ORIGINAL STUDY
Structure-Function Correlation Using Confocal Laser Ophthalmoscope in Primary Open-Angle Glaucoma and Pseudoexfoliative Glaucoma Theofanis Pappas, MD,* Panayiota Founti, MD,* Xiang Jun Yin, PhD,w Archimidis Koskosas, MD,* Eleftherios Anastasopoulos, MD,* Angeliki Salonikiou, MD,* Vasilios Kilintzis, PhD,* Antonios Antoniadis, PhD,* Nikolaos Ziakas, MD,* and Fotis Topouzis, MD, PhD*
Purpose: To compare Heidelberg Retina Tomograph (HRT) optic disc parameters and structure-function correlation between primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG). Design: Prospective, observation case series. Patients and Methods: A total of 54 POAG and 33 PEXG cases, consecutively recruited from a University Glaucoma Service, underwent a comprehensive ophthalmic examination, including HRT optic disc imaging. Glaucoma definition required the presence of both structural and functional damage. One eye per subject was included in the analysis. T test, Mann-Whitney U test, and analysis of covariance were used to compare HRT parameters between POAG and PEXG, adjusting for age, mean deviation (MD) in the visual field, intraocular pressure, and disc area. The correlation between HRT and MD was assessed in each group. Results: Cup area (P = 0.048), height variation contour (P = 0.016), and cup/disc area ratio (P = 0.023) were higher in POAG, whereas the mean retinal nerve fiber layer thickness Received for publication March 19, 2014; accepted January 7, 2015. From the *1st Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece; and wNational Center for Chronic and Non-communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. T.P., P.F., F.T.: conception an design of the study; T.P., A.K., E.A., F.T.: data collection; T.P., P.F., X.J.Y., A.K., E.A., A.S., V.K., A.A., N.Z., F.T.: analysis and interpretation of the data; T.P., P.F., A.S., F.T.: writing the article; T.P., P.F., X.J.Y., A.K., E.A., A.S., V.K., A.A., N.Z., F.T.: critical revision of the article; T.P., P.F., X.J.Y., A.K., E.A., A.S., V.K., A.A., N.Z., F.T.: final approval of the article. The study was approved by the Aristotle University Medical School, Ethics Committee. The IRB approval was prospective and informed consent statements for research from each participant were obtained. All study procedures adhered to the principles outlined in the Declaration of Helsinki for research involving human subjects. This research has been co-financed by the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) - Research Funding Program: THALES. Investing in knowledge society through the European Social Fund. Disclosure: The remaining authors declare no conflict of interest. F.T. is on Advisory Board for Pfizer Ophthalmics and Merc & Co; received lecture fees from Alcon Laboratories Inc. and Pfizer Inc.; received grant support from Alcon Laboratories and Pfizer Inc. Reprints: Fotis Topouzis, MD, PhD, 1st Department of Ophthalmology, Aristotle University of Thessaloniki, AHEPA Hospital, St. Kiriakidi 1, Thessaloniki 54636, Greece (e-mail: ftopouzis@ otenet.gr). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/IJG.0000000000000233
J Glaucoma
Volume 25, Number 4, April 2016
(P = 0.048), retinal nerve fiber layer cross-section area (P = 0.044), and rim area (P = 0.048) were lower in POAG, compared with PEXG. The correlation of HRT parameters with MD was significant only in the POAG group. Conclusions: At a similar level of functional damage, POAG subjects presented with more pronounced structural damage than PEXG subjects. The correlation between HRT and visual field parameters was more evident in POAG, compared with PEXG. Key Words: structure-function correlation, open-angle glaucoma, confocal laser ophthalmoscope
(J Glaucoma 2016;25:377–382)
P
rimary open-angle glaucoma (POAG) is the most common type of glaucoma,1 whereas pseudoexfoliative glaucoma (PEXG) is one of the most common types of secondary open-angle glaucoma.2 There is evidence to suggest that PEXG is not just a variant of POAG, as it has been previously hypothesized.3 For the same level of intraocular pressure (IOP), subjects with pseudoexfoliation (PEX) are at higher risk for glaucoma compared with subjects without PEX.4 This means that, in addition to IOP, there may be non–IOP-related factors involved in the development of PEXG. Moreover, POAG and PEXG do not seem to share the same risk factors,5 which may suggest differences in their pathophysiology. Clinical