Original Article

Translaminar Pressure Difference and Ocular Perfusion
Pressure in Glaucomatous Eyes with Different Optic

Disc Sizes

Natasha F. S. Cruz, MD1; Katia S. Santos, MD1; Mateus L. Matuoka, MD1; Niro Kasahara, MD1,2

1Department of Ophthalmology, Irmandade da Santa Casa de Misericordia de Sao Paulo, Sao Paulo, Brazil
2Santa Casa de Sao Paulo School of Medical Sciences, Sao Paulo, Brazil

ORCID:
Natasha F. S. Cruz: https://orcid.org/0000-0002-5209-9204

Niro Kasahara: https://orcid.org/0000-0003-4101-0304

Abstract
Purpose: Intracranial pressure (ICP) and ocular perfusion pressure (OPP) are both involved
with the pathogenesis of glaucoma. The orbital ICP determines a retrolaminar counter
pressure that is antagonistic to the intraocular pressure (IOP). The purpose of this study
is to evaluate whether the translaminar pressure difference (TLPD) and the OPP varies in
glaucoma patients with different optic disc sizes.
Methods: In this university hospital-based, observational, cross-sectional clinical study, all
patients underwent an ophthalmic evaluation. Blood pressure, height, weight, and the results
of retinal nerve fiber layer examination with optical coherence tomography examination
were recorded. TLPD and OPP were calculated for each patient using proxy algorithms to
attain indirect surrogate parameter values. Patients’ eyes were stratified into three quantiles
according to optic disc sizes and the differences compared. Data from both eyes were used
after using the appropriate correction for inter-eye dependency.
Results: The sample consisted of 140 eyes of 73 patients with primary open-angle glaucoma
and suspects. Patients with large disc size presented with higher TLPD as compared to those
with average and small-sized discs (2.4 ± 4.5, 2.8 ± 3.8, and 3.7 ± 4.7 mmHg for first, second,
and third tertile, respectively (P < 0.000). OPP did not vary according to the optic disc size.
Conclusion: Glaucoma patients with larger optic discs have higher TLPD. The pathological
significance of this finding warrants further investigation.

Keywords: Cerebrospinal Fluid Pressure; Glaucoma; Ocular Perfusion Pressure; Optic Disc;
Translaminar Pressure

J Ophthalmic Vis Res 2021; 16 (2): 171–177

INTRODUCTION

Primary open-angle glaucoma (POAG) is a
highly prevalent, sight-threatening, multifactorial

Correspondence to:

Niro Kasahara, MD. Department of Ophthalmology,
Irmandade da Santa Casa de Misericordia de Sao Paulo,
Sao Paulo, Brazil.
E-mail: niro.kasahara@fcmsantacasasp.edu.br
Received: 23-06-2019 Accepted: 08-01-2020

Access this article online

Website: https://knepublishing.com/index.php/JOVR

DOI: 10.18502/jovr.v16i2.9080

disease. Its pathogenesis is associated with both
mechanical and vascular factors. Mechanical
factors including increased intraocular pressure
(IOP) with posterior bulging of the cribriform blade,
compression of the nerve fibers, and reduction
of the retrograde and anterograde flow and

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How to cite this article: Cruz NFS, Santos KS, Matuoka ML, Kasahara
N. Translaminar Pressure Difference and Ocular Perfusion Pressure in
Glaucomatous Eyes with Different Optic Disc Sizes. J Ophthalmic Vis Res
2021;16:171–177.

© 2021 CRUZ ET AL. THIS IS AN OPEN ACCESS ARTICLE DISTRIBUTED UNDER THE CREATIVE COMMONS ATTRIBUTION LICENSE | PUBLISHED BY

KNOWLEDGE E 171

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Translaminar Gradient and Optic Disc Size; Cruz et al

vascular factors including decrease of perfusion
pressure in the optic nerve head and deficiency
in autoregulation leading to apoptosis of retinal
ganglion cells and visual function loss may be
involved.[1]

Recently, the intracranial pressure (ICP) was
thought to be involved in the pathogenesis
of POAG. Some clinical and population studies
reported that glaucoma patients have a lower ICP
compared to that of normal subjects.[2, 3] From an
anatomical perspective, the ICP at the orbit level
and the optic nerve tissue pressure determine the
retrolaminar counter pressure which is antagonistic
to the IOP. Thus, it may be part of the critical
translaminar gradient or simply a translaminar
pressure difference (TLPD). Presuming that there
is a higher difference in the cribrosa translaminal
pressure, a marked translaminar pressure gradient
may damage the optic nerve, and therefore a
low orbital ICP may be associated with the
pathogenesis of glaucoma. There has been a
debate as to whether this is an epiphenomenon or
that there is an actual causal relationship between
ICP and glaucoma.[4]

