4th Consensus Meeting:
Fort Lauderdale, FL, May 5, 2007
edited by Robert N. Weinreb, James D. Brandt, David Garway-Heath and Felipe A. Medeiros
2007. xviii and 128 pages with 57 figures, of which 7 in full color, and 7 tables. Hardbound.
ISBN-10: 90 6299 213
ISBN-13: 978-90-6299-213 3
Published by Kugler Publications.
Click here for more information on all publications in the Consensus series.
- Basic Science of Intraocular Pressure
- Measurement of Intraocular Pressure
- IOP as a Risk Factor for Glaucoma Development & Progression
- Epidemiology of Intraocular Pressure
- Clinical Trials & Intraocular Pressure
- Target IOP in Clinical Practice
Basic Science of Intraocular Pressure
- IOP is determined by contributions from aqueous humor production (measured
as aqueous flow), trabecular outflow, uveoscleral outflow and episcleral venous
- Aqueous flow has a distinctive circadian rhythm, being lower at night than
during the day.
Comment: Aqueous flow is not affected by exfoliation syndrome, pigment
dispersion syndrome, primary open angle glaucoma, or ocular hypertension.
Comment: Aqueous flow is reduced by diabetes mellitus and myotonic dystrophy.
- The best technique to measure aqueous flow in humans is by fluorophotometry.
Comment: Limitations and assumptions associated with fluorophotometry
- a rate of diffusion of fluorescein into the iris, limbal vessels and
tear film is assumed;
- fluorescein is distributed uniformly throughout the anterior chamber and
- a lens-iris barrier is present to block the egress of the tracer into
the posterior chamber;
- Short-term fluctuations in aqueous flow of less than 30 minutes are
- The trabecular outflow pathway is comprised of the trabecular
meshwork, the juxtacanalicular connective tissue (JCT), the endothelial
lining of Schlemm’s canal, the collecting channels and aqueous veins.
Comment: Normal outflow resistance resides in the inner wall region of
Schlemm’s canal (SC), including JCT and inner endothelial lining of SC. Cells in
trabecular meshwork influence the hydraulic conductivity of the inner wall region
and outflow resistance by modulating extracellular matrix turnover and/or by actively
changing cell shape.
Comment: Trabecular outflow is under the influence of ciliary muscle tone.
- Outflow facility in healthy human eyes is the range of 0.1
to 0.4 µl / min / mmHg.
Comment: Outflow facility is reduced in primary open angle glaucoma, ocular
hypertension, and exfoliation and pigment dispersion syndromes with accompanying
Comment: In chronic open-angle glaucoma there is an increase in extracellular
material in the juxtacanalicular connective tissue and decrease in number of pores
in Schlemm’s canal endothelium.
- Outflow facility can be measured with tonography and fluorophotometry.
Both methods have inherent limitations associated with their use.
- The uveoscleral outflow pathway is comprised of the ciliary muscle, supraciliary
space, suprachoroidal space, sclera and other less defined areas.
- Uveoscleral outflow is 25-57% of total outflow in young healthy humans and
uveoscleral outflow decreases with aging.
Comment: Uveoscleral outflow is reduced in ocular hypertension with an
without exfoliation syndrome, increased in uveitis, and unchanged in pigment
dispersion syndrome with ocular hypertension.
- In clinical studies, uveoscleral outflow is calculated from the modified
Comment: Inherent variability is great and reproducibility is fair. Invasive
methods to measure uveoscleral outflow are:
- 1. The tracer collection method;
- 2. The indirect isotope method
Episcleral venous pressure
- Episcleral venous pressure in healthy humans is 8 to 10 mmHg.
Comment: It is affected by body position, inhalation of O2, application of cold
temperature and treatment with vasoactive drugs.
Comment: Episcleral venomanometry is used in clinical studies. This measurement
is difficult to make and highly variable.
Comment: Direct cannulation is used in animal studies. This is an accurate
but invasive method.
Measurement of Intraocular Pressure
- On average, greater central corneal thickness (CCT) results in
overestimation of intraocular pressure (IOP) as measured by Goldmann applanation
Comment: The extent to which CCT contributes to the measurement error
(in relation to other factors) in individual patients under various conditions
has yet to be established.
