6. Ocular Risk Factors and Ocular Biomechanics

What is the normal range of intraocular pressure (IOP), and how is IOP related to glaucoma?

• Normal IOP: 10–21 mmHg

• IOP is no longer part of the definition of glaucoma.

• However, elevated IOP is the greatest risk factor for glaucoma.

• Lowering IOP is currently the only proven treatment to slow glaucoma progression.

What factors determine intraocular pressure (IOP)?

IOP = AHP − TMOut − UvScOut + EVP

Where:

• AHP = Aqueous humor production ↑ → increases IOP

• TMOut = Trabecular meshwork outflow ↑ → decreases IOP

• UvScOut = Uveoscleral outflow ↑ → decreases IOP

• EVP = Episcleral venous pressure ↑ → increases IOP

What is the major mechanism of elevated IOP in primary open-angle glaucoma (POAG) and ocular hypertension?

Reduced trabecular meshwork outflow (TMOut) is the primary cause.

Structural changes include:

1. Increased extracellular matrix in the juxtacanalicular tissue (JCT) beneath Schlemm's canal.

2. Loss of endothelial cells causing thickening of trabecular lamellae.

3. Formation of plaques in the corneoscleral beams and juxtacanalicular meshwork.

Result: Increased resistance to aqueous humor drainage → elevated IOP.

Which trabecular meshwork changes are classically associated with POAG?

• Protein/extracellular matrix accumulation in the JCT

• Paucity (loss) of endothelial cells with trabecular thickening

• Plaque formation in the trabecular meshwork

Net effect: Increased outflow resistance through the conventional pathway → increased IOP.

What is the relationship between intraocular pressure (IOP) and primary open-angle glaucoma (POAG)?

• As IOP increases, the prevalence/risk of POAG rises sharply.

• The relationship is continuous—there is no single IOP cutoff that separates glaucoma from non-glaucoma eyes.

• Higher IOP = progressively greater likelihood of glaucoma.

Why is an IOP of 21 mmHg an imperfect threshold for diagnosing glaucoma?

Because there is significant overlap between normal and glaucomatous eyes:

• Some patients develop glaucoma with IOP ≤ 21 mmHg (normal-tension glaucoma).

• Many individuals with IOP > 21 mmHg never develop glaucomatous damage (ocular hypertension).

How can you distinguish normal-tension glaucoma, ocular hypertension, and POAG based on IOP?

• Normal-tension glaucoma (NTG): Glaucomatous optic nerve damage despite IOP within the normal range (≤21 mmHg).

• Ocular hypertension (OHT): Elevated IOP (>21 mmHg) without glaucomatous damage.

• POAG: Glaucomatous optic neuropathy, often associated with elevated IOP, but not required for diagnosis.

Why can't a single IOP cutoff be used to diagnose glaucoma?

Because there is substantial overlap between normal and glaucomatous eyes:

• Some patients have glaucoma at low/normal IOP (normal-tension glaucoma).

• Some patients have high IOP without glaucoma (ocular hypertension).

• No threshold perfectly separates "safe" from "glaucomatous" IOP.

How do sensitivity and specificity change as the IOP threshold for diagnosing glaucoma increases?

• Lower IOP cutoff → high sensitivity, low specificity.

• Higher IOP cutoff → low sensitivity, high specificity.

When is IOP typically highest, and what causes its diurnal fluctuation?

IOP is highest during sleep and often peaks in the early morning.

Contributors:

• Circadian variations in aqueous humor dynamics

• Supine (lying) position

• Increased overnight corneal edema

What factors contribute to normal physiologic fluctuations in IOP?

Short-term fluctuations:

• Respiration

• Cardiac cycle (ocular pulse)

Longer-term fluctuations:

• Circadian rhythm

• Sleep/wake cycle

• Body position changes

Ocular pulse amplitude (OPA):

• Represents IOP changes with each heartbeat

• Typically ranges from ~0.9–7.2 mmHg

What everyday activities can transiently increase IOP?