Several population-based and clinical studies
support a strong association between ocular
blood flow and the risk of POAG prevalence
and progression.[5, 6] The underlying pathologic
mechanism is related to the reduction in
blood perfusion caused by impaired vascular
autoregulation. The ocular perfusion pressure
(OPP) is a physiologic function that delivers arterial
blood to capillary bed for the eye tissues.[7]

Clinical variables such as TLPD and the OPP are
potential players in the glaucoma optic neuropathy.
Moreover, the optic disc size can vary substantially
in the population.[8, 9] There is evidence suggesting
that large optic discs may be more susceptible
to glaucoma than small discs.[10] Uncertainties
regarding whether the TLPD and OPP differ
according to the optic disc size and its influence
in the glaucoma optic neuropathy exist. This cross-
sectional, observational study aimed to assess
whether TLPD and OPP vary in glaucoma patients
and suspects according to the size of the optic
discs.

METHODS

This cross-sectional, observational clinical study
was approved by the Committee on Human

Research of the institution. The participants were
patients from the Glaucoma Service, Santa Casa
de Misericordia of Sao Paulo Hospital. The
study adhered to the tenets of the Declaration
of Helsinki and its late amendments and the
Resolution 466/12, National Council of Health,
Brazilian Ministry of Health. After explaining the
study procedures, all participants signed the
informed consent.

Study Population and Inclusion Criteria

The sample included patients who were diagnosed
with POAG and met the following inclusion criteria:
age > 40 years, any sex and ethnicity; no previous
ocular lasers or incisional surgeries, except for
cataract which occurred more than a year ago;
optic disc with the presence of concentric increase
or localized defect (notching) of the neural rim, disc
hemorrhage, or a retinal nerve fiber layer (RNFL)
defect; visual field defect characterized by at least
three adjacent points on the pattern deviation
map with P < 5% and one of the points with
P < 1%, and/or pattern standard deviation (PSD)
decreased with P < 5%, and/or glaucoma hemifield
test (GHT) outside normal limits on a reliable exam.
Perimetric examination with up to 20% of fixation
loss and <15% of false positives and false negatives
were considered reliable. Subjects with optic disc
features of POAG and normal visual fields were
included as suspects.

Procedures

After a brief medical interview, patients
participated in the study procedures. Demographic
data including age, gender, ethnicity, and medical
history (comorbidities and previous surgeries) were
collected prior to the evaluations. Height (cm) was
measured with the patient’s back against the wall,
without shoes, and feet together using a standard
stadiometer. The body weight (kg) was measured
on a calibrated manual platform scale with the
patient wearing light clothing. The body mass
index (BMI) of each participant was determined as
the body mass divided by the square of the body
height (kg/m2). Brachial arterial blood pressure was
measured with the aneroid sphygmomanometer
(Gurin Products, LLC, Tustin, CA, USA) using the
right arm with the patient in a sitting position.

The participants received a complete ophthalmic
examination which included measurement of visual

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Translaminar Gradient and Optic Disc Size; Cruz et al

acuity in the Snellen table with optical correction,
anterior segment biomicroscopy with a slit lamp,
tonometry with the Goldmann applanation
tonometer (Haag-Streit AG, Switzerland) after
taking a drop of fluorescein and proparacaine,
gonioscopy with Goldmann goniolens (Ocular
Instruments, Bellevue, Washington, USA), and
optical disc evaluation with the 78D Volk lens
(Volk Optical Inc., Mentor, OH, USA) after
pharmacological mydriasis with tropicamide
eye drops 0.5% and visual field examination.
Computerized perimetry was performed with the
HFV 750 (Carl-Zeiss Humphrey, Dublin, CA, USA),
SITA standard program 24-2, with appropriate
optical correction by a technician.

Optical coherence tomography (OCT) was
performed with the OCT Angiography RTVue®
Avanti XR (Version 2015.1.0.90; Optovue Inc.,
Fremont, CA, USA). The OCT images were
obtained at a rate of 26,000 A-scan/s and with a
frame rate between 256 and 4096 A-scan/frame.
This provided a high tissue resolution (depth
resolution of 5.0 μm and transverse resolution of
15 μm). The acquisition of images in all patients
followed the same procedure and was carried out
by one technician. The retinal ganglion cells in the
macular region were assessed using the Nerve
Fiber Scan Protocol after pharmacologic dilation
of the pupils. Images were excluded if the signal
strength index (SSI) < 40; with overt decentration
of the measurement circle location; or with overt
misalignment of the surface detection algorithm
on at least 10% of consecutive A-scans or 15% of
cumulative A-scans, and a new image was taken
again. The RNFL, cup-to-disc (C/D) ratio, and disc
area were retrieved from the OCT results.

