If one eye appears to be getting smaller than the other, what causes need to be ruled out?

Differential Diagnosis for Apparent Eye Size Asymmetry

When one eye appears smaller than the other, you must systematically distinguish between true enophthalmos (posterior globe displacement), pseudoptosis (apparent lid droop from globe malposition), contralateral proptosis (making the normal eye appear smaller), and primary eyelid ptosis—each requiring different urgent workup pathways. 1

Initial Clinical Assessment Framework

Determine the True Anatomical Problem

First, establish whether the "smaller" eye represents:

• Enophthalmos (posterior globe displacement): Measure with exophthalmometry or assess by viewing from above the patient's head to compare globe positions 1
• Pseudoptosis: Upper lid appears lower due to globe retraction, but levator function is normal 2
• Contralateral proptosis: The "normal" eye is actually abnormally prominent, making the other appear small 1
• True ptosis: Actual drooping of the upper eyelid (>2mm difference) with reduced levator function 3

Critical Red Flags Requiring Urgent Imaging

Obtain immediate MRI with contrast if any of these are present: 1

• Unilateral proptosis with orbital asymmetry: Concerning for orbital mass, optic nerve tumor, extraocular muscle pathology, lacrimal gland lesion, or skull base/cavernous sinus involvement 1
• Associated vision loss or diplopia: May indicate compressive optic neuropathy or restrictive extraocular muscle disease 1
• Pupillary abnormalities: RAPD of ≥0.3 log units suggests optic nerve or severe retinal pathology, not simple amblyopia 1, 4
• Painful ophthalmoplegia: Consider carotid-cavernous fistula, orbital inflammation, or posterior-draining vascular malformation 1

Enophthalmos: Specific Causes to Rule Out

Life-Threatening/Urgent Conditions

Orbital metastasis (especially breast cancer): Presents with progressive enophthalmos, may have desmoplastic features causing tissue retraction 5, 6

Silent sinus syndrome: Chronic maxillary sinus atelectasis causing ipsilateral enophthalmos, hypoglobus, and pseudoptosis; appears on CT/MRI as maxillary sinus collapse with inferior orbital floor displacement 1, 2, 5

Orbital varix: Vascular malformation causing intermittent enophthalmos/proptosis, may worsen with Valsalva 5, 6

Traumatic Causes (Even Remote History)

Orbital floor fracture: Even old injuries can cause late enophthalmos from orbital volume expansion or fat atrophy 1, 5, 6

• Obtain non-contrast orbital CT if any trauma history, even remote 1
• CT superior for identifying bony orbit integrity and displaced fractures 1

Developmental/Congenital Causes

Microphthalmia or anophthalmia: Small or absent globe from developmental abnormality 1

Horner syndrome: May present with apparent enophthalmos (actually mild ptosis and miosis creating illusion); look for anisocoria >1mm, reduced sweating, and iris heterochromia 1, 7

Inflammatory/Atrophic Processes

Extraocular muscle atrophy: From chronic progressive external ophthalmoplegia (CPEO), oculopharyngeal muscular dystrophy (OPMD), or other myopathies 8, 6

Desmoplastic neoplastic processes: Scirrhous tumors causing tissue contraction 1

Proptosis (Contralateral Eye): Key Differentials

Thyroid Eye Disease

Bilateral exophthalmos (though may be asymmetric): Most common cause of bilateral proptosis in adults 1

• Look for eyelid retraction, conjunctival injection, extraocular muscle restriction
• MRI shows extraocular muscle enlargement with tendon sparing 1

Unilateral Mass Lesions

Orbital tumors: Intrinsic to globe, optic nerve, extraocular muscles, lacrimal glands, or adjacent soft tissues 1

Carotid-cavernous fistula: Presents with proptosis, orbital congestion, chemosis (anterior-draining) or diplopia and pain (posterior-draining) 1

• MRI orbits with and without contrast is optimal for soft tissue characterization and lesion localization 1

Ptosis: Causes Requiring Specific Workup

Neurogenic Causes

Third nerve palsy: Look for associated ophthalmoplegia, pupil involvement (compressive lesion) vs. pupil-sparing (microvascular) 1, 3, 8

