What is the differential diagnosis (Ddx) for elevated intraocular pressure in a patient, particularly in adults over 40 years old with a family history of glaucoma and underlying medical conditions such as diabetes, hypertension, or a history of eye trauma?

Differential Diagnosis for Elevated Intraocular Pressure

Elevated intraocular pressure (IOP >21 mmHg) has a broad differential diagnosis that must be systematically evaluated, as IOP elevation alone is neither diagnostic of glaucoma nor benign—comprehensive assessment of the optic nerve, angle structures, and secondary causes is mandatory before labeling a patient as having simple ocular hypertension. 1, 2

Primary Categories of Elevated IOP

Primary Open-Angle Conditions

• Ocular hypertension (OHT): IOP >21 mmHg without optic disc damage or visual field defects, affecting 3-6 million Americans over age 40 1
• Primary open-angle glaucoma (POAG): Elevated IOP with characteristic optic nerve damage and/or visual field loss 1
• Normal-tension glaucoma: Note that approximately 50% of glaucoma patients have IOP ≤21 mmHg, so "normal" pressure does not exclude glaucomatous damage 2, 3

Secondary Open-Angle Glaucomas

The American Academy of Ophthalmology specifically identifies these secondary causes that must be excluded: 1

• Pseudoexfoliation syndrome: Accumulation of extracellular matrix material in trabecular meshwork 1
• Pigment dispersion syndrome: Iris pigment liberation causing trabecular meshwork obstruction 1
• Traumatic angle recession: History of blunt or penetrating ocular trauma causing mechanical damage to drainage structures 1, 4
• Steroid-induced glaucoma: Corticosteroid use (topical, periocular, systemic, or inhaled) causing trabecular meshwork dysfunction
• Uveitic glaucoma: Inflammatory debris and trabecular meshwork damage from intraocular inflammation
• Lens-related mechanisms: Phacolytic glaucoma, lens particle glaucoma, or phacomorphic angle closure 4
• Neovascular glaucoma: Secondary to retinal ischemia (diabetic retinopathy, central retinal vein occlusion)

Diabetes-Related IOP Elevation

Given the patient context of diabetes, specific mechanisms include: 5

• Diabetic-associated OHT: Increased aqueous osmotic gradient and extracellular matrix accumulation in trabecular meshwork 5
• Post-laser IOP elevation: Paradoxically, early panretinal photocoagulation protects against OHT, while delayed treatment or silicone oil use promotes it 5
• Autonomic dysfunction: Diabetic autonomic neuropathy affecting aqueous dynamics 5

Angle-Closure Mechanisms

Gonioscopy is mandatory to exclude these conditions, which require fundamentally different management: 1, 3

• Primary angle-closure suspect/glaucoma: Narrow angles with appositional or synechial closure
• Plateau iris configuration: Anteriorly positioned ciliary processes
• Pupillary block: Relative obstruction to aqueous flow from posterior to anterior chamber

Trauma-Related Mechanisms

Given the patient's history of eye trauma: 4

• Acute traumatic hyphema: Blood in anterior chamber obstructing trabecular meshwork 4
• Ghost cell glaucoma: Degenerated red blood cells from vitreous hemorrhage
• Hemolytic glaucoma: Macrophages laden with hemoglobin blocking outflow
• Angle recession glaucoma: Can develop years after blunt trauma 4
• Lens subluxation/dislocation: Mechanical pupillary block or trabecular obstruction 4

Critical Risk Stratification

The American Academy of Ophthalmology emphasizes that multiple risk factors dramatically increase progression risk from OHT to POAG—patients with your described profile (age >40, family history, diabetes) require heightened surveillance. 1, 3

High-Risk Features Requiring Aggressive Monitoring:

• Age >40 years: Risk increases progressively with each decade 1
• Family history of glaucoma: 9.2-fold increased odds with first-degree relative 3
• Diabetes mellitus: 40-140% higher odds of POAG development 1, 3
• Thin central corneal thickness (≤510 μm): Independent risk factor beyond IOP measurement artifact 1, 3, 6
• Large cup-to-disc ratio: Structural vulnerability marker 1, 6
• Disc hemorrhage: Strong predictor of progression 1

Additional Risk Factors:

• Hypertension with low diastolic perfusion pressure (<50 mmHg): Compromises optic nerve perfusion 1, 3
• Myopia: Particularly high axial myopia increases risk 1, 3
• African or Latino/Hispanic ethnicity: Higher prevalence and earlier onset 1

Essential Diagnostic Workup

Every patient with elevated IOP requires comprehensive evaluation—IOP measurement alone has only 47.1% sensitivity for glaucoma and should never guide management in isolation. 2

Mandatory Initial Assessment:

• Gonioscopy: Confirm open angles and exclude secondary angle-closure mechanisms 1, 3
• Central corneal pachymetry: Assess both IOP measurement accuracy and independent risk 3, 6
• Optic nerve head examination: Document cup-to-disc ratio, rim thickness, disc hemorrhages 1, 3
• Retinal nerve fiber layer (RNFL) assessment: Clinical examination and OCT imaging provide complementary information 1, 3
• Visual field testing: Establish baseline, though early glaucoma may have normal fields initially 3
• Optic nerve photography: Document baseline appearance for longitudinal comparison 3

Critical Pitfall to Avoid:

Do not diagnose or exclude glaucoma based on a single IOP measurement or one normal visual field—serial monitoring over time is the only reliable method to assess true risk and detect early progression. 2, 3

Clinical Decision Algorithm

1. Measure IOP and perform complete examination including gonioscopy, pachymetry, optic nerve assessment, and visual field testing 1, 3

2. If angle-closure mechanism identified on gonioscopy: Refer for laser peripheral iridotomy or other angle-opening procedures—fundamentally different disease requiring different treatment 3

3. If open angles confirmed, systematically exclude secondary causes: Review medication history (steroids), assess for pseudoexfoliation/pigment dispersion, evaluate for uveitis, examine lens status, assess trauma history 1, 4

4. Risk stratify based on cumulative factors: Patients with multiple risk factors (age >40, family history, diabetes, thin cornea, suspicious disc) have substantially higher progression risk requiring closer monitoring 1, 3, 6

5. For high-risk OHT: The Ocular Hypertension Treatment Study demonstrated that treatment reduces 5-year progression from 9.5% to 4.4%, though >90% of untreated patients did not progress 1, 7

6. Establish longitudinal monitoring protocol: Serial IOP measurements, optic nerve examinations, and visual field testing at intervals determined by cumulative risk—this is the only way to truly assess individual glaucoma risk 3