characteristics are also different between POAG and PEXG. Typically, PEXG has higher IOP values2 and larger 24-hour IOP fluctuations than POAG.6 In addition, despite the fact that PEXG is less likely to be undiagnosed than POAG,7 in clinical settings patients with PEXG present with more advanced visual field (VF) loss at diagnosis than patients with POAG.8,9 In addition, it has been reported that for the same level of initial IOP, POAG patients present with more advanced damage in the VF than PEXG patients.10 These 2 common types of open-angle glaucoma also seem to differ in terms of structural characteristics. On the basis of optic disc photograph evaluation, earlier studies have found that PEXG patients present with smaller optic disc size than POAG patients.11,12 It has also been reported that neuroretinal rim loss in POAG is commonly located in the lower-temporal and upper-temporal sectors, whereas in PEXG it tends to be more diffuse.12 However, to the best of our knowledge, structural differences between POAG and PEXG have not been previously quantified. In addition, the correlation of such structural differences with functional damage has not been investigated. In view of the above www.glaucomajournal.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
377
Pappas et al
J Glaucoma
differences between POAG and PEXG, one may form the hypothesis that structure-function correlation is different in these 2 types of glaucoma. The purpose of this study is to compare structural characteristics of the optic disc using the Heidelberg Retina Tomograph (HRT) and to assess structure-function correlation between POAG and PEXG.
PATIENTS AND METHODS This was a prospective, clinic-based, observation case series. Patients 18 years and above with POAG or PEXG who attended a Glaucoma University Clinic (“Papageorgiou” Hospital, Aristotle University of Thessaloniki, Greece) were consecutively invited to participate in the study. The study was approved by the Aristotle University Hospital Ethics Committee. All study procedures adhered to the principles outlined in the Declaration of Helsinki for research involving human subjects, and all participants gave written informed consent before their participation. Glaucoma definition was based on conservative and strict criteria that required the presence of both structural and functional damage, irrespective of IOP (Table 1). Subjects were classified as POAG if they had glaucoma and open, normal-appearing anterior chamber angle, and the absence of other (secondary) causes of open-angle glaucoma in either eye. Subjects were classified as PEXG if they had glaucoma, normal-appearing anterior chamber, and PEX in either eye. PEX was defined as the presence of pseudoexfoliative material in either eye at the pupil margin and/or on the lens capsule. Before pupil dilation, a detailed high-magnification slit-lamp assessment of the pupil margin was performed. After pupil dilation, the anterior lens surface from each eye was scanned from left to right using a narrow slit-lamp beam, and then was examined using a vertical broad slit-lamp beam, looking specifically for early signs of PEX, including pregranular radial lines, and established granular deposits. Three independent ophthalmologists (T.P., A.K., F.T.) assessed the structural glaucomatous damage. A consensus agreement between at least 2 of them was required to assign the diagnosis of glaucoma and to confirm the presence of pseudoexfoliative material. The study excluded patients with any stage of diabetic retinopathy, late age-related macular degeneration, and a
TABLE 1. Glaucoma Definition Glaucomatous optic disc 1. Thinning or notching of the optic disc rim or 2. Asymmetry between the 2 eyes of more than 0.2 C/D and Confirmed* visual field defect in at least one eye Three contiguous points more than 5 dB depressed or one point more than 10 dB depressed and either: 1. PSD with a P-value index < 5% or 2. A GHT index outside normal limits *A glaucomatous visual field defect was considered confirmed when it was repeated in at least 2 visual field examinations involving the same index on test and retest and occurring in the same field location. Only reliable visual field tests were considered. A visual field was considered reliable when false positive errors < 33%, false negative errors < 33%, and fixation losses < 33%. GHT indicates glaucoma hemifield test; PSD, pattern standard deviation.
