Opinion
VIEWPOINT
Jennifer K. Sun, MD, MPH Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts; and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Lloyd Paul Aiello, MD, PhD Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts; and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
Corresponding Author: Lloyd Paul Aiello, MD, PhD, Beetham Eye Institute, Joslin Diabetes Center, Department of Ophthalmology, Harvard Medical School, One Joslin Place, Boston, MA 02215 (lpaiello@joslin .harvard.edu). jamaophthalmology.com
The Future of Ultrawide Field Imaging for Diabetic Retinopathy Pondering the Retinal Periphery The rigorously standardized and validated grading system for diabetic retinopathy (DR) severity as outlined in the Early Treatment Diabetic Retinopathy Study (ETDRS) in 19911 has allowed clinicians and researchers to compare diabetic retinal disease outcomes across diverse cohorts and to predict risks of retinopathy progression over time. Seminal studies defining current best practices for the evaluation and management of DR and diabetic macular edema have used this ETDRS protocol. However, due primarily to imaging limitations of the era in which it was developed, the ETDRS system only evaluates about 30% of the total retina area. Technological advances now allow us to image more than 80% of the retina with a single 200° field captured in a quartersecond. This new capability raises the important question of whether evaluation of retinal findings in areas outside the standard ETDRS fields may substantially impact patient management. The importance of the retinal periphery in diabetic eye disease has long been recognized. At the 1967 Airlie House Symposium from which the DR classification system originated, William P. Beetham, MD, and Harold F. Spalter, MD, discussed the fact that diabetic lesions were often seen in the retinal periphery and were likely of clinical importance. However, at that time, it required approximately 12 hours’ work to montage the images of the retinal periphery from a single eye, making it unfeasible to include more than the 7 posteriorly located retinal fields on which the ETDRS severity scale is based. Although the value of a detailed peripheral retina examination is recognized, it is often challenging in practice and rarely included in any telemedicine protocols. Ultrawide field (UWF) imaging allows reproducible documentation of peripheral retinal pathology. Multiple studies demonstrate that DR severity graded on retinal UWF images has substantial agreement (κ = 0.77-0.84) with grading from ETDRS photographs.2,3 Ultrawide field images also allow identification of lesions that are not visualized within the ETDRS fields. Diabetic retinopathy lesions are greater in number and/or severity in peripheral as compared with posterior retina in about 50% of eyes, which if considered in DR grading would increase severity in about 10%.3 Recent studies further suggest that the presence of predominantly peripheral DR lesions (PPL) on UWF images is highly associated with increased risk of DR worsening and the onset of proliferative DR.4 Indeed, eyes with any PPL had more than 3-fold increased risk of 2-ormore-step DR progression and a nearly 5-fold increase in risk of progression to proliferative DR over an average of 4 years’ follow-up, independent of baseline DR se-
verity, diabetes duration, and recent glycemic control. Increased risks were correlated with increasing extent of PPL. Other potentially important applications of UWF imaging technology are being investigated, including UWF fluorescein angiography.5 The ETDRS extensively evaluated posterior pole fluorescein angiography, and although it identified more pathology than color fundus photographs alone, it did not substantially improve ability to predict subsequent DR progression. However, given that PPL appear to markedly influence DR progression rates,4 studies are needed to determine whether peripheral nonperfusion on UWF angiography may also have substantial clinical application. This may be particularly pertinent given that peripheral nonperfusion is a common finding in diabetic eyes, even in those with minimal clinically evident lesions. In addition, recent studies suggest that peripheral lesions may result from, and be closely associated with, the location and extent of nonperfusion.6 Whether UWF photographs, UWF angiograms, or both methods are required to provide the most useful additional clinical information remains to be determined. These findings raise a key unanswered question as to whether our current DR severity grading approaches need