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Original article contributed by:
Chantal Josee Boisvert, MD, Ngoc-Anh Tran
Byoung Ug Ryu, Bayan Al Othman, MD and Chantal Josee Boisvert, MD
Bayan Al Othman, MD
Assigned status Up to Date
by Bayan Al Othman, MD on June 30, 2020.
Anisocoria is a condition characterized by unequal pupil sizes. It is relatively common, and causes vary from benign physiologic anisocoria to potentially life-threatening emergencies. Thus, thorough clinical evaluation is important for the appropriate diagnosis and management of the underlying cause.
Generally, anisocoria is caused by impaired dilation (a sympathetic response) or impaired constriction (a parasympathetic response) of pupils. An injury or lesion in either pathway may result in changes in pupil size.
Physiologic (also known as simple or essential) anisocoria is the most common cause of unequal pupil sizes, affecting up to 20% of the population . It is a benign condition with a difference in pupil size of less than or equal to 1 mm . The exact cause is unknown, but it is thought to be due to transient asymmetric supranuclear inhibition of the Edinger-Westphal nucleus that controls the pupillary sphincter . Light and near responses are intact, and the degree of anisocoria is typically equal in light and dark. Physiologic anisocoria may be intermittent, persistent, or even self-resolving.
Congenital anomalies in the structure of the iris may contribute to abnormal pupillary sizes and shapes that present in childhood. Examples include aniridia, coloboma, and ectopic pupil.
Mechanical anisocoria is an acquired defect that results from damage to the iris or its supporting structures. Causes include physical injury from ocular trauma or surgery, inflammatory conditions such as iritis or uveitis, angle closure glaucoma leading to iris occlusion of the trabecular meshwork, or intraocular tumors causing physical distortion of the iris.
Pharmacologic anisocoria can present as mydriasis or miosis following administration of agents that act on the pupillary dilator or sphincter muscles. Anticholinergics such as atropine, homatropine, tropicamide, scopolamine, and cyclopentolate lead to mydriasis and cycloplegia by inhibiting parasympathetic M3 receptors of the pupillary sphincter and ciliary muscles. Scopolamine patches, glycopyrrolate antiperspirants, nasal vasoconstrictors, herbals such as Jimson weed, blue nightshade, and Angel’s trumpet can dilate pupils . The use of pilocarpine, a non-selective muscarinic receptor agonist in the parasympathetic nervous system, may result in a small and poorly reactive pupil. Sympathomimetics, such as adrenaline, clonidine, and phenylephrine, cause mydriasis through their actions at ɑ-1 receptors of the pupillary dilator muscle. Prostaglandins, opioids, and organophosphate insecticides can constrict pupils as well .
Horner’s syndrome (oculosympathetic palsy) is classically described by the triad of ptosis, miosis, and anhidrosis, although clinical presentations may vary. Anisocoria is greater in the dark due to a defect in the pupillary dilator response secondary to lesions along the sympathetic trunk. Central or first-order lesions are often caused by stroke, lateral medullary syndrome, neck trauma or demyelinating disease. Preganglionic or second-order neuron lesions may be caused by a Pancoast tumor, mediastinal or thyroid mass, cervical rib, neck trauma, or surgery. Postganglionic or third-order neuron lesions include carotid artery dissection, cavernous sinus lesion, otitis media, and head or neck trauma. Further pharmacologic work-up (see diagnostic procedures) is useful in confirming Horner’s and distinguishing the order of the lesion.
Adie’s tonic pupil results from damage to the parasympathetic ciliary ganglion or short ciliary nerves that innervate the sphincter pupillae and ciliary muscle. Aberrant reinnervation and upregulation of postsynaptic receptors lead to the clinical presentation of a tonically dilated pupil with near stimulation and poor reactivity to light. Ninety percent of cases occur in women between the ages of 20-40 years, 80% of cases are unilateral, and 70% of cases are associated with decreased deep tendon reflexes (Adie’s syndrome) . Adie’s pupil may involve an orbital process, while bilateral cases may indicate systemic processes .