Volume 25, Number 4, April 2016
history of surgery or laser within 3 months before study enrolment (excluded eye). Before clinical examination, a questionnaire was administered that queried demographic data, ophthalmic, medical, and family history. All study participants had a standardized eye examination with visual acuity measurement using Early Treatment Diabetic Retinopathy Study charts, VF test, applanation tonometry, gonioscopy, slitlamp anterior segment examination, dilated fundus slitlamp biomicroscopy, central corneal thickness (CCT) measurement, and optic disc imaging with the HRT. IOP was measured using a calibrated Goldmann applanation tonometer (Haag-Streit, Bern, Switzerland). The mean IOP of 3 readings in each eye was recorded as the IOP for that eye. CCT was measured using ultrasound caliper (Quantel Medical, France). The average of 5 measurements in each eye was defined as the CCT for that eye. The 24-2 Swedish Interactive Thresholding Algorithm of the Humphrey Automated Field Analyzer II (Humphrey Zeiss, Dublin, CA) was used for VF testing.13 According to the definition of glaucoma used in the study, 2 VF tests were required per eye; the second VF was used for data analyses.
HRT Optic Disc Evaluation Optic discs were imaged with HRTI (Heidelberg Engineering, Heidelberg, Germany). The HRT is designed for quantitative descriptions of fundus topography with main application in the analysis of the morphology of the optic nerve head and follow-up measurements in glaucoma (software version 2.02). Using a laser beam of a 670-nm diode laser, HRT scans 32 sequential 256 256 pixel slices. Three-dimensional image (single image) can be obtained by combining data from the 32 different focal places. Before image acquisition, refractive error and keratometry readings were obtained and they were entered into the HRT software to help correct for magnification errors. Using a 10-degree field of view for HRT, 3 consecutive single image series were taken under the same experimental conditions for all subjects. As suggested from previous reproducibility studies, to obtain high reproducible topographic measurements, a mean topography was calculated from these 3 single images for each subject and used for further analysis.14 The border of the optic disc was defined at the inner edge of the scleral ring of Elschnig by drawing a contour line. The standard reference plane was used in all images. Quality assessment of the mean images and contour line drawing were performed by an experienced observer (T.P.) who was masked to the clinical examination findings. When the quality indication of the mean HRT images was good (SD < 30, HRT software), meaning good reproducibility of the 3 single images acquisition, then the optic disc parameters were calculated on a mean topography image. When quality indication was >30 showing poor quality of the mean image, the best single image was used.
Data Handling and Statistical Methods One eye per subject was included in the analysis. In case of unilateral glaucomatous damage, the glaucomatous eye was included in the analysis. If both eyes were eligible, the eye with the better quality of the HRT image was selected. If both eyes were eligible and the quality of the HRT image was the same, the eye with the lower mean deviation (MD) in the VF was selected; if the MD was also the same, 1 eye was randomly selected.
