What are the steps to diagnose and manage a patient with one enlarged pupil (anisocoria)?

Diagnostic and Management Approach to Anisocoria (One Enlarged Pupil)

Immediate Assessment

Determine which pupil is abnormal by examining pupillary responses in both bright and dim illumination, then assess for associated neurological signs including ptosis, extraocular movement limitations, headache, or altered mental status. 1

Critical Red Flags Requiring Urgent Evaluation

• New-onset pupil-involving third nerve palsy 1
• Anisocoria with headache, altered mental status, or other neurological deficits 1
• Anisocoria following head trauma 1
• Any pupil-involving third nerve palsy with concern for posterior communicating artery aneurysm 2

Systematic Diagnostic Algorithm

Step 1: Pupillary Light Response Testing

Perform the swinging-light test in a darkened room using a bright light source, with the patient fixing their gaze on a distant object. 3 Direct the light alternately at each eye for less than 5 seconds, observing both direct and consensual pupillary responses. 3

Key distinction: Do not confuse anisocoria (difference in pupil size) with relative afferent pupillary defect (RAPD, which is a difference in pupillary response to light). 3

Step 2: Assess for Third Nerve Palsy

Examine for the classic triad: 2

• Pupillary involvement (dilated, poorly reactive pupil)
• Ptosis (complete or incomplete)
• Extraocular motility dysfunction (inability to adduct, elevate, or depress the eye)

Pupil-Involving Third Nerve Palsy (URGENT)

This requires immediate neuroimaging with MRI with gadolinium and MRA or CTA to rule out posterior communicating artery aneurysm. 2 If high suspicion persists despite normal MRA/CTA, proceed with catheter angiography after brain MRI with and without contrast. 2

Other causes include tumors (meningioma, schwannoma, metastatic lesions), trauma, subarachnoid hemorrhage, and viral illnesses. 2 Neurosurgical consultation is required if aneurysm is identified. 1

Pupil-Sparing Third Nerve Palsy

A classic pupil-sparing third nerve palsy presents with normal pupillary function, complete ptosis, and complete motility dysfunction—this is 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, you cannot assume microvascular etiology—proceed with neuroimaging (MRI with gadolinium and MRA or CTA). 2

Step 3: Rule Out Pharmacologic Mydriasis

Common pitfall: Nebulized ipratropium bromide can leak from facial masks and cause unilateral pharmacologic mydriasis. 4, 5 This is particularly common in patients receiving treatment for asthma or COPD exacerbations. 5

Other pharmacologic causes include: 2, 6

• Topical anticholinergics (atropine, scopolamine, tropicamide)
• Antihistamines with antimuscarinic effects
• Tropane alkaloids from Datura plants
• Systemic medications causing ciliary body edema (sulfonamides, topiramate) 2

Diagnostic test: Perform pilocarpine testing. 4, 5 Pharmacologic mydriasis will not constrict with pilocarpine 1%, whereas other causes (except iris sphincter damage) will show some response. 4, 7 The condition typically resolves within 24 hours. 4, 5

Step 4: Evaluate for Acute Angle-Closure Crisis

If the enlarged pupil is mid-dilated, oval, or asymmetric with associated symptoms, consider acute angle-closure: 2

Clinical presentation: 2

• Blurred vision with halos around lights
• Eye pain and headache
• Nausea/vomiting
• Conjunctival hyperemia
• Corneal edema
• Mid-dilated, poorly reactive pupil
• Elevated intraocular pressure

Immediate management: Perform gonioscopy to assess angle closure, measure IOP by Goldmann applanation tonometry, and initiate IOP-lowering therapy. 2 The fellow eye requires urgent evaluation and prophylactic laser iridotomy. 2

Step 5: Consider Tonic Pupil (Adie's Pupil)

In the well patient without neurological signs, tonic pupil syndrome is a common benign cause of isolated dilated pupil. 7 The pupil is dilated, reacts poorly to light but better to accommodation (light-near dissociation), and shows segmental iris sphincter palsy on slit-lamp examination. 7

Step 6: Assess for Cavernous Sinus Pathology

If multiple cranial nerve palsies are present (third, fourth, and/or sixth nerve involvement), suspect cavernous sinus lesion. 2, 1 Obtain MRI with contrast of brain and orbits, and refer to neurology or neurosurgery. 1

Physical Examination Components

Perform comprehensive slit-lamp biomicroscopy examining: 2

• Pupil size, shape, and reactivity
• Presence of ptosis
• Extraocular movements
• Conjunctival hyperemia
• Corneal clarity and edema
• Anterior chamber depth
• Iris abnormalities (atrophy, posterior synechiae)
• Lens position and clarity

Perform gonioscopy if angle-closure is suspected. 2

Common Pitfalls to Avoid

• Do not assume microvascular etiology in partial third nerve palsies, even if the pupil is spared. 2
• Do not delay imaging in pupil-involving third nerve palsy—aneurysms can present with initially normal-appearing pupils. 2
• Do not overlook medication history, particularly nebulized anticholinergics and topical agents. 2, 5
• Do not confuse RAPD with anisocoria—these are distinct findings requiring different workups. 3

Follow-Up

Follow-up depends on the underlying etiology and specialist recommendations. 1 Pathological causes require ongoing monitoring based on the specific diagnosis. 1