to be updated to include findings now obtainable using UWF imaging. If such findings contribute substantially to risk prediction, cohort characterization, or treatment response, then such revision would be warranted. A large, multicenter observational study sponsored by the Diabetic Retinopathy Clinical Research Network (DRCR.net) will address this issue by assessing the relationship of baseline parameters on UWF color fundus photographs and UWF fluorescein angiography, such as presence of PPL and peripheral nonperfusion, with long-term DR outcomes. Approximately 350 eyes with a diverse range of baseline nonproliferative DR severity levels will be imaged at baseline and annual visits over the course of 4 years. Findings from this study should help determine whether imaging of the retinal periphery provides substantive clinical management benefits and which findings are most helpful. Diabetic retinopathy telemedicine initiatives might benefit substantially from UWF imaging if evaluation of the retinal periphery proves to be an important prognostic factor for DR, particularly given UWF imaging’s higher DR detection rates, increased imaging and grading efficiencies, and lower ungradable image rates.7 Currently, multiple options exist for acquiring UWF retinal images; however, all have limitations including high cost, low portability, difficult service, and/or need for exten-
(Reprinted) JAMA Ophthalmology Published online December 30, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 01/24/2016
E1
Opinion Viewpoint
sive imager training. As technology improves and equipment costs fall, UWF imaging should become increasingly accessible to telemedicine initiatives worldwide. In summary, accumulating evidence suggests that UWF imaging identifies findings in the retinal periphery that may substantially improve rates of DR detection, better characterize DR severity, and more accurately define risk of DR progression. Large, multicenter clinical studies such as the ongoing DRCR.net protocol may provide definitive evidence that evaluation of peripheral lesions is critical for optiARTICLE INFORMATION Published Online: December 30, 2015. doi:10.1001/jamaophthalmol.2015.5384. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Aiello received past travel-only support from Optos. No other disclosures were reported. Funding/Support: Joslin Diabetes Center received a loan of 2 Optos imaging devices and support in part from the Massachusetts Lions Eye Research Fund. Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript or decision to submit the manuscript for publication.
mal assessment of diabetic retinal disease. Such results may support a need to redefine our current DR severity classification systems to incorporate the new findings and thus improve the ability to predict the natural history of DR and to guide therapeutic interventions. Broad use,especiallyintelemedicineapplications,willbedependentoneventual reduced costs and more portable designs. Nonetheless, this new imaging modality holds promise for providing a noninvasive clinical and research tool that may significantly influence the future ophthalmic care of patients with diabetes worldwide.
stereoscopic color fundus photographs: an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology. 1991;98(5)(suppl):786-806. 2. Kernt M, Hadi I, Pinter F, et al. Assessment of diabetic retinopathy using nonmydriatic ultra-widefield scanning laser ophthalmoscopy (Optomap) compared with ETDRS 7-field stereo photography. Diabetes Care. 2012;35(12):2459-2463. 3. Silva PS, Cavallerano JD, Sun JK, Soliman AZ, Aiello LM, Aiello LP. Peripheral lesions identified by mydriatic ultrawide field imaging: distribution and potential impact on diabetic retinopathy severity. Ophthalmology. 2013;120(12):2587-2595. 4. Silva PS, Cavallerano JD, Haddad NM, et al. Peripheral lesions identified on ultrawide field imaging predict increased risk of diabetic
retinopathy progression over 4 years. Ophthalmology. 2015;122(5):949-956. 5. Wessel MM, Aaker GD, Parlitsis G, Cho M, D’Amico DJ, Kiss S. Ultra-wide-field angiography improves the detection and classification of diabetic retinopathy. Retina. 2012;32(4):785-791. 6. Silva PS, Dela Cruz AJ, Ledesma MG, et al. Diabetic retinopathy severity and peripheral lesions are associated with nonperfusion on ultrawide field angiography. Ophthalmology. 2015; S0161-6420(15)00773-3. 7. Silva PS, Cavallerano JD, Tolls D, et al. Potential efficiency benefits of nonmydriatic ultrawide field retinal imaging in an ocular telehealth diabetic retinopathy program. Diabetes Care. 2014;37(1): 50-55.