378 | www.glaucomajournal.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
J Glaucoma
Volume 25, Number 4, April 2016
Confocal Laser Ophthalmoscope in POAG and PEXG
Statistical analyses were performed using statistical software SAS version 9.1 (Cary, NC). w2 test was used to compare the distribution of data among different groups. T test (between 2 subgroups) was used to compare the mean of continuous variables with normal distribution (HRT parameters between POAG and PEXG). Mann-Whitney U test was used to explore the difference of continuous variables between 2 groups when the variables did not meet the criteria for t test. Analysis of covariance was used while adjusting for age, MD, IOP, and disc area. The Spearman rank correlation coefficient (rs) was used to determine the correlation between HRT parameters and MD. P-values were considered statistically significant when
Structure-Function Correlation Using Confocal Laser Ophthalmoscope in Primary Open-Angle Glaucoma and Pseudoexfoliative Glaucoma Theofanis Pappas, MD,* Panayiota Founti, MD,* Xiang Jun Yin, PhD,w Archimidis Koskosas, MD,* Eleftherios Anastasopoulos, MD,* Angeliki Salonikiou, MD,* Vasilios Kilintzis, PhD,* Antonios Antoniadis, PhD,* Nikolaos Ziakas, MD,* and Fotis Topouzis, MD, PhD*
Purpose: To compare Heidelberg Retina Tomograph (HRT) optic disc parameters and structure-function correlation between primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG). Design: Prospective, observation case series. Patients and Methods: A total of 54 POAG and 33 PEXG cases, consecutively recruited from a University Glaucoma Service, underwent a comprehensive ophthalmic examination, including HRT optic disc imaging. Glaucoma definition required the presence of both structural and functional damage. One eye per subject was included in the analysis. T test, Mann-Whitney U test, and analysis of covariance were used to compare HRT parameters between POAG and PEXG, adjusting for age, mean deviation (MD) in the visual field, intraocular pressure, and disc area. The correlation between HRT and MD was assessed in each group. Results: Cup area (P = 0.048), height variation contour (P = 0.016), and cup/disc area ratio (P = 0.023) were higher in POAG, whereas the mean retinal nerve fiber layer thickness Received for publication March 19, 2014; accepted January 7, 2015. From the *1st Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece; and wNational Center for Chronic and Non-communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. T.P., P.F., F.T.: conception an design of the study; T.P., A.K., E.A., F.T.: data collection; T.P., P.F., X.J.Y., A.K., E.A., A.S., V.K., A.A., N.Z., F.T.: analysis and interpretation of the data; T.P., P.F., A.S., F.T.: writing the article; T.P., P.F., X.J.Y., A.K., E.A., A.S., V.K., A.A., N.Z., F.T.: critical revision of the article; T.P., P.F., X.J.Y., A.K., E.A., A.S., V.K., A.A., N.Z., F.T.: final approval of the article. The study was approved by the Aristotle University Medical School, Ethics Committee. The IRB approval was prospective and informed consent statements for research from each participant were obtained. All study procedures adhered to the principles outlined in the Declaration of Helsinki for research involving human subjects. This research has been co-financed by the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) - Research Funding Program: THALES. Investing in knowledge society through the European Social Fund. Disclosure: The remaining authors declare no conflict of interest. F.T. is on Advisory Board for Pfizer Ophthalmics and Merc & Co; received lecture fees from Alcon Laboratories Inc. and Pfizer Inc.; received grant support from Alcon Laboratories and Pfizer Inc. Reprints: Fotis Topouzis, MD, PhD, 1st Department of Ophthalmology, Aristotle University of Thessaloniki, AHEPA Hospital, St. Kiriakidi 1, Thessaloniki 54636, Greece (e-mail: ftopouzis@ otenet.gr). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/IJG.0000000000000233
J Glaucoma
Volume 25, Number 4, April 2016
(P = 0.048), retinal nerve fiber layer cross-section area (P = 0.044), and rim area (P = 0.048) were lower in POAG, compared with PEXG. The correlation of HRT parameters with MD was significant only in the POAG group. Conclusions: At a similar level of functional damage, POAG subjects presented with more pronounced structural damage than PEXG subjects. The correlation between HRT and visual field parameters was more evident in POAG, compared with PEXG. Key Words: structure-function correlation, open-angle glaucoma, confocal laser ophthalmoscope
(J Glaucoma 2016;25:377–382)
P
