Approach to the patient with anisocoria

INTRODUCTION — Causes of anisocoria range in seriousness from a normal, physiologic condition to one that is immediately life threatening. When a patient presents with anisocoria, the fear of a serious condition, such as an intracranial aneurysm, often leads clinicians to obtain numerous tests, which are not always necessary. A logical clinical approach appreciating the mechanisms of anisocoria permits prompt recognition of true emergencies and often obviates the need for invasive and costly testing (algorithm 1) [1].

NEUROANATOMY AND PHYSIOLOGY — Pupillary size is governed by the balance of actions of two opposing muscle groups of the iris: the dilator and sphincter pupillae. Regulation of the pupillary size is predominantly achieved by reflex mechanisms in response to the amount of ambient light. Other factors influencing pupillary size include patient age, emotional state (adrenergic tone), state of arousal, and intraocular pressure [1,2].

Constriction — Pupillary constriction to light and near stimuli is mediated via parasympathetic (cholinergic) nerve fibers that travel along the third cranial nerve. The pupillary light reflex pathway is a four-neuron pathway (figure 1) [1,2]:

●Light information from retinal ganglion cells travels though the optic nerves, optic chiasm (where the nasal fibers decussate), and the optic tracts, before synapsing in the pretectal nuclei of the dorsal midbrain. Both pretectal nuclei receive input from both eyes.

●Each pretectal nucleus sends axons to both Edinger-Westphal nuclei. This duality of pathways provides the anatomic basis for the consensual response to light (ie, the fact that both pupils constrict equally in response to a light stimulus in one eye).

●Parasympathetic fibers for pupillary constriction travel along the third cranial nerve to the ipsilateral ciliary ganglion within the orbit.

●The pupillary sphincter muscle (and ciliary muscle for lens accommodation) is innervated by the postganglionic parasympathetic fibers.

The constriction of the pupil to near stimuli is also accomplished through the parasympathetic pathways. The near-reflex pathway descends from higher cortical centers directly to the Edinger-Westphal nuclei, bypassing the pretectal nuclei in the dorsal midbrain. This distinction between the light and near pathways forms the basis for some forms of pupillary light-near dissociation (ie, pupils that do not react to light but react to near stimuli), in which the dorsal midbrain and pretectal nuclei are damaged selectively [1,2].

Dilation — Pupillary dilation is mediated through three-neuron sympathetic (adrenergic) pathways that originate in the hypothalamus (figure 2):

●The first-order neuron descends caudally from the hypothalamus to the first synapse, which is located in the cervical spinal cord (levels C8-T2, also called ciliospinal center of Budge).

●The second-order neuron travels from the sympathetic trunk, through the brachial plexus, over the lung apex. It then ascends to the superior cervical ganglion located near the angle of the mandible and the bifurcation of the common carotid artery.

●The third-order neuron then ascends within the adventitia of the internal carotid artery, through the cavernous sinus, where it is in close relation to the sixth cranial nerve [1,3]. The oculosympathetic pathway then joins the ophthalmic (V1) division of the fifth cranial nerve (trigeminal nerve). In the orbit and the eye, the oculosympathetic fibers innervate the iris dilator muscle as well as Müller's muscle, a small smooth muscle in the eyelids responsible for a minor portion of the upper lid elevation and lower lid retraction.

EXAMINATION OF THE PUPIL — Pupillary examination is best conducted in dim light. It is essential to turn the lights off to evaluate the pupils. Horner syndrome, in particular, is usually overlooked in an illuminated room. We often employ a storage room or closet if necessary [4]. A bright light (such as from a fully charged ophthalmoscope) and a pupillary size gauge (usually found on near acuity cards) are the only tools necessary for pupillary evaluation. The patient should be relaxed and fixing on a distant object, rather than focusing on the examiner's light, which may cause miosis from the pupillary near reaction.

The size, shape, and position of each pupil should be noted in light and dark conditions. In a normal patient, the pupils are symmetric in size (difference less than 0.4 mm), shape, and position (figure 3). Pupillary reactivity is then assessed to light and near stimuli.