REFERENCES 1. Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from
E2
JAMA Ophthalmology Published online December 30, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 01/24/2016
jamaophthalmology.com
VIEWPOINT
Jennifer K. Sun, MD, MPH Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts; and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Lloyd Paul Aiello, MD, PhD Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts; and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
Corresponding Author: Lloyd Paul Aiello, MD, PhD, Beetham Eye Institute, Joslin Diabetes Center, Department of Ophthalmology, Harvard Medical School, One Joslin Place, Boston, MA 02215 (lpaiello@joslin .harvard.edu). jamaophthalmology.com
The Future of Ultrawide Field Imaging for Diabetic Retinopathy Pondering the Retinal Periphery The rigorously standardized and validated grading system for diabetic retinopathy (DR) severity as outlined in the Early Treatment Diabetic Retinopathy Study (ETDRS) in 19911 has allowed clinicians and researchers to compare diabetic retinal disease outcomes across diverse cohorts and to predict risks of retinopathy progression over time. Seminal studies defining current best practices for the evaluation and management of DR and diabetic macular edema have used this ETDRS protocol. However, due primarily to imaging limitations of the era in which it was developed, the ETDRS system only evaluates about 30% of the total retina area. Technological advances now allow us to image more than 80% of the retina with a single 200° field captured in a quartersecond. This new capability raises the important question of whether evaluation of retinal findings in areas outside the standard ETDRS fields may substantially impact patient management. The importance of the retinal periphery in diabetic eye disease has long been recognized. At the 1967 Airlie House Symposium from which the DR classification system originated, William P. Beetham, MD, and Harold F. Spalter, MD, discussed the fact that diabetic lesions were often seen in the retinal periphery and were likely of clinical importance. However, at that time, it required approximately 12 hours’ work to montage the images of the retinal periphery from a single eye, making it unfeasible to include more than the 7 posteriorly located retinal fields on which the ETDRS severity scale is based. Although the value of a detailed peripheral retina examination is recognized, it is often challenging in practice and rarely included in any telemedicine protocols. Ultrawide field (UWF) imaging allows reproducible documentation of peripheral retinal pathology. Multiple studies demonstrate that DR severity graded on retinal UWF images has substantial agreement (κ = 0.77-0.84) with grading from ETDRS photographs.2,3 Ultrawide field images also allow identification of lesions that are not visualized within the ETDRS fields. Diabetic retinopathy lesions are greater in number and/or severity in peripheral as compared with posterior retina in about 50% of eyes, which if considered in DR grading would increase severity in about 10%.3 Recent studies further suggest that the presence of predominantly peripheral DR lesions (PPL) on UWF images is highly associated with increased risk of DR worsening and the onset of proliferative DR.4 Indeed, eyes with any PPL had more than 3-fold increased risk of 2-ormore-step DR progression and a nearly 5-fold increase in risk of progression to proliferative DR over an average of 4 years’ follow-up, independent of baseline DR se-
verity, diabetes duration, and recent glycemic control. Increased risks were correlated with increasing extent of PPL. Other potentially important applications of UWF imaging technology are being investigated, including UWF fluorescein angiography.5 The ETDRS extensively evaluated posterior pole fluorescein angiography, and although it identified more pathology than color fundus photographs alone, it did not substantially improve ability to predict subsequent DR progression. However, given that PPL appear to markedly influence DR progression rates,4 studies are needed to determine whether peripheral nonperfusion on UWF angiography may also have substantial clinical application. This may be particularly pertinent given that peripheral nonperfusion is a common finding in diabetic eyes, even in those with minimal clinically evident lesions. In addition, recent studies suggest that peripheral lesions may result from, and be closely associated with, the location and extent of nonperfusion.6 Whether UWF photographs, UWF angiograms, or both methods are required to provide the most useful additional clinical information remains to be determined. These findings raise a key unanswered question as to whether our current DR severity grading approaches need to be updated to