- Compared to GAT, CCT has a lesser effect on IOP measured by dynamic
contour tonometry (DCT) and the ocular response analyzer (ORA) (corneal
compensated IOP). CCT has a greater effect on IOP measured by NCT and Rebound
- Currently we have insufficient evidence comparing different tonometers
in the same population. However, there are some data to suggest that Goldmann
applanation tonometry is more precise (lowest measurement variability),
compared to other methods.
- Precision and agreement of tonometry devices should be reported in a
- Coefficient of repeatability (for intra-observer variation)
- Mean difference (or difference trend over range) and 95% limits
of agreement (for inter-observer and inter-instrument differences)
Comment: Under ideal circumstances for measurement, precision figures
reported for GAT are:
- Intraobserver variability: 2.5 mmHg (two readings by the same observer
will be within this figure for 95% of subjects)
- Interobserver variability: ± 4 mmHg (95% confidence limits either
side of mean difference between observers)
- In clinical practice these figures may be considerably higher •
Intra-class correlation coefficients are not clinically useful
- Currently there are no data to support a specific frequency of calibration
verification for GAT.
Comment: The frequency for verification of GAT calibration of at
least twice yearly is suggested.
For clinical research, a verification error > ± 1 mmHg should be the threshold
to send the tonometer for recalibration; the threshold for clinical practice
may be higher and requires a cost-benefit analysis.
- Correction nomograms that adjust GAT IOP based solely on CCT are neither
valid nor useful in individual patients.
Comment: A thick cornea gives rise to a greater probability of an
IOP being over-estimated (and a thin cornea of an IOP being under-estimated),
but the extent of measurement error in individual patients cannot be ascertained
from the CCT alone.
- Measurement of CCT is important in assessing risk for incident glaucoma
among ocular hypertensives in the clinical setting, though the association
between CCT and glaucoma risk may be less strong in the population at large.
- The corneal modulus of elasticity likely has a greater effect on GAT
IOP measurement error than CCT, especially with corneal pathology and after
Comment: The corneal modulus of elasticity increases with age, thus
generating artifactual increases in Goldmann tonometry with age.
Comment: A higher modulus of elasticity is associated with greater
- Consideration of corneal visco-elasticity is essential for determining
the ocular mechanical resistance to tonometry and hence improving the accuracy
of IOP measurement.
Comment: Corneal aging affects the visco-elasticity of the tissue
and adds another layer of complexity to determining the mechanical resistance
of the cornea to tonometry.
- Large amounts of corneal edema produce an underestimation of IOP when
measured by applanation tonometry.
Small amounts of corneal edema (as induced by contact lens wear) probably
cause an overestimation of IOP.
- To obtain a GAT measurement, which is relatively unaffected by daytime
changes in CCT, the patient should desirably have been awake with his/her
eyes open for at least two hours prior to the measurement being made.
- The wearing of contact lenses on the day when tonometry is performed
may lead to an artifactually raised IOP as measured by GAT. Comment:
Contact lens wearing patients should have tonometry performed after having
been awake, without contact lenses, for at least two hours for contact lens-induced
and diurnal corneal edema to resolve.
- There are changes in corneal biomechanics following many forms of keratorefractive
surgery, associated with a mean fall in IOP as measured by applanation tonometry.
Comment: Although there is a mean fall across patients in measured
IOP, there is a wide variability in response.
- DCT and ORA (corneal compensated IOP) may both be less sensitive to
changes in corneal biomechanics following keratorefractive surgery and have
less variance than standard applanation tonometry.
- The use of a lid speculum, sedatives and general anesthetics can significantly
affect IOP measurement in children, and tonometers vary in their accuracy
in pediatric eyes.
Comment: The clinician should adopt a consistent protocol for the
measurement of IOP in children so that through experience the ‘normal’ range
for their protocol can be determined.
IOP as a Risk Factor for Glaucoma Development & Progression
- There is strong evidence to support higher mean IOP as a significant factor
for the development of glaucoma.
- There is strong evidence to support higher mean IOP as a significant risk
factor for glaucoma progression.
- IOP is more variable in glaucomatous than in healthy eyes, but both 24-hour
IOP fluctuation and IOP variation over periods longer than 24 hours tends to
be correlated with mean IOP.
- There is currently insufficient evidence to support 24-hour IOP fluctuation
as a risk factor for glaucoma development or progression.
Comment: 24 hour IOP measurements are comprised of day-time (diurnal)
and night-time (nocturnal) periods.
