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Peripapillary Perfused Capillary Density in True Versus Pseudoexfoliation Syndrome: An OCTA Study

01 Sep 2020-bioRxiv (Cold Spring Harbor Laboratory)-
TL;DR: Greater loss of annular PCD in the PEX group than in the TEX and control groups suggests more pronounced microvascular disturbance in PEX, which is in contrast to normal control measured by OCTA.
Abstract: Purpose: To compare peripapillary perfused capillary density (PCD) among eyes with true exfoliation syndrome (TEX), eyes with pseudoexfoliation syndrome (PEX), and healthy control eyes. Materials and Methods: In this observational cross-sectional study, eyes with and without TEX or PEX were assessed by optical coherence tomography angiography (OCTA) imaging. Bilateral OCTA images (4.5 × 4.5 mm 2 ) centered at the optic nerve head were obtained using a commercial spectral domain OCTA system. Optic nerve head perfusion was quantified using the split-spectrum amplitude decorrelation angiography algorithm. Categorical and continuous variables were compared using the chi-squared test and one-way analysis of variance, respectively. The generalized estimating equation was used to adjust for confounding factors and determine inter-ocular associations. Results: We enrolled 39 eyes with TEX, 31 eyes with PEX, and 32 control eyes. There were no significant differences among the three groups regarding age, intraocular pressure, cup-to-disc ratio, blood pressure, or axial length (all p>0.05). There were significant differences in global PCD among the three groups (p=0.01). There were significant differences in annular PCD between the TEX and PEX groups (p=0.027). Conclusions: While both global and annular PCDs did not differ between the TEX and control groups, greater loss of annular PCD in the PEX group than in the TEX and control groups suggests more pronounced microvascular disturbance in PEX. Synopsis/Precis: Greater microvascular attenuation in PEX compared with TEX and normal control measured by OCTA.

Summary (2 min read)

Introduction

  • Several studies have shown that many patients exhibit idiopathic forms of TEX.2,3 Nonetheless, vascular insufficiency has not been studied with respect to TEX pathogenesis.
  • Pseudoexfoliation syndrome (PEX) is an age-related systemic disorder characterized by the production and accumulation of pseudoexfoliation material.
  • PEX is one of the most common causes of secondary open-angle glaucoma.
  • Previous OCTA studies of peripapillary perfused capillary density (PCD) in patients with PEX, pseudoexfoliation glaucoma, or primary open-angle glaucoma provided evidence of microvascular disturbances.

Materials and methods

  • This cross-sectional study was approved by the Center of Ethical Reinforcement for Human Research at Mahidol University.
  • Written informed consent was obtained from all participants before enrollment, and the study protocol adhered to the tenets of the Health Insurance Portability and Accountability Act and the Declaration of Helsinki.

20/40 and age > 20 years. The diagnosis of TEX was based on characteristic anterior

  • Lens capsule delamination, intraoperative double-ring sign, and pigment deposition on delaminated membrane.
  • Exclusion criteria for all participants were eyes with a history of ocular surgery except uncomplicated cataract surgery, any ocular diseases other than cataract, history on systemic steroid usage, diabetes mellitus, and cardiovascular disease other than treated systemic hypertension.
  • Scans with signal strength <7/10 were excluded.
  • 8 A spectral domain OCT system (AngioVue Software Version 2018.1.0.33, Optovue, Fremont, CA, USA) was used with a single imaging session consisting of two volumetric raster scans (one vertical and one horizontal) centered on the optic nerve head and covering an area 4.5 4.5 mm.
  • Perfused vessel imaging was performed using the split-spectrum amplitude decorrelation angiography algorithm.

OCTA image analysis

  • OCTA images were analyzed using built-in Optovue software18, 20 with the large blood vessel removal algorithm.
  • In patients with bilateral pathology or healthy eyes (i.e., both eyes with TEX or PEX, or both healthy controls), both eyes were included for analysis.
  • The normality of the numerical data distribution was assessed using the Shapiro–Wilk test.
  • Categorical and continuous variables were compared using the chi-squared test and one-way analysis of variance, respectively; a Bonferroni post hoc test was used to assess the differences between pairs of groups following analysis of variance.
  • The generalized estimating equation was used to determine interocular associations, adjusted for age, sex, axial length, and blood pressure.

Results

  • Initially, there were 48 eyes with TEX, 34 eyes with PEX, and 32 control eyes in this study.
  • Demographic characteristics among the 10 three groups are demonstrated in Table 1.
  • There were significant differences in sectoral circumpapillary RNFL thicknesses among the three groups, including marked differences in the inferior and temporal sectors (p<0.001).
  • Pairwise comparison showed that both global and annular PCDs did not significantly differ between the TEX and control groups (p=0.564 and p=0.555, respectively; Table 2).