Horner syndrome: Ptosis with miosis and anhidrosis; anisocoria >1mm is clinically significant 1, 7, 3

Myasthenia gravis: Fluctuating ptosis/diplopia, variable EOM involvement pattern over time, fatigability 3, 8

• Test with ice pack test or edrophonium challenge
• Obtain acetylcholine receptor antibodies

Myogenic Causes

Chronic progressive external ophthalmoplegia (CPEO): Bilateral ptosis with ophthalmoparesis, superior rectus often involved, fat replacement of EOM on imaging 8

Oculopharyngeal muscular dystrophy (OPMD): Progressive ptosis with dysphagia, superior rectus involvement 8

Mechanical/Structural Causes

Levator dehiscence: Acquired aponeurotic ptosis, most common in elderly, good levator function despite ptosis 3

Eyelid tumors or inflammation: Mechanical weight causing lid droop 3

Pediatric-Specific Considerations

Congenital Abnormalities

Structural anomalies: Newborns should be evaluated for cataracts, corneal opacities, ptosis, and anophthalmia/microphthalmia 1

Leukocoria with orbital asymmetry: White pupillary reflex suggests intraocular pathology (retinoblastoma, persistent fetal vasculature, infection); requires urgent ophthalmology evaluation 1

Strabismus Mimicking Asymmetry

Pseudoesotropia: Prominent epicanthal folds and wide nasal bridge create illusion of eye asymmetry 1

• Perform corneal light reflex test: symmetric reflexes centered on pupils rules out true strabismus 1
• Cover-uncover test is more accurate than corneal reflex alone 1

Amblyopia Risk

Congenital ptosis covering pupil: Must be corrected to prevent amblyopia and permanent vision loss 3

Significant refractive error asymmetry: Can cause apparent size difference; perform cycloplegic refraction 1

Diagnostic Algorithm

Step 1: Measure and Localize

• Exophthalmometry or superior view assessment to quantify globe position 1
• Measure palpebral fissure heights and levator function bilaterally 3
• Pupil examination: Size, symmetry, reactivity, swinging-light test for RAPD 1, 4

Step 2: Risk Stratify for Imaging

Immediate MRI orbits with/without contrast if: 1

• Unilateral proptosis or progressive enophthalmos
• Vision loss, RAPD ≥0.3 log units, or optic nerve dysfunction
• Painful ophthalmoplegia or cranial nerve palsy
• Leukocoria or suspected intraocular mass

CT orbits without contrast if: 1

• Trauma history (even remote)
• Suspected orbital floor fracture
• Acute presentation where metallic foreign body possible

Sinus CT if: 2, 5

• Enophthalmos with hypoglobus
• Suspected silent sinus syndrome

Step 3: Specialized Testing Based on Findings

If ptosis with fluctuation/fatigability: Myasthenia workup (ice test, antibodies, EMG) 3, 8

If bilateral progressive ptosis with ophthalmoplegia: Consider mitochondrial myopathy (CPEO), obtain muscle biopsy, genetic testing 8

If anisocoria >1mm: Pharmacologic testing for Horner syndrome (apraclonidine or cocaine drops) 1, 7

If thyroid eye disease suspected: Thyroid function tests, TSH receptor antibodies 1

Common Pitfalls to Avoid

Do not confuse anisocoria (pupil size difference) with RAPD (pupillary response difference): These represent entirely different pathophysiologic processes 4, 7, 9

Do not assume amblyopia if RAPD ≥0.3 log units present: This threshold mandates investigation for optic nerve or retinal pathology 1, 4, 9

Do not miss silent sinus syndrome: Often misdiagnosed; look specifically for maxillary sinus changes on imaging in unilateral enophthalmos cases 2, 5

Do not delay imaging in progressive unilateral proptosis: Orbital masses, including metastases, require urgent characterization 1, 5

In children, do not dismiss as "pseudoesotropia" without proper corneal reflex and cover testing: True strabismus requires different management 1