The Wills Eye Manual

Chapter 2. Differential Diagnosis of Ocular Signs



Trauma, iatrogenic (e.g., intraocular surgery or laser), iris neovascularization, blood dyscrasia or clotting disorder (e.g., hemophilia), anticoagulation, herpes simplex or zoster iridocyclitis, Fuchs heterochromic iridocyclitis, intraocular tumor (e.g., juvenile xanthogranuloma, retinoblastoma, angioma).


Infectious keratitis, severe anterior uveitis (e.g., HLA-B27 associated, Behcet disease), endophthalmitis, contaminant during intraocular surgery (i.e., toxic anterior segment syndrome), retained lens particle, intraocular foreign body, intraocular tumor necrosis (e.g., pseudohypopyon from retinoblastoma), tight contact lens, severe inflammatory reaction from a recurrent corneal erosion, drugs (e.g., rifampin).

Blood in Schlemm Canal on Gonioscopy

Iatrogenic (compression of episcleral vessels by a gonioprism), Sturge-Weber syndrome, arteriovenous fistula (e.g., carotid- cavernous sinus fistula [c-c fistula]), superior vena cava obstruction, hypotony.


Conjunctival Swelling (Chemosis)

Allergy, ocular or periocular inflammation, postoperative, drugs, venous congestion (e.g., c-c fistula), angioneurotic edema, myxedema.

Conjunctival/Corneal Dryness (Keratoconjunctivitis Sicca)

Exposure (e.g., lagophthalmos, proptosis, poor blink reflex), Sjogren syndrome, vitamin A deficiency, mucous membrane pemphigoid, postcicatricial conjunctivitis, Stevens-Johnson syndrome, radiation, chronic dacryoadenitis.

Corneal Crystals

See 4.14, Crystalline Keratopathy.

Corneal Edema

1. Congenital: Birth trauma (e.g., forceps injury), congenital glaucoma, congenital hereditary endothelial dystrophy (bilateral), posterior polymorphous corneal dystrophy (PPCD).

2. Acquired: Trauma, chemical injury, contact lens overwear, acute increase in intraocular pressure (e.g., angle-closure glaucoma), corneal hydrops (decompensated keratoconus), herpes simplex or zoster keratitis, uveitis, postoperative edema, aphakic or pseudophakic bullous keratopathy, Fuchs endothelial dystrophy, failed corneal graft, iridocorneal endothelial (ICE) syndrome, PPCD.

Corneal Opacification in Infancy

Birth trauma (e.g., forceps injury), infectious keratitis, metabolic abnormalities (bilateral; e.g., mucopolysaccharidoses), anterior segment dysgenesis (e.g., Peters anomaly, sclerocornea), edema (e.g., congenital glaucoma), congenital hereditary endothelial or stromal dystrophy (bilateral), PPCD, corneal dermoid.

Dilated Episcleral Vessels (Without Ocular Irritation or Pain)

Underlying uveal neoplasm, arteriovenous fistula (e.g., c-c fistula), polycythemia vera, leukemia, ophthalmic vein or cavernous sinus thrombosis, extravascular blockage of ophthalmic or orbital venous outflow.

Enlarged Corneal Nerves

Multiple endocrine neoplasia type 2 (i.e., medullary thyroid carcinoma and pheochromocytoma), neurofibromatosis, acanthamoeba keratitis, keratoconus, failed corneal graft, Fuchs endothelial dystrophy, PPCD, multiple myeloma, Refsum syndrome, Riley-Day dysautonomia, trauma, congenital glaucoma, leprosy, ichthyosis, idiopathic, normal variant.

Follicles on the Conjunctiva

See 5.1, Acute Conjunctivitis and 5.2, Chronic Conjunctivitis.

Membranous Conjunctivitis

Classic teaching is that membrane removal is difficult and causes bleeding. Streptococci, pneumococci, Corynebacterium diphtheriae, herpes simplex, chemical injury, ligneous conjunctivitis, ocular vaccinia, rarely epidemic keratoconjunctivitis or Stevens-Johnson syndrome (more often causes pseudomembranous conjunctivitis).

Pseudomembranous Conjunctivitis

Classic teaching is that pseudomembrane removal is easy and does not cause bleeding. All the causes of membranous conjunctivitis listed above, gonococci, staphylococci, chlamydia (especially in newborns), mucous membrane pemphigoid, superior limbic keratoconjunctivitis.