Statistical Analysis

The OPP was determined according to the
following formula:

OPP = [2/3 mean AP] – IOP; where, the mean
AP (arterial pressure) is 1/3 [SAP – DAP] + DAP.
SAP is the systolic arterial pressure and DAP is the
diastolic arterial pressure.

The predictive ICP was calculated according to
the equation of Xie et al:[11, 12]

ICP = (0.44 ××× BMI) + (0.16 ××× DBP) – (0.18 ××× age) –
1.91; where, ICP is intracranial pressure (mmHg), BMI
is body mass index (kg/m2), DBP is diastolic blood
pressure (mmHg), and age input is in years.

The TLPD was calculated as the arithmetic
difference between the IOP and ICP (TLPD = IOP
– ICP).[13]

The sample was stratified into three quantiles
according to the optic disc size, that is, the disc
area (mm2) as measured by the OCT. Participants’
eyes with the same optic disc area were clustered
together in the same quantile. The difference
between the three groups was compared using
the ANOVA test. Data from both eyes were used
after applying the suitable correction for inter-eye
dependency. Statistical significance was set at P
< 0.05. All analyses were performed by MedCalc
software, version 9.3.7.0 (MedCalc Software bvba,
Belgium).

RESULTS

The sample consisted of 73 patients who were
either diagnosed with POAG or suspected of
having POAG. The demographic features of all
participants stratified by the optic disc area tertiles
are displayed in Table 1. Most patients were White
and female. The three groups did not differ in age,
gender, or ethnic distribution. After applying the
appropriate correction for inter-eye dependency,
140 eyes were included in the final analysis. The
clinical features for each eye according to disc area
tertile are depicted in Table 2. The groups did not
differ in either structural (RNFL thickness and C/D)
or functional (MD and PSD) variables. The OPP
was lower in patients with smaller disc sizes and
higher in patients with average discs. However, the
difference did not reach statistical significance (P
= 0.136). Nevertheless, patients with larger optic
disc area presented a higher TLPD as compared to
patients with small or average discs (2.4 ± 4.5, 2.8
± 3.8, and 3.7 ± 4.7 mmHg in the first, second, third
tertile, respectively P < 0.001).

DISCUSSION

In this observational study, glaucoma patients
with larger optic discs presented higher TLPD as
compared to patients with smaller optic discs. To
the best of our knowledge, this was the first study to
evaluate the TLPD according to the optic disc size.

Differences in the size of the optic discs
are associated with specific anatomical tissues
variation of the RNFL and the optic nerve. These
disc size-dependent variations may affect the risk

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Translaminar Gradient and Optic Disc Size; Cruz et al

Table 1. Demographic features of the study population according to optic disc size

Variable First tertile (n = 25) Second tertile (n = 23) Third tertile (n = 25) P-value

Age (yr) 69.2 ± 8.7 64.8 ± 9.8 67.4 ± 9.3 0.563
Gender (M:F) 11:14 9:14 10:16 0.982

Ethnicity 0.968

White 15 14 17

Non-white 10 9 9

M, male; F, female

Table 2. Clinical characteristics of 140 eyes stratified by optic disc size.

Variable 1st tertile (n = 46 eyes) 2nd tertile (n = 46 eyes) 3rd tertile (n = 48 eyes) P-value

Disc area (mm2) 1.8 ± 0.2 2.2 ± 0.1 2.8 ± 0.3 <.001
RNFL (μm) 74.5 ± 16.9 75.6 ± 15.8 79.4 ± 17.4 0.330
Vertical C/D 0.78 0.84 0.85 0.08

MD (dB) -12.0 ± 8.7 -13.3 ± 9.4 -11.1 ± 7.5 0.961
PSD (dB) 6.9 ± 3.6 6.4 ± 3.3 7.1 ± 4.1 0.590
OPP (mmHg) 50.9 ± 7.2 55.2 ± 13.6 51.6 ± 10.0 0.136
TLPD (mmHg) 2.8 ± 3.8 2.4 ± 4.5 3.7 ± 4.7 <.001

RNFL, average retinal nerve fiber layer thickness; C/D, median cup to disc ratio; MD, mean deviation; PSD, pattern standard
deviation; OPP, ocular perfusion pressure; TLPD, translaminar pressure difference

and susceptibility to glaucoma.[10] Some of the
structural features observed in large optic discs
include a proportionally larger number of nerve
fibers, a larger neural rim area, a higher cup-to-disk
ratio, and a larger and more numerous pores in the
lamina cribrosa.[14–20]