Temporary IOP elevations can occur with:

• Blinking

• Eye movements

• Eye rubbing

• Smartphone use/near work

What are the major reasons a single IOP measurement may not reflect a patient's true IOP burden?

• IOP fluctuates throughout the day and night.

• Peak IOP often occurs outside office hours, especially during sleep/early morning.

• Respiration and heartbeat cause moment-to-moment changes.

• Activities such as eye rubbing and smartphone use can transiently raise IOP.

Which aspect of IOP is most strongly associated with glaucoma progression: average IOP or IOP variability?

High IOP variability is an independent risk factor for glaucoma progression.

Patients with larger fluctuations in IOP are more likely to experience:

• Visual field (VF) loss

• Structural optic nerve damage

How does IOP variability affect visual field outcomes in glaucoma?

Studies (e.g., AGIS, CIGTS) show that:

• Greater standard deviation/range of IOP is associated with worse visual field progression.

• Patients with more stable IOP tend to have slower deterioration of visual function.

What is the relationship between IOP fluctuation and retinal nerve fiber layer (RNFL) loss?

Greater IOP fluctuation is associated with:

• Faster RNFL thinning

• More rapid structural glaucoma progression

Why is a single IOP measurement often inadequate in glaucoma suspects?

Because IOP varies throughout the day, a single reading may miss the patient's:

• Peak IOP (Tmax)

• True IOP range

• Degree of fluctuation

What is Tmax, and why is it important in glaucoma evaluation?

Tmax = the highest intraocular pressure recorded in a patient.

Importance:

• Peak IOP may occur outside routine office visits.

• Higher peak pressures are associated with greater risk of glaucoma progression.

• Identifying Tmax helps guide treatment decisions.

What strategies can be used to better capture a patient's true IOP profile and Tmax?

• Alternate morning and afternoon appointments.

• Obtain at least one IOP measurement within 1-2 hours of awakening.

• Perform serial tonometry (≥3 measurements during the same day).

• Use the same tonometer when comparing serial readings.

What is the only universally accepted treatment for glaucoma, and how does IOP reduction affect disease progression?

• Lowering IOP is the only universally accepted treatment shown to slow glaucoma progression.

• Higher presenting IOP is associated with greater risk of disease progression.

• EMGT finding: For every 1 mmHg reduction in IOP, the rate of glaucoma progression decreases by approximately 10%.

What are the key clinical implications of IOP level in glaucoma management?

• Higher baseline/presenting IOP → greater risk of future progression.

• Lowering IOP reduces both structural and functional deterioration.

• Treatment decisions often aim for a target IOP based on disease severity and risk of progression.

What is Goldmann Applanation Tonometry (GAT), and why is it considered the gold standard?

• Gold standard method for measuring IOP.

• A form of applanation tonometry that estimates IOP by flattening a fixed area of cornea.

• Assumes a central corneal thickness (CCT) of approximately 520 µm.

• Flattens a corneal area of 3.06 mm diameter.

What are important limitations and sources of variability with Goldmann Applanation Tonometry (GAT)?

• Repeated measurements can slightly lower IOP by mechanically enhancing aqueous outflow.

• Interobserver variability is approximately ±1.5 mmHg.

• Accuracy is affected by corneal thickness, corneal biomechanics, fluorescein amount, and technique.

What factors cause Goldmann tonometry to overestimate IOP?

Overestimation occurs when more force is required to flatten the cornea.

Causes:

• Thick mires (excess fluorescein)

• Examiner pressing on lids/globe

• Blepharospasm

• Valsalva maneuver

• Superior gaze >15°

• Thick, stiff cornea

What factors cause Goldmann tonometry to underestimate IOP?

Underestimation occurs when less force is required to flatten the cornea.

Causes:

• Thin mires (inadequate fluorescein)

• Repeated measurements

• Think soft cornea

How do corneal thickness and biomechanics affect Goldmann tonometry?

• Thick/stiff cornea → falsely elevated IOP readings.

• Thin/soft cornea → falsely reduced IOP readings.

How does central corneal thickness (CCT) affect Goldmann Applanation Tonometry (GAT) measurements?