Pannus (Superficial Vascular Invasion of the Cornea)

Hypoxia from contact lens tightness or overwear, staphylococcal hypersensitivity, phlyctenule, ocular rosacea, herpes simplex or zoster keratitis, chlamydia (trachoma and inclusion conjunctivitis), chemical injury, superior limbic keratoconjunctivitis (micropannus), vernal keratoconjunctivitis, mucous membrane pemphigoid, aniridia, molluscum contagiosum, leprosy.

Papillae on the Conjunctiva

See 5.1, Acute Conjunctivitis and 5.2, Chronic Conjunctivitis.

Pigmentation/Discoloration of the Conjunctiva

Complexion-associated melanosis (perilimbal), primary acquired melanosis, nevus, melanoma, ocular and oculodermal melanocytosis (blue-gray, not conjunctival but episcleral), Addison disease, pregnancy, radiation, jaundice, resolving subconjunctival hemorrhage, conjunctival or subconjunctival foreign body, pharmacologic (e.g., chlorpromazine, topical epinephrine), cosmetic (e.g., mascara/makeup deposits, tattoo).

Symblepharon (Fusion of the Palpebral and Bulbar Conjunctiva)

Mucous membrane pemphigoid, Stevens-Johnson syndrome, chemical injury, trauma, epidemic keratoconjunctivitis, atopic conjunctivitis, chronic conjunctivitis, radiation, drugs, congenital, iatrogenic (e.g., postsurgical).

Verticillata (Whorl-Like Opacity in the Corneal Epithelium)

Amiodarone, chloroquine, atovaquone, Fabry disease and carrier state, phenothiazines, indomethacin, topical Rho kinase inhibitors (e.g., netarsudil, ripasudil).


Eyelid Edema

See “Eyelid Swelling” in Chapter 1, Differential Diagnosis of Ocular Symptoms.

Eyelid Lesion

See 6.11, Malignant Tumors of the Eyelid.

Ptosis and Pseudoptosis

See 6.1, Ptosis.


Bone Spicules (Widespread Pigment Clumping)

See 11.28, Retinitis Pigmentosa and Inherited Chorioretinal Dystrophies.

Bull’s-Eye Macular Lesion

Age-related macular degeneration (AMD), Stargardt disease or fundus flavimaculatus, albinism, cone dystrophy, rod-cone dystrophy, chloroquine or hydroxychloroquine retinopathy, adultonset foveomacular vitelliform dystrophy, Spielmeyer-Vogt syndrome, central areolar choroidal dystrophy.

See 11.32, Chloroquine/Hydroxychloroquine Toxicity.

Choroidal Folds

Orbital or choroidal tumor, posterior scleritis, idiopathic orbital inflammatory syndrome, hypotony, thyroid eye disease, retinal detachment, marked hyperopia, scleral laceration, papilledema, postoperative.

Choroidal Neovascularization (Gray-Green Membrane or Blood Deep to the Retina)

More Common. AMD, polypoidal choroidal vasculopathy, ocular histoplasmosis syndrome, high myopia, angioid streaks, choroidal rupture (trauma).

Less Common. Optic nerve head drusen, tumors, retinal scarring after laser photocoagulation, posterior uveitis (e.g., Vogt-Koyanagi- Harada disease, multifocal choroiditis, serpiginous choroiditis), idiopathic.

Cotton-Wool Spots

See 11.5, Cotton-Wool Spot.


See 10.22, Transient Visual Loss/Amaurosis Fugax; 11.6, Central Retinal Artery Occlusion; 11.7, Branch Retinal Artery Occlusion; 11.33, Crystalline Retinopathy.

 Platelet-fibrin (dull gray and elongated): Carotid disease, less commonly cardiac.

 Cholesterol (sparkling yellow, usually at an arterial bifurcation): Carotid disease.

 Calcium (dull white, typically around or on the disc): Cardiac disease.

 Cardiac myxoma (common in young patients, particularly in the left eye; often occludes the ophthalmic or retrobulbar central retinal artery and is not visualized).

 Talc and cornstarch (small, yellow-white glistening particles in macular arterioles; may produce peripheral retinal neovascularization): Intravenous drug use.