Oculomotor (third) nerve palsy varies in presentation and etiology. The oculomotor nerve innervates 4 out of the 6 extraocular muscles (superior rectus, medial rectus, inferior rectus, and inferior oblique), the sphincter pupillae muscle, the ciliary muscle, and the levator palpebrae muscle. Third nerve palsies rarely present as isolated mydriasis; associated findings include ptosis, an ipsilateral “down and out” gaze, and loss of accommodation. Compressive lesions from head trauma, intracranial aneurysms, uncal herniation, and tumors typically involve the pupil as they affect the superficial parasympathetic fibers that innervate the pupil. Ischemic or diabetic oculomotor nerve palsies typically spare the pupil .
Trigeminal autonomic cephalalgias include primary headache disorders that may result in anisocoria, miosis, or ptosis . They present with unilateral head pain with ipsilateral autonomic symptoms, such as lacrimation and rhinorrhea .
Autoimmune autonomic ganglionopathy is a disorder of autoantibodies that target autonomic ganglia . It affects sympathetic and parasympathetic systems that may result in pupillary abnormalities, anisocoria, orthostatic hypotension, and anhidrosis .
Physiologic control of pupillary function is dictated by sympathetic and parasympathetic innervation to the pupillary dilator and the pupillary sphincter muscles, respectively. Pupillary function is autonomic, largely occurring in response to light stimulation and adrenergic tone.
The sympathetic pathway is a three-order neuron pathway that mediates pupillary dilation. The first-order neuron originates from the posterolateral hypothalamus and travels caudally down the brainstem to the ciliospinal center of Budge (C8-T2). The second-order neuron continues over the lung apex and synapses at the superior cervical ganglion located at the carotid bifurcation. The third-order neuron ascends along the carotid artery into the cavernous sinus to ultimately synapse at the pupillary dilator muscle, the Muller muscle of the upper eyelid, and the smooth muscle of the lower eyelid.
The parasympathetic pathway is a four-order neuron pathway that controls pupillary constriction and accommodation. Afferent light stimulus is received by retinal ganglion cells whose axons traverse as the optic nerve, optic chiasm, and optic tract to eventually synapse at the pretectal nuclei of the dorsal midbrain at the level of the superior colliculi. The second-order neuron connects each pretectal nucleus to bilateral Edinger-Westphal nuclei in the midbrain and allows for the consensual light reflex. The Edinger-Westphal nucleus then supplies parasympathetic fibers to the third cranial nerve which traverses the cavernous sinus and enters the orbit via the superior orbital fissure to synapse at the ipsilateral ciliary ganglion. Postganglionic fibers of the short ciliary nerve reach the pupillary sphincter and ciliary muscles.
Figure 1. Anisocoria algorithm. Solid arrows indicate recommended approaches to diagnosis. Dotted arrows indicate optional workup. MRA, magnetic resonance angiography; CTA, computed tomography angiography.
A careful history to elucidate the onset and chronicity of anisocoria may be useful for determining its etiology. Old photographs may provide information since symptoms may not exist or go unnoticed. Chronic anisocoria without associated symptoms may point to a benign process such as physiologic anisocoria, whereas sudden-onset anisocoria in the setting of other symptoms may be more worrisome. For example, anisocoria with headaches, confusion, altered mental status, and other focal neurologic deficits suggest an underlying mass effect and may require further neurologic work-up and intervention.
Complete ophthalmic history is important as coexisting ocular conditions, previous surgeries or trauma to the head or orbit may contribute to anisocoria. A thorough review of medications, especially topical eye drops, may provide explanations for pharmacologic anisocoria. A discussion about exposures to certain narcotics, insecticides (organophosphates) or plants (Brugmansia Angel’s trumpet or Datura Devil’s trumpet), should also be considered.
External eye structures should be examined for associated ocular manifestations. Ptosis and gaze deviation may suggest an oculomotor nerve palsy, whereas proptosis may indicate and underlying space-occupying lesion within the orbit.
A thorough pupillary exam is crucial, and it is best done in dim light with the patient’s eyes fixed on a distant object to eliminate the near reaction. Pupils should be compared for size in light and in dark (normal size difference is less than 0.4 mm), shape, position, symmetry, and reactivity. The pupils should be evaluated for direct and consensual responses that are normally equal in speed and magnitude. Accommodation to near stimuli should also be examined as light-near dissociation. Impaired light reaction in the setting of a normal near reaction may suggest Adie’s tonic pupil or Argyll Robertson pupil of syphilis.
