Anisocoria

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

The causes of anisocoria are varied, and relate to alterations of the autonomic nervous system and/or the iris muscle.

From the autonomic nerve standpoint, the parasympathetic system constricts the iris, whereas 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 nerve 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.

Frequency

United States

Anisocoria is common, although no overall prevalence statistics are available. The incidence and prevalence data for anisocoria vary by 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.  Anisocoria may also be caused by sight-threatening origins, such as angle closure glaucoma.  Yet other causes of anisocoria are completely benign (eg, simple or physiologic anisocoria), although the unnecessary evaluation of these disorders may produce morbidity inadvertently.

Isolated anisocoria is usually asymptomatic and incidentally discovered; however, anisocoria may be associated with visual or other symptoms (eg, unilateral photosensitivity with mydriasis, decreased accommodation and ptosis with Horner syndrome) or produce other features prompting evaluation (eg, diplopia, 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, certain plants 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, carotid dissection wiht Horner syndrome, some oculomotor palsies (both ischemic and compressive/aneurysmal origins), and lesions which also affect adjacent pain sensitive structures (eg, cavernous sinus lesions).

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 narrow the 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 avoiding the abbreviation PERRLA (pupils equal, round, reactive to light and accommodation). The abbreviation provides no information on pupil size, and "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 (if relevant), and comment on the presence or absence of a relative afferent pupillary defect (RAPD) and dilation lag (if appropriate).

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 often 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 likely of clinical relevance.[3]

In addition to noting light reaction, it is often useful to observe the pupil reaction to dark; the slowed dilation of a miotic pupil to dark (dilation lag) is a hallmark of Horner syndrome.  

An iris notch may suggest trauma or sphincter rupture as contributing factors to impaired pupil motion. 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.  Dysarthria, dysphagia, ptosis (from associated Horner syndrome), dysesthesia and dyscoordination are suggestive of brainstem localization (eg, lateral medullary syndrome).  

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]  

Physiologic anisocoria may appear with similar difference in pupil size under both light and dark conditions.  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, especially if dermatochalasis co-exists. 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 proven to be a reliable substitute.[5, 6]  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 dilates (reversal of anisocoria) due to the drug's weak alpha-1 activity acting on a denervated supersensitive pupil. However, false-negative results have been reported in this setting, and sedation may occur in young children.[7]

Hydroxyamphetamine (Paredrine) stimulates norepinephrine release from an intact third-order sympathetic neuron, and addresses the question "Is the 3rd order sympathetic neuron intact?".  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.

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.  It should be noted that hydroxyamphetamine has become difficult to obtain of recent.  

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. 

Cavernous sinus disease may produce a third-order Horner syndrome, often accompanied by dysfunction of adjacent cranial nerve III, IV, V, or VI palsy causing facial dysesthesia or diplopia.

Horner syndrome is a component of trigeminal autonomic cephalgia in some cases (e.g., cluster or 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.

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

Oculomotor aberrancy may affect the pupil, producing miosis with gaze in direction of oculomotor controlled muscles (adduction, supraduction, infraduction).

Pharmacologic pupil

The pharmacologically dilated pupil is larger than in most other causes of anisocoric mydriasis (often maximally dilated to 8-9 mm initially).

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

The remainder of the examination in pharmacoligic mydriasis (ie, motility, eyelids, fundus, trigeminal function) should be normal, except uncorrected 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), iris ischemia, 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

Adie tonic pupil responds poorly to light, but briskly and tonically to near stimulation (the pupil takes longer to redilate after this near-induced miosis). 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

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.

Lab studies depend upon the specific etiology.

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 with MRI, CT or a combinaiton of these 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 occasionally 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 very helpful sequence when dissection is suspected.

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 depend upon the specific etiology.

Histologic findings depend upon the specific etiology

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

Medical care depends upon the underlying pathophysiology.

If the patient has associated accommodation paresis, 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 depends upon the specific etiology.

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

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

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

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.

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.

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.

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).