Discussion

  • The authors study revealed significant differences in PCD among the three groups.
  • Multivariable analysis demonstrated a significant reduction in PCD in the PEX group, compared with the TEX group.
  • There were some limitations in their study.
  • OCTA imaging might be beneficial for detection of vessel density loss.
  • The authors findings suggested greater microvascular attenuation in eyes with PEX than in eyes with TEX or control eyes, which implies that PEX and TEX are separate diseases, rather than two subtypes of a single disease.

Figure Legend

  • .CC-BY 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
  • The copyright holder for this preprintthis version posted September 1, 2020.

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1
Peripapillary Perfused Capillary Density in True Versus
Pseudoexfoliation Syndrome: An OCTA Study
Phantaraporn Tangtammaruk
1
, Purit Petpiroon
1
, Wasu Supakonatanasan
1
,
Chaiwat Teekhasaenee
1
, Yanin Suwan
1*
1
Department of Ophthalmology, Ramathibodi Hospital, Mahidol University,
Bangkok 10400, Thailand
*Correspondence author
E-mail: yanin.suwan@gmail.com
Department of Ophthalmology, Ramathibodi Hospital, Mahidol University
270 Rama VI, Thung Phaya Thai, Ratchathewi, Bangkok, Thailand, 10400
Tel: (66)-2-201-2729; Fax: (66)-2-201-1516
.CC-BY 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted September 1, 2020. ; https://doi.org/10.1101/2020.09.01.277293doi: bioRxiv preprint

2
Abstract
Purpose: To compare peripapillary perfused capillary density (PCD) among
eyes with true exfoliation syndrome (TEX), eyes with pseudoexfoliation
syndrome (PEX), and healthy control eyes.
Materials and Methods: In this observational cross-sectional study, eyes
with and without TEX or PEX were assessed by optical coherence
tomography angiography (OCTA) imaging. Bilateral OCTA images (4.5 4.5
mm
2
) centered at the optic nerve head were obtained using a commercial
spectral domain OCTA system. Optic nerve head perfusion was quantified
using the split-spectrum amplitude decorrelation angiography algorithm.
Categorical and continuous variables were compared using the chi-squared
test and one-way analysis of variance, respectively. The generalized
estimating equation was used to adjust for confounding factors and
determine inter-ocular associations.
Results: We enrolled 39 eyes with TEX, 31 eyes with PEX, and 32 control
eyes. There were no significant differences among the three groups
regarding age, intraocular pressure, cup-to-disc ratio, blood pressure, or
axial length (all p>0.05). There were significant differences in global PCD
among the three groups (p=0.01). There were significant differences in
annular PCD between the TEX and PEX groups (p=0.027).
.CC-BY 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted September 1, 2020. ; https://doi.org/10.1101/2020.09.01.277293doi: bioRxiv preprint

3
Conclusions: While both global and annular PCDs did not differ between the
TEX and control groups, greater loss of annular PCD in the PEX group than in
the TEX and control groups suggests more pronounced microvascular
disturbance in PEX.
Synopsis/Precis:
Greater microvascular attenuation in PEX compared with TEX and normal
control measured by OCTA.
.CC-BY 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted September 1, 2020. ; https://doi.org/10.1101/2020.09.01.277293doi: bioRxiv preprint

4
Introduction
True exfoliation syndrome (TEX) is a disease characterized by
delamination of anterior lens capsule, which was first reported in 1922 by
Elsching.
1,2
Occupational exposures by steelworkers, blacksmiths,
glassblowers, and bakers may increase the risk of TEX.
3
Several studies
have shown that many patients exhibit idiopathic forms of TEX.
2,3
Nonetheless, vascular insufficiency has not been studied with respect to TEX
pathogenesis.
Pseudoexfoliation syndrome (PEX) is an age-related systemic disorder
characterized by the production and accumulation of pseudoexfoliation
material. PEX is one of the most common causes of secondary open-angle
glaucoma.
4
Several studies have shown an association between PEX and
increased systemic vasculopathy, as well as between PEX and ocular
vasculopathy.
5-15
It has been proposed that pericellular accumulation of
pseudoexfoliation material may disrupt the normal cellular basement
membrane, thereby leading to endothelial dysfunction.
16
Iris vasculopathy,
endothelial basement membrane abnormalities, and lumen obliteration have
been described in patients with PEX.
5–7
In addition to altered intraocular
pressure, ocular blood flow disturbance constitutes evidence of the
pathogenesis of pseudoexfoliation glaucoma progression.
5
.CC-BY 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted September 1, 2020. ; https://doi.org/10.1101/2020.09.01.277293doi: bioRxiv preprint

