Pupillary Asymmetry (Anisocoria)

Anisocoria refers to asymmetry in pupillary diameter between the two eyes. When pathologic, anisocoria indicates a disorder of pupillary constriction or dilation. If the disorder is of pupillary constriction, the larger pupil is abnormal, since it does not constrict as well to light. If the problem is of pupillary dilation, the smaller pupil is abnormal, as it has dilated less than the other pupil. To distinguish between these, the size of the pupils should be assessed in both dark and light. If the size difference between the pupils increases in dark, it suggests that the smaller pupil did not adequately dilate, since maximal dilation should occur in dark. However, if anisocoria is more prominent in light, it indicates that the larger pupil did not adequately constrict to light. If the difference in pupillary diameter is equal in both light and dark, it indicates physiologic anisocoria, which is a normally occurring phenomenon. Note that an afferent visual process (e.g., optic neuropathy) should not cause anisocoria when both pupils are observed under the same degree of lighting.

A.

Horner syndrome is caused by lesions of the oculosympathetic pathway extending from the hypothalamus to the lower cervical and upper thoracic spinal cord, sympathetic chain, superior cervical ganglion, and along the internal carotid artery. Because sympathetic fibers innervate the iris dilator and result in pupillary dilation, Horner syndrome causes a pupil that dilates incompletely in dark, resulting in anisocoria that is greater in dark than light, with the smaller, constricted pupil being the abnormal one. The oculosympathetic pathway also innervates the tarsal muscles of the eyelid, and thus ptosis is also typically present in Horner syndrome. Diagnosis can be confirmed by apraclonidine or cocaine eyedrop testing. Apraclonidine is a weak sympathomimetic, but in Horner syndrome there is upregulation of postsynaptic receptors on the iris dilator resulting in denervation hypersensitivity; therefore, apraclonidine will dilate a Horner pupil more than a normal pupil, thus reversing the anisocoria. In contrast, cocaine is a norepinephrine reuptake inhibitor and dilates a normal pupil but not a Horner pupil, thereby accentuating the anisocoria.
B.

The pupils constrict under two circumstances: (1) when light enters the eye (pupillary light reflex), and (2) when attempting to view a target at near, such as when reading (near response). Light-near dissociation refers to a pupil that does not constrict to light but does constrict to near. Tonic pupil is the most common cause of unilateral light-near dissociation (see section C). Other causes of light-near dissociation include severe retinal or optic nerve disease (differentiated pupil), dorsal midbrain lesions (Parinaud syndrome), aberrant regeneration of a third nerve palsy (pupillary sphincter becomes reinnervated by oculomotor rather than pupillomotor fibers and constricts during attempted adduction rather than to light), and Argyll-Robertson pupils (classically described in syphilis but also seen in diabetes).
C.

Tonic pupil is caused by a lesion of the ciliary ganglion. Because the fibers for the pupillary light reflex synapse at the ciliary ganglion whereas the fibers for the near response pass through but do not synapse in it, tonic pupil is often characterized by light-near dissociation. There is also delayed redilation following pupillary constriction to near. Tonic pupil is typically idiopathic and thought to be postviral or autoimmune. When bilateral and accompanied by areflexia, it is termed Adie syndrome. Other causes include local orbital processes and autonomic neuropathy (e.g., diabetes, amyloidosis, multiple systems atrophy). Over time, a tonic pupil may become smaller than the unaffected pupil.
D.

Pupillary involvement is more likely to occur with compressive rather than vasculopathic or other intrinsic processes affecting the oculomotor nerve because the parasympathetic fibers responsible for pupillary constriction are located superficially along the outside of the nerve, whereas the fibers that innervate the levator palpebrae and extraocular muscles are located more internally. Potential causes include an ipsilateral mass lesion (e.g., tumor, aneurysm) or uncal herniation.
E.

Pharmacologic pupillary dilation (mydriasis) occurs most commonly due to antimuscarinic agents that block the neuromuscular junction at the pupillary sphincter. Sympathomimetics also cause mydriasis. This may be intentional due to the instillation of mydriatic eyedrops or unintentional due to accidental ocular contact with anticholinergics (e.g., inhaled ipratropium, scopolamine patch). Mechanical causes of impaired pupillary constriction include iris trauma or tears, adhesions between the iris and cornea (anterior synechiae) or lens (posterior synechiae), and acute angle-closure glaucoma; these are associated with other abnormalities on slit lamp biomicroscopy.

Tonic pupil, third nerve palsy, and pharmacologic pupil can also be distinguished using eyedrop testing with pilocarpine, a muscarinic agonist. One drop of dilute pilocarpine (0.125%) is instilled in each eye. The normal response is to not constrict, as this concentration is too low to cause physiologic pupillary constriction. However, if the larger pupil constricts, it indicates a tonic pupil that has experienced denervation hypersensitivity (upregulation of postsynaptic receptors) and is therefore able to constrict in response to small amounts of pilocarpine. If there is no constriction to low-dose pilocarpine, then one drop of high-dose (1%) pilocarpine is used. If the larger pupil constricts, it indicates a third nerve palsy. If there is no constriction, it indicates a pharmacologic or mechanical pupil that is incapable of constriction due to saturation of postsynaptic receptors by a muscarinic antagonist or a structural abnormality of the pupillary sphincter.