What is the differential diagnosis for anisocoria?

Differential Diagnosis of Anisocoria

The differential diagnosis of anisocoria includes physiological anisocoria, third nerve palsy (especially from posterior communicating artery aneurysm), Horner syndrome, pharmacologic mydriasis, Adie's tonic pupil, acute angle-closure glaucoma, cavernous sinus lesions, and traumatic causes. 1, 2

Life-Threatening Causes Requiring Urgent Evaluation

Third Nerve Palsy

• Pupil-involving third nerve palsy is the most concerning cause, particularly from posterior communicating artery aneurysm, and requires immediate neuroimaging with MRI with gadolinium and MRA or CTA. 1, 2
• Associated findings include ptosis and extraocular muscle weakness (inability to adduct, elevate, or depress the eye). 1, 2
• Other causes include tumors, trauma, subarachnoid hemorrhage, and cavernous sinus pathology. 2
• Even with partial extraocular muscle involvement or incomplete ptosis, if the pupil is normal, do not assume microvascular etiology—neuroimaging is still required. 1
• Classic pupil-sparing third nerve palsy (normal pupil, complete ptosis, complete motility dysfunction) is almost always microvascular from diabetes, hypertension, or hyperlipidemia. 1

Intracranial Hemorrhage and Increased Intracranial Pressure

• Anisocoria with headache, altered mental status, or other neurological deficits suggests possible intracranial hemorrhage. 2
• Signs of increased intracranial pressure (papilledema, decreased consciousness) require prompt evaluation. 2
• Anisocoria following head trauma requires urgent evaluation. 1

Cavernous Sinus Lesions

• May present with multiple cranial nerve palsies (III, IV, VI, and V1). 2
• Requires MRI with contrast of brain/orbits and referral to neurology or neurosurgery. 1

Benign and Non-Urgent Causes

Physiological Anisocoria

• Small difference in pupil size (usually <1 mm) that remains relatively constant in different lighting conditions. 2
• Common benign condition requiring no intervention. 2

Horner Syndrome

• Characterized by miosis, ptosis, and anhidrosis (though anhidrosis may be absent). 3, 4
• Pupillometry measuring dilation lag can discriminate Horner syndrome from physiological anisocoria with 95% sensitivity using the change of anisocoria at 3-4 seconds after light-off (Δ3-4 cutoff of 0.35 mm). 3
• Pharmacological testing with 1% apraclonidine is considered the gold standard—positive test shows increase in smaller pupil size and decrease in larger pupil. 3, 4
• Cocaine 10% eye drops and hydroxyamphetamine can also be used for diagnosis and localization. 4

Adie's Tonic Pupil

• Dilated pupil with poor or absent light reaction but preserved near response (light-near dissociation). 4, 5
• Pilocarpine 0.1% eye drops cause constriction in Adie's pupil due to denervation supersensitivity. 4

Pharmacologic Mydriasis

• Caused by topical anticholinergics (atropine, scopolamine, ipratropium bromide), antihistamines, and tropane alkaloids. 1, 6, 5
• Ipratropium bromide nebulizer treatment can cause unilateral mydriasis if aerosol leaks from the mask edge into the ipsilateral eye. 6
• Scopolamine exposure (transdermal patches or powder) can cause unilateral or bilateral mydriasis. 5
• Pilocarpine 1% will not constrict a pharmacologically dilated pupil, confirming the diagnosis. 1, 4
• Critical pitfall: Scopolamine-induced mydriasis may show inconsistent response to pilocarpine, sometimes initially constricting then returning to mydriasis. 5

Acute Angle-Closure Glaucoma

• Enlarged pupil is mid-dilated, oval, or asymmetric with associated symptoms (eye pain, blurred vision, halos). 1
• Requires immediate gonioscopy, intraocular pressure measurement, and IOP-lowering therapy. 1
• Fellow eye requires urgent evaluation and prophylactic laser iridotomy. 1

Diagnostic Algorithm

Step 1: Determine Which Pupil is Abnormal

• Check pupillary responses in both bright and dim illumination. 1, 2
• If anisocoria is greater in bright light, the larger pupil is abnormal (suggests third nerve palsy, Adie's pupil, or pharmacologic mydriasis). 7, 4
• If anisocoria is greater in dim light, the smaller pupil is abnormal (suggests Horner syndrome). 7, 4

Step 2: Assess for Associated Findings

• Look for ptosis, extraocular movement limitations, headache, and other neurological deficits. 1, 2
• Perform slit-lamp biomicroscopy to examine pupil size, shape, and reactivity. 1
• Perform gonioscopy if acute angle-closure is suspected. 1

Step 3: Pharmacological Testing When Appropriate

• Use pilocarpine 1% to diagnose pharmacologic mydriasis (will not constrict). 1, 4
• Use pilocarpine 0.1% to diagnose Adie's pupil (will constrict due to supersensitivity). 4
• Use apraclonidine 1% or cocaine 10% to diagnose Horner syndrome. 3, 4

Step 4: Obtain Detailed History

• Medication exposure (nebulizers, eye drops, transdermal patches, herbal supplements). 6, 5
• Recent trauma, headache, neurological symptoms. 1, 2
• Previous episodes, family history. 7

Common Pitfalls

• Do not assume microvascular third nerve palsy without neuroimaging if there is any pupil involvement, partial ptosis, or incomplete extraocular muscle dysfunction. 1
• Do not rely solely on pilocarpine response for pharmacologic anisocoria—scopolamine can show atypical responses. 5
• Prevent ipratropium-induced mydriasis by using well-fitting masks, protective goggles, or eye patches during nebulizer treatments. 6
• Physiological anisocoria can be confused with Horner syndrome—use pupillometry or pharmacological testing to differentiate. 3