GAT is most accurate when CCT ≈ 520 µm.

• Thin corneas → falsely underestimate IOP

• Thick corneas → falsely overestimate IOP

Magnitude of error: Can alter measured IOP by up to ±5 mmHg.

Why are CCT-based IOP correction formulas no longer routinely used?

Although correction tables were created to estimate a "true" IOP:

• The relationship between CCT and IOP error is not linear

• Significant individual variation exists

• Corneal biomechanics matter in addition to thickness

• Corrected IOP values did not improve prediction of POAG

What were the major findings of the Ocular Hypertension Treatment Study (OHTS)?

Population:

• Ocular hypertension (IOP 24–32 mmHg)

• No glaucomatous damage at baseline

After 5 years:

• 9.5% of observed patients developed POAG

• 4.4% of treated patients developed POAG

What does OHTS teach us about the relationship between elevated IOP and glaucoma?

Even among patients with elevated IOP:

• Most do NOT develop POAG over 5 years (~90% of untreated patients).

• Some patients still develop POAG despite treatment (~4–5%).

High-yield takeaway:

• Elevated IOP is a major risk factor, not the disease itself.

• Lowering IOP reduces risk, but glaucoma development depends on additional factors.

What is the Number Needed to Treat (NNT) from OHTS?

Approximately 20 at-risk patients must be treated for 5 years to prevent 1 case of POAG.

In the Ocular Hypertension Treatment Study (OHTS), what baseline characteristic best distinguished patients who converted to POAG from those who did not?

Central corneal thickness (CCT) was a major predictor of conversion to POAG.

• Converters to POAG: average CCT ≈ 553 µm

• Non-converters: average CCT ≈ 574 µm

What is the relationship between central corneal thickness (CCT) and the risk of developing POAG in ocular hypertension?

There is an inverse relationship between CCT and glaucoma risk:

• Thinner cornea → higher risk

• Thicker cornea → lower risk

In OHTS:

• Patients with CCT < 555 µm were about 3× more likely to develop POAG than those with CCT > 588 µm.

Why is central corneal thickness (CCT) important in glaucoma risk assessment?

CCT affects glaucoma risk in two ways:

1. Measurement effect: Thin corneas cause GAT to underestimate IOP.

2. Biologic risk factor: Thin corneas independently predict a higher likelihood of developing POAG.

What did the 20-year follow-up of the Ocular Hypertension Treatment Study (OHTS) show about early vs delayed treatment?

After 20 years:

• POAG incidence was 49% in the original observation group (treatment delayed ~5 years).

• POAG incidence was 42% in the original treatment group.

• Visual field loss occurred in about 25% of participants.

What is the clinical lesson from the 20-year OHTS follow-up regarding treatment of ocular hypertension?

Not all patients with ocular hypertension require immediate treatment.

• Many patients remain glaucoma-free for years.

• The long-term difference between immediate and delayed treatment was relatively modest (42% vs 49% POAG).

• Treatment decisions should be based on individual risk factors (especially CCT, IOP, age, cup-disc ratio, etc.).

How does central corneal thickness (CCT) affect progression in patients who already have glaucoma?

The Early Manifest Glaucoma Trial (EMGT) showed:

• Thin CCT independently predicts visual field progression.

• The risk is greatest in patients with higher IOPs.

What is the overall relationship between CCT and glaucoma across OHTS and EMGT?

Thin CCT is a major glaucoma risk factor at every stage.

• OHTS: Thin corneas increase conversion from ocular hypertension → POAG.

• EMGT: Thin corneas increase progression of established glaucoma.

Why might a thin cornea be associated with greater glaucoma susceptibility?

Proposed explanation:

• Corneal thickness may reflect the biomechanical strength of other ocular tissues.

• Patients with thicker corneas may have a stronger/thicker lamina cribrosa that better tolerates elevated IOP.

• Thinner corneas may indicate greater susceptibility to retinal ganglion cell axon damage.

Does a thicker central corneal thickness (CCT) predict a thicker lamina cribrosa?

