What is the appropriate workup for a patient presenting with anisocoria (uneven pupils)?

Workup for Anisocoria (Uneven Pupils)

Begin by determining which pupil is abnormal through observation in both bright and dim lighting, then immediately assess for life-threatening causes—specifically pupil-involving third nerve palsy, which requires urgent neuroimaging to exclude posterior communicating artery aneurysm. 1, 2

Initial Bedside Assessment

Pupillary Examination in Different Lighting

• Check pupil size in bright and dim illumination to identify which pupil is abnormal 1, 2
• Measure pupil size precisely; anisocoria >1mm warrants investigation for pathological causes 3, 1
• Assess pupil shape (mid-dilated, oval, or irregular pupils suggest specific pathologies) 3
• Test direct and consensual light responses in both eyes 3
• Evaluate for relative afferent pupillary defect (RAPD); a large RAPD demands investigation for compressive optic neuropathy or retinal pathology 3, 1

Critical Associated Findings

• Assess for ptosis (eyelid droop), which combined with anisocoria suggests third nerve palsy or Horner syndrome 1, 2
• Test extraocular movements in all directions; limitations indicate third nerve palsy or cavernous sinus pathology 1, 2
• Evaluate for neurological deficits: headache, altered mental status, or focal neurological signs 1, 2
• Check for head trauma history 1

Urgent Neuroimaging Indications (Life-Threatening Causes)

Obtain immediate MRI with gadolinium plus MRA or CTA for:

• Any pupil-involving third nerve palsy (dilated pupil with poor light reaction) to exclude posterior communicating artery aneurysm 1, 2
• Partial third nerve palsy (incomplete ptosis or selective muscle weakness) even with normal pupil—do not assume microvascular etiology 1
• Anisocoria with headache, altered mental status, or other neurological deficits 1, 2
• Anisocoria following head trauma 1
• Multiple cranial nerve palsies suggesting cavernous sinus lesion 1, 2

Critical pitfall to avoid: Never assume microvascular etiology unless there is complete ptosis, complete extraocular motility dysfunction, AND entirely normal pupil function 1

Slit-Lamp Biomicroscopy and Ocular Examination

Perform detailed anterior segment examination to identify specific causes:

Acute Angle-Closure Crisis

• Mid-dilated, oval, or asymmetric pupil with poor reactivity 3
• Conjunctival hyperemia, corneal edema, anterior chamber shallowing 3
• Measure intraocular pressure by Goldmann applanation tonometry 3
• Perform gonioscopy in both eyes to evaluate angle anatomy 3, 1
• This requires immediate IOP-lowering therapy and ophthalmology consultation 1

Iris and Lens Abnormalities

• Irregular pupil shape suggests traumatic sphincter damage, iritis, or congenital coloboma 3, 1
• Iris atrophy, posterior synechiae, or abnormal iris configuration 3
• Lens position abnormalities or glaukomflecken 3

External Examination

• Assess levator function, eyelid retraction, globe position (proptosis or retraction) 3, 1
• Evaluate for dysmorphic features or oculofacial anomalies 3

Pharmacologic Testing

Pilocarpine Testing for Pharmacologic Mydriasis

• Apply pilocarpine 1% to the dilated pupil 1, 4
• Pharmacologically dilated pupils (from anticholinergics, antihistamines, or nebulized ipratropium) will NOT constrict 1, 4
• Adie tonic pupil will constrict with pilocarpine 0.1% (denervation supersensitivity) 5, 6
• Third nerve palsy pupils typically show some response to pilocarpine 1% 5

Common scenario: Nebulized ipratropium bromide can leak from face masks and cause unilateral mydriasis; pilocarpine testing confirms this benign cause 4

Cocaine Testing for Horner Syndrome

• Cocaine 10% eye drops can differentiate Horner syndrome from physiologic anisocoria 5, 6
• In Horner syndrome, the affected pupil fails to dilate with cocaine 5, 6

Specific Clinical Scenarios

Pupil-Sparing Third Nerve Palsy

• Complete ptosis and complete extraocular motility dysfunction with normal pupil 1
• Almost always secondary to microvascular disease (diabetes, hypertension, hyperlipidemia) 1
• Generally resolves within 3 months with observation alone 1
• No neuroimaging required if truly complete palsy with entirely normal pupil 1

Physiologic Anisocoria

• Difference typically <1mm, pupils react normally to light 1, 2
• No ptosis or other abnormalities 1
• Remains constant in different lighting conditions 2
• This is a benign condition requiring no further workup 2, 6

Additional Workup When Imaging is Normal

If MRI/MRA/CTA is negative but clinical suspicion remains high:

• Catheter-based angiography for suspected aneurysm 1
• Serologic testing for syphilis and Lyme disease 1
• Lumbar puncture to exclude inflammatory or infectious meningitis 1
• Consider tumors (meningioma, schwannoma, metastases), demyelinating disease, or leptomeningeal disorders 1

Fundus and Optic Nerve Evaluation

• Attempt fundus examination without dilation using direct ophthalmoscope, indirect lens (78D or 90D), or non-mydriatic camera 3
• OCT imaging of optic nerves can often be obtained through undilated pupils 3
• Caution with dilation: In suspected angle-closure, dilation can precipitate acute crisis; perform only after iridotomy if needed 3