Light reflex — The pupillary reaction should be observed both when the light is shined into the eye (observe the pupillary constriction in both eyes) and later as the light is moved down and away from the eye. The magnitude, speed, and symmetry of the direct and consensual responses should be noted.

Dilation lag is the asymmetry in pupillary redilation between the two eyes when the light source is moved away from the eye. It is usually indicative of a sympathetic innervation abnormality causing slower dilation of the affected pupil (Horner syndrome), but is also a feature of the tonic (or Adie) pupil (picture 1) [1,5].

A relative afferent pupillary defect is noted when one pupil's direct response to light is more sluggish than in the opposite eye (see "The detailed neurologic examination in adults", section on 'Afferent pupillary defect'). This is a sensitive test for an abnormality of the afferent visual pathways (eg, optic neuropathy). However, a relative afferent pupillary defect does not cause anisocoria even with severely decreased visual acuity in one eye. There is no anisocoria because of the intact consensual pupillary response to light.

Near reflex — The near target reaction is tested when the light response is abnormal. This is assessed with an accommodative target such as reading the near acuity card, viewed at approximately 1 foot from the eyes. In patients who are unable to converge or are blind, the near reaction can be elicited by having the patient look at their thumb when held at reading distance. The degree of pupillary constriction to near target is normally less than that seen with direct light stimulation.

Light-near dissociation is said to exist when the light reaction is impaired with a normal near reaction. Causes of light-near dissociation are listed in the table (table 1).

CLINICAL APPROACH — The algorithm shows a stepwise clinical approach to diagnosis in a patient with anisocoria (algorithm 1).

Identifying the abnormal side — The first step is to determine whether the abnormal pupil is the large pupil or the small pupil by carefully evaluating the pupillary reactions in dark and light conditions (figure 3) [6].

The small pupil is abnormal if anisocoria is greater in the dark than in light, indicating poor pupillary dilation on the abnormal side (figure 3). This indicates an abnormality of the sympathetic system.

The larger pupil is abnormal if anisocoria is greater in the light than in dark, indicating poor pupillary constriction on the abnormal side (figure 3). This indicates an abnormality of the parasympathetic system.

Associated clinical features — Anisocoria itself is not usually associated with clinical symptoms; however, patients with mydriasis can complain of photosensitivity and decreased near vision because of impaired accommodation.

The evaluation of pupil asymmetry in the setting of coma is discussed separately. (See "Stupor and coma in adults", section on 'Pupils' and "Evaluation of stupor and coma in children", section on 'Pupils'.)

Other historical details or neurologic abnormalities on examination can be helpful in suggesting an etiology. As examples:

●Chronic anisocoria may go unnoticed by patients. Examination of old photographs and a driver's license can be helpful in establishing chronicity of the finding.

●Prior ocular disease (including eye surgeries) and head, ocular, or orbital trauma can cause anisocoria.

●A detailed review of medications, medicated products (such as glycopyrrolate-containing skin wipes), and toxin exposure (including recent handling of plants) can reveal a potential pharmacologic etiology.

●Diplopia, ptosis, and impaired extraocular movements on the side of a large pupil point to a third nerve palsy, while a tonic pupil and pharmacologic mydriasis are usually isolated syndromes without ptosis or diplopia.

●Decreased palpebral fissure on the side of a small pupil suggests Horner syndrome.

CAUSES

Physiologic anisocoria — Physiologic or simple anisocoria is seen in approximately 20 percent of the normal population at any given time [7]. The magnitude of anisocoria may be equal in light and dark, or slightly greater in the dark than in light [8]. The anisocoria is usually less than 0.4 mm difference between sides. There is no dilation lag.

Reviewing the patient's old photographs or driver's license (with a magnifying glass) may help establish the diagnosis, as physiologic anisocoria is usually persistent. Depending on the degree of ambient lighting, the anisocoria may seem to come and go. Occasionally, the anisocoria may switch sides.

Structural defects — Ocular causes responsible for structural defects of the iris can lead to anisocoria and abnormal pupillary shapes (picture 2).