include findings now obtainable using UWF imaging. If such findings contribute substantially to risk prediction, cohort characterization, or treatment response, then such revision would be warranted. A large, multicenter observational study sponsored by the Diabetic Retinopathy Clinical Research Network (DRCR.net) will address this issue by assessing the relationship of baseline parameters on UWF color fundus photographs and UWF fluorescein angiography, such as presence of PPL and peripheral nonperfusion, with long-term DR outcomes. Approximately 350 eyes with a diverse range of baseline nonproliferative DR severity levels will be imaged at baseline and annual visits over the course of 4 years. Findings from this study should help determine whether imaging of the retinal periphery provides substantive clinical management benefits and which findings are most helpful. Diabetic retinopathy telemedicine initiatives might benefit substantially from UWF imaging if evaluation of the retinal periphery proves to be an important prognostic factor for DR, particularly given UWF imaging’s higher DR detection rates, increased imaging and grading efficiencies, and lower ungradable image rates.7 Currently, multiple options exist for acquiring UWF retinal images; however, all have limitations including high cost, low portability, difficult service, and/or need for exten-
(Reprinted) JAMA Ophthalmology Published online December 30, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 01/24/2016
E1
Opinion Viewpoint
sive imager training. As technology improves and equipment costs fall, UWF imaging should become increasingly accessible to telemedicine initiatives worldwide. In summary, accumulating evidence suggests that UWF imaging identifies findings in the retinal periphery that may substantially improve rates of DR detection, better characterize DR severity, and more accurately define risk of DR progression. Large, multicenter clinical studies such as the ongoing DRCR.net protocol may provide definitive evidence that evaluation of peripheral lesions is critical for optiARTICLE INFORMATION Published Online: December 30, 2015. doi:10.1001/jamaophthalmol.2015.5384. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Aiello received past travel-only support from Optos. No other disclosures were reported. Funding/Support: Joslin Diabetes Center received a loan of 2 Optos imaging devices and support in part from the Massachusetts Lions Eye Research Fund. Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript or decision to submit the manuscript for publication.
mal assessment of diabetic retinal disease. Such results may support a need to redefine our current DR severity classification systems to incorporate the new findings and thus improve the ability to predict the natural history of DR and to guide therapeutic interventions. Broad use,especiallyintelemedicineapplications,willbedependentoneventual reduced costs and more portable designs. Nonetheless, this new imaging modality holds promise for providing a noninvasive clinical and research tool that may significantly influence the future ophthalmic care of patients with diabetes worldwide.
stereoscopic color fundus photographs: an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology. 1991;98(5)(suppl):786-806. 2. Kernt M, Hadi I, Pinter F, et al. Assessment of diabetic retinopathy using nonmydriatic ultra-widefield scanning laser ophthalmoscopy (Optomap) compared with ETDRS 7-field stereo photography. Diabetes Care. 2012;35(12):2459-2463. 3. Silva PS, Cavallerano JD, Sun JK, Soliman AZ, Aiello LM, Aiello LP. Peripheral lesions identified by mydriatic ultrawide field imaging: distribution and potential impact on diabetic retinopathy severity. Ophthalmology. 2013;120(12):2587-2595. 4. Silva PS, Cavallerano JD, Haddad NM, et al. Peripheral lesions identified on ultrawide field imaging predict increased risk of diabetic
retinopathy progression over 4 years. Ophthalmology. 2015;122(5):949-956. 5. Wessel MM, Aaker GD, Parlitsis G, Cho M, D’Amico DJ, Kiss S. Ultra-wide-field angiography improves the detection and classification of diabetic retinopathy. Retina. 2012;32(4):785-791. 6. Silva PS, Dela Cruz AJ, Ledesma MG, et al. Diabetic retinopathy severity and peripheral lesions are associated with nonperfusion on ultrawide field angiography. Ophthalmology. 2015; S0161-6420(15)00773-3. 7. Silva PS, Cavallerano JD, Tolls D, et al. Potential efficiency benefits of nonmydriatic ultrawide field retinal imaging in an ocular telehealth diabetic retinopathy program. Diabetes Care. 2014;37(1): 50-55.
REFERENCES 1. Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from
E2
JAMA Ophthalmology Published online December 30, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 01/24/2016
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