 Lipid or air (often see cotton-wool spots rather than emboli): Chest trauma (Purtscher retinopathy) and fracture of long bones.

 Others (tumors, parasites, other foreign bodies).

Macular Exudates

More Common. Diabetes, choroidal neovascular membrane, hypertension.

Less Common. Macroaneurysm, Coats disease (children), peripheral retinal capillary hemangioma, retinal vein occlusion, papilledema, radiation retinopathy.

Normal Fundus With Decreased Vision

Retrobulbar optic neuritis, other optic neuropathy (infiltrative, toxic [e.g., alcohol, tobacco], Leber hereditary optic neuropathy), amblyopia, Stargardt disease or fundus flavimaculatus, cone degeneration, rod monochromatism, cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), nonphysiologic visual loss.

Optociliary Shunt Vessels on the Disc

Orbital or intracranial tumor (especially meningioma), optic nerve glioma, prior central retinal vein occlusion, chronic papilledema (e.g., pseudotumor cerebri), chronic open angle glaucoma.

Retinal Neovascularization

1. Posterior pole: Diabetes, prior central retinal vein or artery occlusion.

2. Peripheral: Sickle cell retinopathy, prior branch retinal vein occlusion, diabetes, sarcoidosis, syphilis, ocular ischemic syndrome (carotid occlusive disease), pars planitis, Coats disease, retinopathy of prematurity, embolization from i.v. drug abuse (e.g., talc retinopathy), chronic uveitis, leukemia, anemia, Eales disease, familial exudative vitreoretinopathy.

Roth Spots (Retinal Hemorrhages With White Centers)

More Common. Diabetes, leukemia, septic chorioretinitis (e.g., from bacterial endocarditis).

Less Common. Pernicious anemia (and rarely other forms of anemia), sickle cell disease, scurvy, systemic lupus erythematosus, other connective tissue diseases.

Sheathing of Retinal Veins (Periphlebitis)

More Common. Syphilis, sarcoidosis, pars planitis, sickle cell disease.

Less Common. Tuberculosis, multiple sclerosis, Eales disease, viral retinitis (e.g., herpes virus, human immunodeficiency virus), Behcet disease, fungal retinitis, bacteremia.


See 11.36, Choroidal Nevus and Malignant Melanoma of the Choroid.


Acute Increase in Intraocular Pressure

Acute angle-closure glaucoma, inflammatory open angle glaucoma, malignant glaucoma, hyphema, glaucomatocyclitic crisis (Posner- Schlossman syndrome), postoperative complications (see “Postoperative Complications” in this chapter), suprachoroidal hemorrhage, c-c fistula, spontaneous closure of cyclodialysis cleft, retrobulbar hemorrhage, other orbital disease.

Chronic Increase in Intraocular Pressure

See 9.1, Primary Open Angle Glaucoma, and 9.5, Chronic Angle-Closure Glaucoma.

Decreased Intraocular Pressure (Hypotony)

Ruptured globe, phthisis bulbi, retinal/choroidal detachment, iridocyclitis, severe dehydration, cyclodialysis cleft, ocular ischemia, drugs (e.g., glaucoma medications), postoperative complications (see “Postoperative Complications” in this chapter), traumatic ciliary body shutdown.


Iris Heterochromia (Irides of Different Colors)

1. Involved iris is lighter than normal: Congenital Horner syndrome, most cases of Fuchs heterochromic iridocyclitis, chronic uveitis, juvenile xanthogranuloma, metastatic carcinoma, Waardenburg syndrome.

2. Involved iris is darker than normal: Ocular melanocytosis or oculodermal melanocytosis, hemosiderosis, siderosis, retained intraocular foreign body, ocular malignant melanoma, diffuse iris nevus, retinoblastoma, leukemia, lymphoma, ICE syndrome, some cases of Fuchs heterochromic iridocyclitis.

Iris Lesion

1. Melanotic (brown): Nevus, melanoma, adenoma, or adenocarcinoma of the iris pigment epithelium.

NOTE: Cysts, foreign bodies, neurofibromas, and other lesions may appear pigmented in heavily pigmented irides.