Congenital defects such as aniridia, iris coloboma, congenital ectopic pupils, persistent pupillary membrane, polycoria, congenital heterochromia, Rieger syndrome, and other developmental anomalies of the anterior segment can produce anisocoria, which is usually present in childhood.

Numerous acquired ocular conditions, such as intraocular inflammation (iritis/iridocyclitis), anterior segment ischemia, trauma, iris sphincter atrophy related to surgical or traumatic injury, mechanical distortion by an intraocular tumor, and angle-closure glaucoma, also produce anisocoria. Associated visual loss, ocular redness, or ocular pain is usually present with acute glaucoma. In the absence of a clear history of one of these disorders, an ophthalmologic evaluation with slit lamp examination will usually reveal the diagnosis.

The small pupil is abnormal — When the small pupil does not dilate as well as the large pupil in dim light, then the small pupil is abnormal (figure 3).

This can occur due to ocular conditions that keep the small pupil from dilating (such as iridocyclitis, previous ocular surgery, or pseudoexfoliation syndrome) or to pharmacologic constriction of the pupil (eg, pilocarpine eye drops). In the absence of these, asymmetric pupillary miosis usually results from dysfunction of the ipsilateral sympathetic pathway (ie, oculosympathetic paresis or Horner syndrome) [9].

Horner syndrome is caused by a lesion anywhere along the sympathetic pathway that supplies the head, eye, and neck (figure 2). The amount of anisocoria is worse in the dark than in the light, and it is associated with dilation lag of 15 to 20 seconds. Topical administration of one to two drops of 4 to 10% cocaine may be required to distinguish a Horner syndrome from physiologic anisocoria. A normal pupil dilates more than the Horner pupil, increasing the degree of anisocoria, a response not seen in physiologic anisocoria.

Apraclonidine drops (used for glaucoma) are now more often used than cocaine to confirm a Horner syndrome, and are widely available, while cocaine eye drops may not be. Apraclonidine has no effect on the size of a normal pupil, but moderately dilates a Horner pupil and increases the palpebral fissure on the side of the Horner syndrome; in effect, apraclonidine reverses the Horner syndrome [1]. Apraclonidine should not be used in young children. (See "Horner syndrome", section on 'Pharmacologic tests'.)

Classic signs of Horner syndrome also include ptosis and anhydrosis (picture 3 and picture 4). The ptosis is minor (2 mm or less) and may be missed. Ptosis involves both upper and lower lids. Unilateral anhidrosis is present in preganglionic lesions. Horner syndrome is discussed separately. (See "Horner syndrome".)

The large pupil is abnormal — When the larger pupil does not constrict as well as the small pupil in response to a light stimulus, then the large pupil is abnormal (figure 3). This results from dysfunction of the ipsilateral parasympathetic pathway (figure 1).

Causes include ocular conditions that keep the large pupil from constricting (such as posterior synechia, previous ocular surgery, ocular trauma, pseudoexfoliation syndrome, or chronic miotic medication use), pharmacologic agents (cycloplegics like atropine, homatropine, tropicamide, cyclopentolate, or other anticholinergic products), tonic pupil (Adie pupil), or third nerve palsy.

The clinical history, associated symptoms, or signs such as visual loss, diplopia, or ptosis help localize the lesion (algorithm 1). Appropriate investigations should be obtained once the mechanism of mydriasis is understood. Indeed, the noncontrast head computed tomography (CT) routinely ordered in the emergency department for a patient with mydriasis is not helpful and can be falsely reassuring.

Traumatic mydriasis — Pupillary dilation following ocular trauma often results from injury to the pupillary sphincter muscle. The pupil in such cases may be irregular in shape. Its ability to react to light and accommodation varies, depending on the extent of the damage. Anisocoria is more evident in bright light, as the pupil fails to constrict due to injury to the sphincter muscle. The pupillary abnormality is isolated without ptosis or diplopia (picture 2).

Tonic pupil — The tonic pupil (also called Adie pupil) results from damage to the ciliary ganglion or short ciliary nerves followed by aberrant reinnervation. In the acute phase, findings may be isolated to unilateral mydriasis with poor light reactivity. Over days and weeks other characteristic signs develop:

●Light-near dissociation. The pupil constricts poorly to light but reacts better to accommodation (near response) (picture 1).