rimary open-angle glaucoma (POAG) is the most common type of glaucoma,1 whereas pseudoexfoliative glaucoma (PEXG) is one of the most common types of secondary open-angle glaucoma.2 There is evidence to suggest that PEXG is not just a variant of POAG, as it has been previously hypothesized.3 For the same level of intraocular pressure (IOP), subjects with pseudoexfoliation (PEX) are at higher risk for glaucoma compared with subjects without PEX.4 This means that, in addition to IOP, there may be non–IOP-related factors involved in the development of PEXG. Moreover, POAG and PEXG do not seem to share the same risk factors,5 which may suggest differences in their pathophysiology. Clinical characteristics are also different between POAG and PEXG. Typically, PEXG has higher IOP values2 and larger 24-hour IOP fluctuations than POAG.6 In addition, despite the fact that PEXG is less likely to be undiagnosed than POAG,7 in clinical settings patients with PEXG present with more advanced visual field (VF) loss at diagnosis than patients with POAG.8,9 In addition, it has been reported that for the same level of initial IOP, POAG patients present with more advanced damage in the VF than PEXG patients.10 These 2 common types of open-angle glaucoma also seem to differ in terms of structural characteristics. On the basis of optic disc photograph evaluation, earlier studies have found that PEXG patients present with smaller optic disc size than POAG patients.11,12 It has also been reported that neuroretinal rim loss in POAG is commonly located in the lower-temporal and upper-temporal sectors, whereas in PEXG it tends to be more diffuse.12 However, to the best of our knowledge, structural differences between POAG and PEXG have not been previously quantified. In addition, the correlation of such structural differences with functional damage has not been investigated. In view of the above www.glaucomajournal.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
377
Pappas et al
J Glaucoma
differences between POAG and PEXG, one may form the hypothesis that structure-function correlation is different in these 2 types of glaucoma. The purpose of this study is to compare structural characteristics of the optic disc using the Heidelberg Retina Tomograph (HRT) and to assess structure-function correlation between POAG and PEXG.
PATIENTS AND METHODS This was a prospective, clinic-based, observation case series. Patients 18 years and above with POAG or PEXG who attended a Glaucoma University Clinic (“Papageorgiou” Hospital, Aristotle University of Thessaloniki, Greece) were consecutively invited to participate in the study. The study was approved by the Aristotle University Hospital Ethics Committee. All study procedures adhered to the principles outlined in the Declaration of Helsinki for research involving human subjects, and all participants gave written informed consent before their participation. Glaucoma definition was based on conservative and strict criteria that required the presence of both structural and functional damage, irrespective of IOP (Table 1). Subjects were classified as POAG if they had glaucoma and open, normal-appearing anterior chamber angle, and the absence of other (secondary) causes of open-angle glaucoma in either eye. Subjects were classified as PEXG if they had glaucoma, normal-appearing anterior chamber, and PEX in either eye. PEX was defined as the presence of pseudoexfoliative material in either eye at the pupil margin and/or on the lens capsule. Before pupil dilation, a detailed high-magnification slit-lamp assessment of the pupil margin was performed. After pupil dilation, the anterior lens surface from each eye was scanned from left to right using a narrow slit-lamp beam, and then was examined using a vertical broad slit-lamp beam, looking specifically for early signs of PEX, including pregranular radial lines, and established granular deposits. Three independent ophthalmologists (T.P., A.K., F.T.) assessed the structural glaucomatous damage. A consensus agreement between at least 2 of them was required to assign the diagnosis of glaucoma and to confirm the presence of pseudoexfoliative material. The study excluded patients with any stage of diabetic retinopathy, late age-related macular degeneration, and a
TABLE 1. Glaucoma Definition Glaucomatous optic disc 1. Thinning or notching of the optic disc rim or 2. Asymmetry between the 2 eyes of more than 0.2 C/D and Confirmed* visual field defect in at least one eye Three contiguous points more than 5 dB depressed or one point more than 10 dB depressed and either: 1. PSD with a P-value index < 5% or 2. A GHT index outside normal limits *A glaucomatous visual field defect was considered confirmed when it was repeated in at least 2 visual field examinations involving the same index on test and retest and occurring in the same field location. Only reliable visual field tests were considered. A visual field was considered reliable when false positive errors < 33%, false negative errors < 33%, and fixation losses < 33%. GHT indicates glaucoma hemifield test; PSD, pattern standard deviation.