2. Amelanotic (white, yellow, or orange): Amelanotic melanoma, inflammatory nodule or granuloma (e.g., sarcoidosis, tuberculosis, leprosy, other granulomatous disease), neurofibroma, patchy hyperemia of syphilis, juvenile xanthogranuloma, medulloepithelioma, foreign body, cyst, leiomyoma, seeding from a posterior segment tumor.

Neovascularization of the Iris

Diabetic retinopathy, ocular ischemic syndrome, prior central or branch retinal vein or artery occlusion, chronic uveitis, chronic retinal detachment, intraocular tumor (e.g., retinoblastoma, melanoma), other retinal vascular disease.


See Also 13.1, Acquired Cataract.

Dislocated Lens (Ectopia Lentis)

See 13.10, Subluxed or Dislocated Crystalline Lens.

Iridescent Lens Particles

Drugs, hypocalcemia, myotonic dystrophy, hypothyroidism, familial, idiopathic.


1. Anterior (marked convexity of the anterior lens): Alport syndrome (hereditary nephritis).

2. Posterior (marked concavity of the posterior lens): Usually idiopathic, may be associated with persistent fetal vasculature.


Afferent Pupillary Defect

1. Severe (2+ to 3+): Optic nerve disease (e.g., ischemic optic neuropathy, optic neuritis, tumor, glaucoma); central retinal artery or vein occlusion; less commonly, a lesion of the optic chiasm or tract; extensive retinal detachment or retinoschisis.

2. Mild (trace to 1+): Any of the preceding, amblyopia, dense vitreous hemorrhage, advanced macular degeneration, branch retinal vein or artery occlusion, less extensive retinal detachment or retinoschisis, or other retinal pathology.

Anisocoria (Pupils of Different Sizes)

See 10.1, Anisocoria.

Limitation of Ocular Motility

1. With exophthalmos and resistance to retropulsion: See 7.1, Orbital Disease.

2. Without exophthalmos or resistance to retropulsion: Isolated third, fourth, or sixth cranial nerve palsy; multiple ocular motor nerve palsies (see 10.10, Cavernous Sinus and Associated Syndromes [Multiple Ocular Motor Nerve Palsies]), myasthenia gravis, chronic progressive external ophthalmoplegia and associated syndromes, orbital blow-out fracture with muscle entrapment, ophthalmoplegic migraine, Duane syndrome, other central nervous system (CNS) disorders.

Optic Disc Atrophy

More Common. Glaucoma; prior central retinal vein or artery occlusion; prior ischemic optic neuropathy; chronic optic neuritis; chronic papilledema; compression of the optic nerve, chiasm, or tract by a tumor or aneurysm; prior traumatic optic neuropathy.

Less Common. Syphilis, retinal degeneration (e.g., retinitis pigmentosa), toxic or metabolic optic neuropathy, Leber hereditary optic atrophy, Leber congenital amaurosis, radiation neuropathy, lysosomal storage disease (e.g., Tay-Sachs disease), other forms of congenital or hereditary optic atrophy (nystagmus almost always present in congenital forms).

Optic Disc Swelling (Edema)

See 10.15, Papilledema.

Optociliary Shunt Vessels

See “Fundus Findings” in this chapter.

Paradoxical Pupillary Reaction (Pupil Dilates in Light and Constricts in Darkness)

Congenital stationary night blindness, congenital achromatopsia, optic nerve hypoplasia, Leber congenital amaurosis, Best disease, optic neuritis, dominant optic atrophy, albinism, retinitis pigmentosa, rarely amblyopia.


Extraocular Muscle Thickening on Imaging

More Common. Thyroid orbitopathy (often spares tendon), idiopathic orbital inflammatory syndrome (involves tendon).

Less Common. Tumor (e.g., lymphoma, metastasis, or spread of lacrimal gland tumor to muscle), c-c fistula, superior ophthalmic vein thrombosis, cavernous hemangioma (usually appears in the muscle cone without muscle thickening), rhabdomyosarcoma (children).

Lacrimal Gland Lesions

See 7.6, Lacrimal Gland Mass/Chronic Dacryoadenitis.

Optic Nerve Lesion (Isolated)

More Common. Optic nerve glioma (especially children), optic nerve meningioma (especially adults).

Less Common. Metastasis, leukemia, idiopathic orbital inflammatory syndrome, sarcoidosis, increased intracranial pressure with secondary optic nerve swelling.