The optic nerve head is located in an area
between the high-pressure intraocular space and
low-pressure subarachnoid space. Hence, the
pressure imbalance between these two spaces can
cause damage to the retinal ganglion cell axons
that pass through the lamina cribrosa pores.[21–23]
The pressure difference across the lamina cribrosa
(IOP minus ICP) is the translaminar pressure
gradient.[24] On physiological grounds, the mean
IOP is meagerly higher than the mean ICP, which
results in a small posteriorly directed translaminar
pressure gradient difference of approximately
4 mmHg.[25] An IOP within statistically normal
limits in conjunction with a low ICP produce
the same pressure gradient across the lámina
cribosa (LC) as a high IOP in conjunction with a
normal ICP.[26] Changes in the TLPD may cause
pathological dysfunction and optic nerve damage
attributable to alterations in axonal transportation,

LC deformation, changes in blood flow or even
all of them in combination.[2, 3, 21–23, 27, 28] A higher
IOP, lower ICP, and larger TLPD correlates with
enlargement in the C/D ratio and reduction in
RNFL thickness.[2, 29] In our study, patients with
a larger optic disc area presented with a higher
TLPD. For these patients the ganglion cell axons
could be more exposed to this pressure gradient.
Thus, patients with larger optic discs may be more
vulnerable to IOP insults, without simultaneous
influence of OPP which did not differ among
the three groups. As such, patients with larger
discs would be more likely to have glaucoma
than patients with smaller optic discs. Interestingly,
in cases of progressive optic neuropathies, the
optic nerve fiber counts and the anatomic reserve
capability are higher in eyes with large optic heads
than those with smaller optic discs.[14] Moreover,
discs >4.4 mm2 have an augmented number of
cilioretinal arteries, which relates to the size of
the optic disc area.[30] These characteristics may
thwart against the TLPD insult and can work as a
compensatory effect.

Recently, Baneke et al have defined the strain
in the LC as the function of TLPD times the

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Translaminar Gradient and Optic Disc Size; Cruz et al

square of its diameter divided by the square of its
thickness [LC stress = (IOP – ICP) . LC radius2/LC
thickness2].[31] In this model, the TLPD and disc
size (radius) were considered as two independent
variables of LC stress. If that is the case, larger
discs would be vulnerable not only by its anatomic
enlarged area but also to a larger TLPD.

A possible association between glaucoma and
decreased OPP was demonstrated in several
previous studies.[32–37] In contrast, the Beijing Eye
Study did not find a clear association between the
OPP and the prevalence of glaucoma.[38] In this
study, the OPP did not vary according to the optic
disc size. Thus, the vascular insult should be the
same for all discs, regardless of the disc size, and
the higher TLPD could be an isolated aggravating
factor and independent of the OPP.

This study has one important limitation. The
measurement of ICP was not performed by the
traditional method using lumbar puncture which
is an invasive examination, with the risks of
spinal cord injury. For ethical reasons, it was
not performed for the study purposes without
specific medical indications. The estimated ICP
was calculated using a mathematical formula
based on the BMI and BP values developed in a
population study of Chinese individuals.[11] It is not
certain how different the calculated ICP is from
the actual one measured by lumbar puncture.
ICP is not only influenced by circadian rhythm,
but also by changes in posture, position, and
pressure fluctuations in other compartments as in
respiratory effort and blood pressure pulsations.[39]
Moreover, the production and resorption of
cerebrospinal fluid rate are not linear, particularly
at different ICP levels.[39] Hence, a linear prediction
model for ICP based on Xie’s formula may be
inaccurate, especially for pathologic conditions.
In POAG cases, hemodynamic disturbances are
known comorbidities and ICP regulation has been
suggested to be abnormal. Moreover, the Cushing
reflex or vasopressor response may be affected
in these patients and the ICP estimation on BP
variation may be too simplistic. Using such a
surrogate measure could be misleading. This is a
fundamental drawback to the study methodology
which limits the generalizability of the finding.
However, this same formula has been used in
other large population studies.[12, 40] Furthermore,
the equation was validated in a cohort of 39
Brazilian patients and showed that the estimated
ICP was very close to the measured ICP (95% limits

of agreement of –5 to +8 between LP measured
and equation-estimated ICP).[41] Moreover, the
measurement of ICP by lumbar puncture may be
different from the retrobulbar ICP. In general, it
is assumed that the lumbar ICP represents the
CSF pressure in the optic nerve. However, given
the extended length between the lumbar spine
and the subarachnoid space of the optic nerve,
it is debatable whether this statement is true,
particularly in patients with optic nerve sheath
diseases and compartmentalization.[42]

In summary, this study revealed that the TLPD
varies according to the optic disc size and that
larger discs tend to have a higher TLPD. Although
additional studies are still needed to elucidate the
possible role of ICP and OPP in the pathogenesis
of glaucoma optic neuropathy, we believe that this
study contributes to the acumen on how the optic
disc size may be important in the pathogenesis of
this disease.

Financial Support and Sponsorship

Nil.

Conflicts of Interest

The authors declare that they have no conflict of
interest.

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