

What are the differential diagnoses for Anisocoria?

Workup

Which lab studies are indicated in the workup of anisocoria?

What is the role of imaging studies in the workup of anisocoria?

Treatment

What is the medical treatment for anisocoria?

What is the surgical treatment for anisocoria?

Which specialist consultations are indicated in the treatment of anisocoria?

Medications

Which agents are used in the diagnosis of anisocoria?

Which medications in the drug class Alpha2-adrenergic agonist agent, ophthalmic are used in the treatment of Anisocoria?

Which medications in the drug class Sympathomimetic agents are used in the treatment of Anisocoria?

Which medications in the drug class Cholinergic agents are used in the treatment of Anisocoria?

Which medications in the drug class Topical anesthetic agents are used in the treatment of Anisocoria?