Orbital Lesions/Proptosis

See 7.1, Orbital Disease.


Leukocoria (White Pupillary Reflex)

See 8.1, Leukocoria.

Nystagmus in Infancy

See Also 10.21, Nystagmus.

Congenital nystagmus, spasmus nutans, congenital cataracts, congenital corneal opacities, aniridia, albinism, optic nerve hypoplasia, Leber congenital amaurosis, CNS (thalamic) injury, optic nerve or chiasmal glioma.


Shallow Anterior Chamber

1. Accompanied by increased intraocular pressure: Pupillary block (acute angle closure) glaucoma, capsular block syndrome, suprachoroidal hemorrhage, malignant glaucoma (aqueous misdirection).

2. Accompanied by decreased intraocular pressure: Wound leak, choroidal detachment, overfiltration after glaucoma filtering procedure.


Wound leak, choroidal detachment, cyclodialysis cleft, retinal detachment, ciliary body shutdown, pharmacologic aqueous suppression, overfiltration after glaucoma filtering procedure.


Progressive Hyperopia

Orbital tumor compressing the posterior globe, elevation of the retina (e.g., subretinal fluid from central serous chorioretinopathy, choroidal thickening from posterior scleritis), presbyopia, hypoglycemia, after radial keratotomy or other refractive surgery.

Progressive Myopia

High (pathologic) myopia, staphyloma and elongation of the globe, diabetes, cataract, corneal ectasia (keratoconus or sequela of corneal refractive surgery), medications (e.g., miotic drops, sulfa drugs, tetracycline), childhood (physiologic).


Altitudinal Field Defect

More Common. Ischemic optic neuropathy, optic neuritis, hemi- or branch retinal artery or vein occlusion.

Less Common. Glaucoma, optic nerve or chiasmal lesion, optic nerve coloboma.

Arcuate Scotoma

More Common. Glaucoma.

Less Common. Ischemic optic neuropathy (especially nonarteritic), optic disc drusen, high myopia, optic neuritis.

Binasal Field Defect

More Common. Glaucoma, bitemporal retinal disease (e.g., retinitis pigmentosa).

Rare. Bilateral occipital disease, tumor or aneurysm compressing both optic nerves or chiasm, chiasmatic arachnoiditis, nonphysiologic.

Bitemporal Hemianopsia

More Common. Chiasmal lesion (e.g., pituitary adenoma, meningioma, craniopharyngioma, aneurysm, glioma).

Less Common. Tilted optic discs.

Rare. Nasal retinitis pigmentosa.

Blind Spot Enlargement

Papilledema, glaucoma, optic nerve drusen, optic nerve coloboma, myelinated nerve fibers off the disc, drugs, disc with myopic crescent, multiple evanescent white dot syndrome (MEWDS), acute idiopathic blind spot enlargement syndrome (may be on same spectrum as MEWDS).

Central Scotoma

Macular disease, optic neuritis, ischemic optic neuropathy (more typically produces an altitudinal field defect), optic atrophy (e.g., from tumor compressing the nerve, toxic or metabolic disease), rarely an occipital cortex lesion.

Constriction of the Peripheral Fields Leaving a Small Central Field (Tunnel Vision)

Glaucoma, retinitis pigmentosa or other peripheral retinal disorders (e.g., gyrate atrophy), chronic papilledema, sequela of panretinal photocoagulation or cryotherapy, central retinal artery occlusion with cilioretinal artery sparing, bilateral occipital lobe infarction with macular sparing, nonphysiologic visual loss, medications (e.g., phenothiazines), vitamin A deficiency, carcinoma, melanoma, autoimmune-associated retinopathy.

Homonymous Hemianopsia

Temporal, parietal, or occipital lobe lesion of the brain (e.g., stroke and tumor more commonly; aneurysm and trauma less commonly), optic tract or lateral geniculate body lesion, migraine (transiently).


Vitreous Opacities

Asteroid hyalosis, vitreous hemorrhage, inflammatory cells from vitritis or posterior uveitis, snowball opacities of pars planitis or sarcoidosis, normal vitreous strands from age-related vitreous degeneration, tumor cells, foreign body, hyaloid remnants, synchysis scintillans, rarely amyloidosis, or Whipple disease.