What causes anisocoria?

Anisocoria: Causes and Clinical Approach

Anisocoria results from disruption of either the parasympathetic (pupil constriction) or sympathetic (pupil dilation) pathways, with causes ranging from benign physiological variation to life-threatening conditions such as third nerve palsy from posterior communicating artery aneurysm, intracranial hemorrhage, or cavernous sinus pathology. 1, 2

Physiological and Benign Causes

Physiological anisocoria is the most common benign cause, presenting as a small pupil size difference (typically <1 mm) that remains relatively constant in different lighting conditions. 1 This represents normal variation in approximately 20% of the population. 3

Benign episodic mydriasis (BEM) causes intermittent pupil asymmetry, predominantly affecting young women with migraine history. 4 Episodes vary from minutes to 48 hours, may alternate between eyes or even present bilaterally, and frequently associate with blurred vision. 4 The pathophysiology remains incompletely understood, but neuroimaging is unnecessary in the absence of other neurological symptoms. 4

Life-Threatening Causes Requiring Urgent Evaluation

Third Nerve Palsy

Pupil-involving third nerve palsy represents a neurological emergency requiring immediate neuroimaging with MRI/gadolinium and MRA or CTA to exclude posterior communicating artery aneurysm. 1, 2 The classic presentation includes:

• Mydriasis (dilated pupil) with poor or absent light reactivity 2
• Associated ptosis 1, 2
• Extraocular muscle weakness (impaired adduction, elevation, and depression) 1, 2

Other causes of third nerve palsy include tumors, trauma, and subarachnoid hemorrhage. 1 Neurosurgical consultation is mandatory if an aneurysm is identified. 2

Pupil-sparing third nerve palsy presents with complete ptosis and complete motility dysfunction but normal pupillary function, almost always secondary to microvascular disease associated with diabetes, hypertension, or hyperlipidemia. 2 However, if there is partial extraocular muscle involvement or incomplete ptosis, even with a normal pupil, microvascular etiology should not be assumed and neuroimaging must be performed. 2

Intracranial Pathology

Anisocoria with headache, altered mental status, or other neurological deficits may indicate intracranial hemorrhage and requires prompt evaluation. 1, 2 Signs of increased intracranial pressure (papilledema, decreased consciousness) mandate urgent assessment. 1

Cavernous sinus lesions may present with multiple cranial nerve palsies (III, IV, VI, and V1), requiring MRI with contrast of brain/orbits and referral to neurology or neurosurgery. 1, 2

Pharmacological Causes

Pharmacologic mydriasis results from exposure to anticholinergic medications and can be diagnosed with pilocarpine testing. 2, 5 Common culprits include:

• Topical anticholinergics, antihistamines, and tropane alkaloids 2
• Nebulized ipratropium bromide leaking from facial masks during respiratory treatments 5
• Various systemic medications with anticholinergic properties 3

The pilocarpine test differentiates pharmacologic anisocoria from neurological causes: pharmacologically dilated pupils will not constrict with pilocarpine 1%, whereas Adie's pupil constricts with pilocarpine 0.1% and third nerve palsy pupils typically respond to pilocarpine 1%. 2, 5, 3

Horner Syndrome

Horner syndrome results from disruption of the sympathetic pathway and presents with:

• Miosis (smaller pupil on affected side) 3, 6
• Ptosis (mild, typically 1-2 mm) 6
• Anhidrosis (depending on lesion location) 6

Cocaine 10% eye drops and hydroxyamphetamine testing help localize the lesion along the sympathetic pathway. 3

Adie's Pupil

Adie's pupil affects predominantly young women (1/20,000 incidence) and presents with:

• Unilateral mydriasis 6
• Sluggish or absent light reaction 3
• Occasionally associated tendinous areflexia 6
• Supersensitivity to pilocarpine 0.1% (diagnostic) 3

Acute Angle-Closure Crisis

Acute angle-closure glaucoma should be considered when the enlarged pupil is mid-dilated, oval, or asymmetric with associated symptoms of eye pain, headache, nausea, and decreased vision. 2 This requires:

• Immediate gonioscopy to assess angle closure 2
• Intraocular pressure measurement 2
• IOP-lowering therapy 2
• Urgent evaluation and prophylactic laser iridotomy of the fellow eye 2

Diagnostic Algorithm

Determine which pupil is abnormal by checking pupillary responses in both bright and dim illumination: 1, 2

• If anisocoria is greater in bright light, the larger pupil is abnormal (parasympathetic defect) 3
• If anisocoria is greater in dim light, the smaller pupil is abnormal (sympathetic defect/Horner syndrome) 3

Assess for red flags requiring urgent neuroimaging: 1, 2

• New-onset pupil-involving third nerve palsy
• Anisocoria with headache, altered mental status, or neurological deficits
• Anisocoria following head trauma
• Signs of increased intracranial pressure

Perform slit-lamp biomicroscopy to examine pupil size, shape, reactivity, and other ocular structures. 2 Gonioscopy is essential if acute angle-closure is suspected. 2

Common Pitfalls

Never assume microvascular etiology in third nerve palsy with partial ptosis or incomplete extraocular muscle involvement, even with normal pupillary function—these patients require neuroimaging. 2

Pharmacologic mydriasis from nebulized ipratropium is frequently overlooked; ask specifically about recent respiratory treatments and mask fit. 5 This can be prevented using better-fitting masks, protective goggles, or eye patches during treatment. 5

Giant cell arteritis must remain in the differential for new-onset vertical diplopia or anisocoria in patients over 50 years. 7