No. Although it was hypothesized that thicker corneas might indicate a thicker, more resistant lamina cribrosa:

• Studies found no significant correlation between CCT and lamina cribrosa thickness.

• However, longer axial length is associated with a thinner lamina cribrosa.

What is the proposed relationship between CCT and glaucoma, and what evidence challenges it?

Hypothesis:

• Thick cornea → thicker/stronger lamina cribrosa → greater resistance to IOP-related damage.

Evidence:

• Studies show no correlation between CCT and lamina cribrosa thickness.

What is corneal hysteresis (CH)?

Corneal hysteresis = the cornea's ability to absorb and dissipate (dampen) external forces.

It reflects the cornea's viscoelastic properties, not just its thickness.

What does it mean that the cornea is viscoelastic?

The cornea exhibits both:

• Elastic behavior: returns to its original shape after deformation.

• Viscous behavior: dissipates energy and does not instantly return to its original form.

What is hysteresis in biomechanics?

Hysteresis = a material's ability to dampen or absorb applied forces.

In the eye:

• Higher corneal hysteresis → greater energy absorption.

• Lower corneal hysteresis → less ability to buffer pressure-related stress.

How do CCT and corneal hysteresis differ?

CCT	Corneal Hysteresis
Measures corneal thickness	Measures biomechanical damping
Static structural measurement	Functional biomechanical measurement
Influences GAT readings	Reflects ability to absorb stress
Risk factor for glaucoma	Often a stronger predictor of progression

How does the Ocular Response Analyzer (ORA) measure corneal hysteresis (CH)?

• ORA uses an air puff to deform the cornea.

• The cornea passes through two applanation events:

  1. Inward applanation

  2. Outward applanation

• Corneal hysteresis (CH) is the difference between these two applanation pressures.

What does a higher corneal hysteresis (CH) value indicate?

• Higher CH = greater ability to dampen external forces

• Better absorption of pressure-related stress

• Greater biomechanical resilience

Is corneal hysteresis only a corneal measurement?

No. Although called "corneal" hysteresis:

• The sclera also contributes to force dissipation.

• CH reflects the biomechanical properties of the entire eye.

What measurements does the Ocular Response Analyzer (ORA) provide?

ORA gives three major values:

1. CH (Corneal Hysteresis) = biomechanical damping capacity

2. IOPg = Goldmann-correlated IOP

3. IOPcc = Corneal-compensated IOP

Which ORA measurement is least affected by central corneal thickness (CCT)?

IOPcc (corneal-compensated IOP)

• GAT and IOPg are influenced by CCT.

• IOPcc incorporates biomechanical information and is less dependent on corneal properties.

What ORA quality metric should be checked before interpreting results?

Waveform Score (WS)

• Evaluate the reliability/quality of the measurement.

• Need a waveform score ≥ 4 for acceptable interpretation (per lecture note).

What are the normal characteristics and associations of corneal hysteresis (CH) in healthy eyes?

Average CH ≈ 10 mmHg

Associations:

• Positive correlation with CCT

  • Thicker cornea → higher CH

• Negative correlation with age

  • Older age → lower CH

• Negative correlation with IOP

  • Higher IOP → lower CH

How does corneal hysteresis (CH) differ among racial groups in healthy populations?

• On average, Black patients have lower CH values than White patients.

• This may contribute to differences in glaucoma susceptibility and risk profiles.

What is the relationship between corneal hysteresis (CH) and central corneal thickness (CCT)?

• Higher CCT → higher CH

• Lower CCT → lower CH

However:

• They are related but not interchangeable.

• CCT measures thickness.

• CH measures biomechanical damping capacity.

What factors are associated with lower corneal hysteresis (CH)?

Lower CH is associated with:

• Older age

• Higher IOP

• Thinner corneas

• Black race (on average)

What corneal hysteresis (CH) values should you know for glaucoma risk assessment?