5
Vascular insufficiency is a notable risk factor for glaucoma
pathogenesis. Various methods have been used to measure optic nerve head
perfusion in both glaucoma and PEX.
5
Fluorescein angiography has been
used to measure vascular blood flow; however, it is both invasive and
inaccurate for measurement of optic nerve head perfusion. Laser speckle
flowgraphy and Doppler imaging are operator-dependent and do not provide
adequate visualization. Furthermore, these methods do not distinguish some
small complex vessels in the optic disc.
17
Optical coherence tomography angiography (OCTA) is a noninvasive
imaging modality that combines optical coherence tomography (OCT)
reconstruction with motion contrast processing to identify retinal
microvasculature.
18
Creation of a retinal blood flow map is performed using
the split-spectrum amplitude decorrelation angiography algorithm, which
compares the decorrelation signals among sequential OCT B-scans taken at
the same cross-sectional level.
8
TEX is presumed to be a subtype of PEX. Previous OCTA studies of
peripapillary perfused capillary density (PCD) in patients with PEX,
pseudoexfoliation glaucoma, or primary open-angle glaucoma provided
evidence of microvascular disturbances.
8,19
However, to the best of our
knowledge, there has been no evidence of vasculopathy in patients with
TEX. The purpose of this study was to compare PCD among eyes with TEX,
eyes with PEX, and healthy control eyes.
.CC-BY 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted September 1, 2020. ; https://doi.org/10.1101/2020.09.01.277293doi: bioRxiv preprint

Citations
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References
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Journal Article
TL;DR: Interruption of BDNF retrograde transport and accumulation of TrkB at the optic nerve head in acute and chronic glaucoma models suggest a role for neurotrophin deprivation in the pathogenesis of RGC death in glau coma.
Abstract: Purpose In both animal model system and in human glaucoma, retinal ganglion cells (RGCs) die by apoptosis. To understand how RGC apoptosis is initiated in these systems, the authors studied RGC neurotrophin transport in experimental glaucoma using acute intraocular pressure (IOP) elevations in rats and chronic IOP elevation and unilateral optic nerve transections in monkeys. Methods Eyes were studied in masked fashion by light and electron microscopy and by immunohistochemistry with antibodies directed against the tyrosine kinase receptors (TrkA, B, and C) and against brain-derived neurotrophic factor (BDNF), as well as by autoradiography to identify retrograde axonal transport of 125I-BDNF injected into the superior colliculus. Results With acute glaucoma in the rat, RGC axons became abnormally dilated, accumulating vesicles presumed to be moving in axonal transport at the optic nerve head. Label for TrkB, but not TrkA, was relatively increased at and behind the optic nerve head with IOP elevation. Abnormal, focal labeling for TrkB and BDNF was identified in axons of monkey optic nerve heads with chronic glaucoma. With acute IOP elevation in rats, radiolabeled BDNF arrived at cells in the RGC layer at less than half the level of control eyes. Conclusions Interruption of BDNF retrograde transport and accumulation of TrkB at the optic nerve head in acute and chronic glaucoma models suggest a role for neurotrophin deprivation in the pathogenesis of RGC death in glaucoma.

502 citations

Journal ArticleDOI
TL;DR: Slit-lamp signs of pseudoexfoliation may identify individuals with an increased vascular risk and was statistically significantly associated with a history of angina or hypertension or a combined history ofAngina, acute myocardial infarction, or stroke.

302 citations

Journal ArticleDOI
TL;DR: The findings of this study suggest that the standard laser Doppler flowmetry technique is predominantly sensitive to blood flow changes in the superficial layers of the optic nerve head and less sensitive to those in the prelaminar and deeper regions, and their relative proportions are not known.

152 citations

Journal ArticleDOI
TL;DR: Pharmacological inhibition of the activity or the induction of inducible nitric oxide synthase may provide neuroprotection for the treatment of glaucoma.
Abstract: The loss of vision in the human eye disease, glaucoma, is due to degeneration of the axons of the retinal ganglion cells. In glaucoma, reactive astrocytes in the optic nerve head contain inducible nitric oxide synthase, which apparently produces excessive nitric oxide that damages the axons. The astrocytes respond to the elevated intraocular pressure that is characteristic of the disease. An important signal transduction pathway for the induction of nitric oxide synthase in response to pressure is the epidermal growth factor receptor tyrosine kinase. Pharmacological inhibition of the activity or the induction of inducible nitric oxide synthase may provide neuroprotection for the treatment of glaucoma.

134 citations

Frequently Asked Questions (2)
Q1. What are the contributions in "Peripapillary perfused capillary density in true versus pseudoexfoliation syndrome: an octa study" ?

In this observational cross-sectional study, eyes with and without TEX or PEX were assessed by optical coherence tomography angiography ( OCTA ) imaging. CC-BY 4. 0 International license available under a ( which was not certified by peer review ) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. 

Future studies should include more precise staging of TEX to avoid bias in the PCD results. Their findings suggested greater microvascular attenuation in eyes with PEX than in eyes with TEX or control eyes, which implies that PEX and TEX are separate diseases, rather than two subtypes of a single disease.