Comment: Diurnal IOP is generally highest after awakening and decreases
during the day-time period.
Comment: Posture is an important variable in the measurement of IOP;
IOP in the sitting position is generally lower than in the supine position.
- There is currently insufficient evidence to support IOP variation over periods
longer than 24 hours as a risk factor for glaucoma development and progression.
- Sufficiently low blood pressure, combined with sufficiently high IOP, generates
low ocular perfusion pressure and is associated with increased OAG prevalence
in cross-sectional studies.
Comment: Physiologic IOP variation occurs in regular rhythmic cycles.
Regular IOP peaks and valleys are normal, and compensatory mechanisms are in
place to preserve the integrity of the tissue and the organism.
Comment: The peaks and troughs in circadian IOP and blood pressure do
not necessarily occur simultaneously.
Epidemiology of Intraocular Pressure
- Self-described race is a poor summary of human biodiversity.
Comment: Self-described race still contains important information that
both correlates well with genetic measures of ancestry and disease risk on a
- Evidence for differences in IOP between blacks and white is contradictory
from available populations-based studies.
- Evidence for a relationship between IOP and age is contradictory from available
- Evidence for a relationship between IOP and gender is contradictory from
available populations-based studies.
- Studies with similar methodology comparing differences in IOP between multiple
racial groups allowing direct comparisons generally have not been performed.
Comment: IOP appears lower in Asian populations than populations with
European and African ancestry, however direct comparisons have not been made.
- Variations in study designs and IOP measurement techniques limit comparison
of mean IOPs across racial, ethnic and regional strata. Comment: Very few population-based
surveys have included important biomarkers such as CCT that may effect the measured
Comment: IOP is higher in eyes with shorter axial anterior chamber depth
as a result of pathological angle-closure.
Comment: Corneal radius of curvature is a potential source of measurement
error, and should be adjusted for when using an applanation tonometer.
- There is a strong positive relationship between IOP and OAG, although prevalent
and incident OAG cases occur commonly at IOP < 22 mmHg.
Clinical Trials & Intraocular Pressure
- The type of clinical trial (i.e., Phase II, III, or IV) influences the study
design and subsequent considerations of treatment groups, recruitment criteria,
- An appropriately-designed clinical trial for efficacy of IOP reduction should
specify a clinically significant treatment effect (delta); probability of a
type 1 error (alpha), usually set at 5%, and a desired power (conventionally
at least 80%).
- Clinical trials in related disease areas should strive to use similar designs
and outcome measures to facilitate meta-analysis (i.e., a pooling of results
of independent trials).
- Clinical trials comparing IOP-lowering efficacy of different treatment should
provide 95% confidence intervals for the difference in IOP reduction.
- Efficacy trials should define a priori the clinically meaningful
difference for that specific study.
Comment: In addition to IOP-lowering, other factors such as safety and
side-effects must be considered in defining a clinically-meaningful difference
for that specific study.
- Protocols should include at least two post-screening IOP measurements acquired
on at least two different days for calculating baseline IOP, prior
- Protocol analyses also should include measurement of baseline IOP, central
corneal thickness and type of glaucoma to allow adjustment for these potentially
confounding variables when comparing IOP-lowering interventions.
Target IOP in Clinical Practice
- The target IOP is the IOP range at which the clinician judges that progressive
disease is unlikely to affect the patient’s quality of life.
Comment: The burdens and risks of therapy should be balanced against
the risk of disease progression.
- The determination of a target IOP is based upon consideration of the amount
of glaucoma damage, the IOP at which the damage has occurred, and the life expectancy
of the patient, and other factors including status of the fellow eye and family
history of severe glaucoma.
Comment: At present, the target IOP is estimated and cannot be determined
with any certainty in a particular patient.
Comment: There is no validated algorithm for the determination of a target
IOP. This does not, however, negate its use in clinical practice.
- It is recommended that the target IOP be recorded so that it is accessible
on subsequent patient visits.
- The use of a target IOP in glaucoma requires periodic re-evaluation.
Comment: This entails examination of the optic nerve and assessment of
visual function to detect glaucomatous progression, the effect of the therapy
upon the patients quality of life, and whether the patient has developed any
new systemic or ocular conditions that might affect the risk/benefit ratio of
Comment: During the re-evaluation, it is essential to determine whether
the IOP target is appropriate and should not be changed, or that it needs to
be lowered or raised.