●Tonic response. When going from light to dark conditions, or after near fixation, the initially larger Adie pupil becomes smaller than its normal fellow and remains tonically constricted, redilating very slowly.

●Denervation supersensitivity. Within 30 minutes of administration of two drops of dilute pilocarpine (0.1%) in both eyes, the initially larger Adie pupil becomes smaller than the normal pupil, which does not usually change in size (picture 1). Denervation supersensitivity is not present in the acute phase and may take several weeks to develop.

Tonic pupil is discussed separately. (See "Tonic pupil".)

Pharmacologic mydriasis — Drugs can produce mydriasis either by stimulation of the sympathetic innervation of the dilator pupillae or inhibition of the parasympathetic innervation to the sphincter pupillae (picture 5). Examples include:

●Topical medications used to treat ocular conditions include the parasympatholytic cycloplegic drugs such as atropine, homatropine, cyclopentolate, and tropicamide, and sympathomimetics such as adrenaline, phenylephrine (also used in topical allergy medications), clonidine, apraclonidine, and rarely brimonidine (used as antiglaucoma medication).

●Other autonomic drugs such as scopolamine patch (used for motion sickness) or glycopyrrolate sweat wipes (used for hyperhidrosis) can also produce pharmacologic mydriasis [10].

●Aerosolized anticholinergic drugs (eg, ipratropium) administered through ventilator masks have also been known to produce unilateral mydriasis [11-13].

●Certain plants (eg, jimsonweed) contain substances with anticholinergic properties and have been known to produce isolated mydriasis [14-16].

When the agent is anticholinergic, the pupil is often largely dilated (8 mm or more) and does not constrict to light. By contrast, sympathomimetic drugs rarely dilate the pupil by more than 1 or 2 mm. Pharmacologic mydriasis is not associated with pain, ptosis, or diplopia.

Pharmacologic mydriasis can be confirmed by demonstrating partial or no constriction following application of 1% pilocarpine eye drop. In all other causes of dilated pupil (except direct damage to pupillary sphincter from trauma or surgery), 1% pilocarpine will cause maximal pupillary constriction.

Third nerve palsy — Mydriasis from isolated third nerve palsies is almost always associated with an extraocular movement deficit and/or ptosis (picture 6). A completely isolated mydriasis is extremely unlikely to be related to a third nerve palsy [1]. Tonic pupil and pharmacologic mydriasis should be specifically excluded by careful neuroophthalmologic evaluation and pharmacologic testing in this setting.

The evaluation of the patient with a third nerve palsy depends on associated symptoms and signs, the pattern of oculomotor nerve involvement, and the age of the patient. Brain imaging studies and/or lumbar puncture are often required. This topic is discussed separately. (See "Third cranial nerve (oculomotor nerve) palsy in adults" and "Third cranial nerve (oculomotor nerve) palsy in children".)

SUMMARY AND RECOMMENDATIONS — Causes of anisocoria range from a benign, physiologic condition to serious, life-threatening conditions. An approach to anisocoria is summarized in the algorithm (algorithm 1).

●Anisocoria represents either impaired dilation or constriction of one pupil. These are mediated by sympathetic and parasympathetic pathways, respectively. (See 'Neuroanatomy and physiology' above.)

●Neurologic examination of the pupils notes their size, shape, and symmetry in light and dark conditions as well as the responses to light and near stimuli. (See 'Examination of the pupil' above.)

●The abnormal pupil can be identified by examination in light and dark conditions. Anisocoria that is greater in the dark identifies the small pupil as abnormal and implies a lesion in the sympathetic pathways. Anisocoria that is more pronounced in light conditions identifies the large pupil as abnormal and implies a lesion in the parasympathetic pathways. (See 'Identifying the abnormal side' above.)

●Anisocoria due to sympathetic lesions is usually a feature of Horner syndrome. (See "Horner syndrome".)

●Parasympathetic causes of anisocoria include trauma, topical drugs, tonic pupil, and third nerve palsy. (See 'The large pupil is abnormal' above.)