Volume 25, Number 4, April 2016
history of surgery or laser within 3 months before study enrolment (excluded eye). Before clinical examination, a questionnaire was administered that queried demographic data, ophthalmic, medical, and family history. All study participants had a standardized eye examination with visual acuity measurement using Early Treatment Diabetic Retinopathy Study charts, VF test, applanation tonometry, gonioscopy, slitlamp anterior segment examination, dilated fundus slitlamp biomicroscopy, central corneal thickness (CCT) measurement, and optic disc imaging with the HRT. IOP was measured using a calibrated Goldmann applanation tonometer (Haag-Streit, Bern, Switzerland). The mean IOP of 3 readings in each eye was recorded as the IOP for that eye. CCT was measured using ultrasound caliper (Quantel Medical, France). The average of 5 measurements in each eye was defined as the CCT for that eye. The 24-2 Swedish Interactive Thresholding Algorithm of the Humphrey Automated Field Analyzer II (Humphrey Zeiss, Dublin, CA) was used for VF testing.13 According to the definition of glaucoma used in the study, 2 VF tests were required per eye; the second VF was used for data analyses.
HRT Optic Disc Evaluation Optic discs were imaged with HRTI (Heidelberg Engineering, Heidelberg, Germany). The HRT is designed for quantitative descriptions of fundus topography with main application in the analysis of the morphology of the optic nerve head and follow-up measurements in glaucoma (software version 2.02). Using a laser beam of a 670-nm diode laser, HRT scans 32 sequential 256 256 pixel slices. Three-dimensional image (single image) can be obtained by combining data from the 32 different focal places. Before image acquisition, refractive error and keratometry readings were obtained and they were entered into the HRT software to help correct for magnification errors. Using a 10-degree field of view for HRT, 3 consecutive single image series were taken under the same experimental conditions for all subjects. As suggested from previous reproducibility studies, to obtain high reproducible topographic measurements, a mean topography was calculated from these 3 single images for each subject and used for further analysis.14 The border of the optic disc was defined at the inner edge of the scleral ring of Elschnig by drawing a contour line. The standard reference plane was used in all images. Quality assessment of the mean images and contour line drawing were performed by an experienced observer (T.P.) who was masked to the clinical examination findings. When the quality indication of the mean HRT images was good (SD < 30, HRT software), meaning good reproducibility of the 3 single images acquisition, then the optic disc parameters were calculated on a mean topography image. When quality indication was >30 showing poor quality of the mean image, the best single image was used.
Data Handling and Statistical Methods One eye per subject was included in the analysis. In case of unilateral glaucomatous damage, the glaucomatous eye was included in the analysis. If both eyes were eligible, the eye with the better quality of the HRT image was selected. If both eyes were eligible and the quality of the HRT image was the same, the eye with the lower mean deviation (MD) in the VF was selected; if the MD was also the same, 1 eye was randomly selected.
378 | www.glaucomajournal.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
J Glaucoma
Volume 25, Number 4, April 2016
Confocal Laser Ophthalmoscope in POAG and PEXG
Statistical analyses were performed using statistical software SAS version 9.1 (Cary, NC). w2 test was used to compare the distribution of data among different groups. T test (between 2 subgroups) was used to compare the mean of continuous variables with normal distribution (HRT parameters between POAG and PEXG). Mann-Whitney U test was used to explore the difference of continuous variables between 2 groups when the variables did not meet the criteria for t test. Analysis of covariance was used while adjusting for age, MD, IOP, and disc area. The Spearman rank correlation coefficient (rs) was used to determine the correlation between HRT parameters and MD. P-values were considered statistically significant when