The slit-lamp examination can provide additional information for associated or coexisting ocular conditions. Congenital, traumatic and surgical causes of anisocoria will often be associated with other structural defects. The anterior chamber can be examined for signs of iritis or uveitis. Abnormal gonioscopy and tonometry findings may suggest angle closure glaucoma. The clinical picture of Adie’s tonic pupil under slit-lamp examination shows iris sector palsy and vermiform iris movement .
A detailed neurologic exam is important to localize lesions, look for accompanying signs of cranial nerve involvement, and assess for focal neurologic deficits in the sensory, motor, and deep tendon reflex pathways.
Signs & Symptoms
Isolated anisocoria is often asymptomatic, though mydriasis may cause glare, photosensitivity, and impaired accommodation. Complaints of pain, headaches, ptosis, diplopia, blurred vision, numbness, weakness or ataxia may warrant further evaluation for more life-threatening conditions including traumatic injury, intracranial mass, aneurysm or carotid dissection.
In the diagnostic work-up for anisocoria, it is useful to distinguish between anisocoria that is greater in the dark and anisocoria that is greater in the light. This is followed by a series of pharmacologic tests to further determine the exact etiology .
Anisocoria that is greater in the dark suggests a lesion in the sympathetic pathway, which results in an abnormal pupil that is smaller or unable to dilate in response to removal of a light stimulus. Causes include Horner’s syndrome, Argyll Robertson pupil, iritis, mechanical anisocoria, and pharmacologic anisocoria from miotics, narcotics, or insecticides.
In this setting, one to two drops of 4-10% cocaine is administered to both eyes and evaluated after 30 to 45 minutes. Cocaine prevents the reuptake of norepinephrine at the post-synaptic third-order neuron, allowing dilation of the normal pupil. There is an increased pupillary asymmetry in Horner’s syndrome because the sympathetic pathway to the affected pupil is low in norepinephrine to begin with. Apraclonidine, a strong α-2 and weak α-1 agonist, is a more readily available alternative to cocaine. While 0.5-1% apraclonidine causes constriction of the normal pupil due to its strong α-2 adrenergic activity, it causes reversal of anisocoria in Horner’s by moderately dilating the affected pupil that has undergone denervation supersensitivity (when supersensitivity is present, apraclonidine’s weak α-1 agonist activity predominates) .
The use of 1% hydroxyamphetamine (Paredrine) can provide localization to the defect in Horner’s syndrome. Hydroxyamphetamine requires an intact third-order sympathetic neuron to stimulate norepinephrine release. Therefore, an asymmetric dilation suggests a third-order or postganglionic lesion whereas equal pupillary dilation indicates a central or preganglionic lesion . Pharmacologic localization may be challenging as hydroxyamphetamine is recommended to be administered 48 hours following apraclonidine or cocaine due to possible false positive and negative rates .
On the other hand, anisocoria that is greater in the light suggests a parasympathetic defect, resulting in an abnormal pupil that is larger or unable to constrict in response to a light stimulus. Causes include Adie’s tonic pupil, oculomotor nerve palsy, traumatic injury to the iris, or pharmacologic dilation from mydriatics/cycloplegics (atropine, tropicamide, cyclopentolate), or cocaine.
The use of pilocarpine can be diagnostic in this setting. Low doses of 0.1% pilocarpine or 2.5% methacholine do not constrict a normal pupil but result in the constriction of Adie’s tonic pupil due to hypersensitivity from the upregulation of cholinergic receptors. If no constriction is observed, a higher dose of 1% pilocarpine is used. Pupillary constriction suggests an oculomotor nerve palsy, whereas no response indicates a pharmacologic cause to the anisocoria.
If the history and physical examination lead to clinical suspicion for Argyll Robertson pupil, VDRL, and FTA-ABS tests for screening and confirmation of syphilis are recommended. Lumbar punctures for VDRL, FTA-ABS, and total protein and cell count may be indicated in the evaluation of neurosyphilis.
When pharmacologic and laboratory tests are unequivocal, or when clinical suspicion persists for an underlying aneurysm, hemorrhage or tumor, imaging of the head, neck, and chest can help identify causes of Horner’s or oculomotor nerve palsies.