Anisocoria Clinical Presentation

The history of anisocoria is dependent on the specific pathophysiology.

The pupil size difference itself seldom produces specific symptoms (eg, unilateral photosensitivity with mydriasis). Associated features (with an underlying condition) may produce symptoms that lead to evaluation (eg, diplopia, photophobia, pain, ptosis, blur).

Anisocoria may also be discovered incidentally by an observer.

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

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, or ptosis help generate a differential diagnosis.

• Pupil size (in mm) should be assessed in both light and dark. Illumination 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) should always 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, 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) or a slit lamp greatly assists this endeavor.
• 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.
  • 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.^[2]
• 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" are relevant: pupils, ptosis, proptosis, pain, poor movement/paresis, paresthesia.
  • 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 typical of microvascular ocular motor neuropathies. Proptosis often indicates a space-occupying lesion within the orbit.

The causes of anisocoria are diverse and varied; refer to the following flowchart to deduce the specific cause.^[3] See the diagram below.

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

Horner syndrome

Two conditions produce normally reactive pupils with anisocoria greater in darkness: Horner 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.

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.^{[4, 5]} In patients with Horner syndrome, reversal of anisocoria usually occurs after bilateral instillation of apraclonidine. However, false-negative results have been reported in this setting.^[6]

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 test already discussed).
• 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.
• 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. 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 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.

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 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.

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^[7] , exposure to toxic plants such as Datura [Angel's Trumpet]^[8] ).

Mechanical

Mechanical damage to the iris muscle itself resulting from trauma, surgical intervention (eg, cataract extraction), or inflammation (or the effects or prior inflammation) within the eye (uveitis) 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 normal motility and corneal edema 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), 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.