Know these numbers:

• < 9 mmHg → Risk factor for glaucoma conversion/progression

• 9–9.5 mmHg → Suspicious for conversion/progression

• ~10 mmHg → Normal/Average CH

• > 11 mmHg → Potentially protective against conversion/progression

How does corneal hysteresis (CH) affect the risk of conversion from ocular hypertension (OHTN) to POAG?

• Patients who developed glaucoma: CH = 9.5 ± 1.5 mmHg

• Patients who did not develop glaucoma: CH = 10.2 ± 2.0 mmHg

• Each 1 mmHg decrease in CH → 21% increased risk of developing glaucoma

What is the relationship between corneal hysteresis (CH) and RNFL thinning in POAG?

• Low CH is associated with faster RNFL thinning over time.

• CCT was not associated with RNFL thinning.

How does corneal hysteresis (CH) affect visual field progression in POAG?

Each 1 mmHg lower CH → 0.25%/year faster visual field index (VFI) loss.

How do CH and baseline IOP interact in predicting visual field loss?

The effect of low CH is strongest when IOP is high.

For each 1 mmHg lower CH:

• Baseline IOP > 30 mmHg → 0.89%/year faster VFI loss

• Lower baseline IOP → 0.11%/year faster VFI loss

Why is corneal hysteresis (CH) considered a better predictor of glaucoma progression than central corneal thickness (CCT)?

• CH explains 17.4% of visual field loss

• CCT explains only 5.2% of visual field loss

How does glaucoma treatment affect corneal hysteresis (CH)?

The following treatments increase CH:

• Filtering surgery

• Laser surgery

• Topical prostaglandin analogs (PGAs)

Lowering IOP can improve the eye's biomechanical damping properties.

Can corneal hysteresis (CH) predict response to prostaglandin analogs (PGAs)?

Yes, Patients with lower baseline CH tend to have a greater IOP-lowering response to PGAs than patients with higher baseline CH. Low CH not only indicates higher glaucoma risk, it may also predict a larger treatment response to PGAs.

What are the most important clinical implications of corneal hysteresis (CH)?

Low CH is associated with:

• Increased risk of OHTN → POAG conversion

• Faster RNFL thinning

• Faster visual field loss

High CH is associated with:

• Greater ability to dampen biomechanical stress

• Potential protection against glaucomatous damage

What is the proposed mechanism by which high corneal hysteresis protects against glaucoma progression?

Eyes with higher CH may have optic nerve head tissues (lamina cribrosa and peripapillary sclera) that better dampen IOP-related mechanical forces.

Result:

• Reduced stress on retinal ganglion cell axons

• Slower glaucomatous damage

What are the key features, advantages, and limitations of the Tono-Pen?

Mechanism: Measures IOP based on the force required to displace a small plunger.

Advantages:

• Portable

• Can be used in the supine position

• Useful when GAT is difficult (bedridden patients, irregular positioning)

Limitation:

• Less accurate than Goldmann tonometry, especially at very low or very high IOPs.

How does the iCare tonometer measure IOP, and what are its advantages?

Mechanism: Rebound tonometry

• Small probe briefly contacts the cornea.

• IOP is calculated from the probe's rebound characteristics.

Advantages:

• No air puff

• No anesthetic required

• Quick and easy to use

• Available in home-monitoring versions

Compare Tono-Pen and iCare tonometry.

Tono-Pen

• Applanation/plunger-based

• Requires topical anesthetic

• Portable

• Can be used supine

• Less accurate than GAT

iCare

• Rebound tonometry

• No anesthetic needed

• Portable

• Home-use versions available

• Useful for serial/home measurements

What is the major clinical advantage of the iCare Home tonometer?

It allows patients to obtain multiple IOP measurements outside the clinic, helping detect:

• Peak IOP (Tmax)

• Diurnal fluctuation

• Day-to-day variability

• IOP spikes missed during office visits

Why is home IOP monitoring valuable in glaucoma suspects and glaucoma patients?

A single office IOP measurement may miss:

• Peak pressure

• Nocturnal/morning elevations

• Clinically important fluctuations

Home monitoring provides a more complete IOP profile, which can improve risk assessment and treatment decisions.