Human retinal microvascular imaging using adaptive optics scanning light ophthalmoscopy
© Chui et al. 2016
Received: 2 December 2015
Accepted: 21 February 2016
Published: 1 May 2016
Retinal microvascular imaging is an especially promising application of high resolution imaging since there are increasing options for therapeutic intervention and need for better structural and functional biomarkers to characterize ocular and systemic vascular diseases.
Adaptive optics scanning light ophthalmoscopy (AOSLO) is an emerging technology for improving in vivo imaging of the human retinal microvasculature, allowing unprecedented visualization of retinal microvascular structure, measurements of blood flow velocity, and microvascular network mapping. This high resolution imaging technique shows significant potential for studying physiological and pathological conditions of the retinal microvasculature noninvasively.
This review will briefly summarize the abilities of in vivo human retinal microvasculature imaging in healthy controls, as well as patients with diabetic retinopathy, retinal vein occlusion, and sickle cell retinopathy using AOSLO and discuss its potential contribution to scientific research and clinical applications.
KeywordsRetina Adaptive optics Blood vessels Capillaries Diabetic retinopathy Sickle cell retinopathy Retinal vein occlusion Fluorescein angiography
The retina has one of the highest metabolic demands per unit weight of any tissue in the human body , making it especially vulnerable to disease processes that damage the vascular network and lessen the oxygen and nutrient supply to the tissue. The ability to detect these disease manifestations early is important as it offers the opportunity to intervene systemically as well as locally in order to slow, stop or even reverse these changes. Macroscopic features of the retinal vasculature, such as arteriolar narrowing, arteriovenous nicking, hemorrhages and microaneurysms have traditionally been used as signs of progressive cardiovascular disease, as well as hypertension and diabetes mellitus. Studying microscopic features of the retinal vasculature would theoretically enable earlier detection of disease. Thus, our ability to image retinal microvasculature is important for providing better knowledge of the normal physiological retina and pathological process, allowing development of new strategies to prevent or delay disease progression.
Recently, advances in high resolution imaging techniques such as adaptive optics and optical coherence tomography angiography (OCTA) have expanded our ability to map the living human retinal vasculature noninvasively without the use of exogenous contrast agents [2–8]. In particular, adaptive optics scanning light ophthalmoscopy (AOSLO) is an emerging technology for the visualization of microscopic structures in the living human retina to an extent that had not been previously possible with conventional clinical imaging modalities . This imaging technique utilizes deformable mirrors to correct for ocular aberrations, allowing high resolution non-invasive imaging of retinal structures including retinal nerve fibers, retinal microvasculature, photoreceptors, retinal pigment epithelium, and lamina cribrosa [4, 9–18]. Specifically, the non-invasive nature of AOSLO imaging makes it very appealing for screening, detecting, and monitoring subclinical microvascular changes in the human retina, which may enable earlier intervention against retinal diseases.
AOSLO imaging with confocal and nonconfocal detection schemes
Confocal detection schemes
Nonconfocal detection schemes
Comparison of perfusion maps—IVFA, AOSLO, and OCTA
Since it was introduced by Novotny and Alvis in 1961, intravenous fluorescein angiography (IVFA) has been the clinical gold standard for assessing retinal vascular disease . It produces an analyzable picture of the retinal vasculature in vivo and is able to detect pathological features such as non-perfusion, infarctions, edema, neovascularization, microaneurysms and leakage at blood–retinal barrier ruptures [21, 33]. It has helped with diagnosis, as well directing treatment of a variety of conditions ranging from diabetic macular edema to retinopathy of prematurity [34, 35]. While IVFA has fostered many discoveries about retinal vasculopathies, it has some limitations. It offers a widefield view of the vasculature, but has inherent limitations in axial and lateral resolution. IVFA has difficulty revealing capillaries with smaller diameters, and those that are anatomically deeper and further from the fovea, as suggested by examination of comparable flat-mounted histological sections . In addition, there is concern about the invasive nature of IVFA due to the use of an exogenous contrast agent, which occasionally produces minor reactions such as nausea and pruritus, and much more rarely anaphylaxis and death [37–41].
Nonconfocal AOSLO coupled with motion contrast processing reveals maps of retinal microvasculature perfusion with detail comparable to confocal AOSLO FA, but without the need for any exogenous contrast agent . This image processing technique takes advantage of the motion of multiply scattering particles, in this case, intravascular erythrocytes, which serve as intrinsic markers revealing the perfusion status of retinal microvasculature [2, 29]. Limitations of this technique include motion artifacts, inability to visualize fluorescein leakage or pooling, and difficulty in detecting blood vessels with slow or intermittent perfusion in comparison to IVFA and confocal AOSLO FA.
OCTA imaging is a new and emerging technology based on motion contrast with widespread clinical potential for mapping the retinal vasculature, detecting retinal vascular abnormalities and monitoring disease progression (Fig. 1e). Similar to nonconfocal AOSLO, OCTA is completely non-invasive, not requiring an exogenous contrast agent. In comparison to adaptive optics imaging techniques, OCTA’s major advantage is the much shorter imaging time. OCTA also has a major advantage over IVFA or confocal AOSLO FA, since it is able to delineate the different layers of retinal capillary beds including the choriocapillaris in a single scan . However, since it relies on motion contrast, it is subject to projection artifacts from more superficial vessels shadowing upon the deeper layer vessels, more prone to motion artifacts, and is unable to show leakage or slowed perfusion. Both nonconfocal AOSLO and OCTA provide attractive alternatives to IVFA or confocal AOSLO FA, since they allow frequent non-invasive evaluation and follow up exams.
Despite their advantages, AOSLO and OCTA are relatively new to the clinic and not yet considered routine techniques for imaging retinal vasculature. As with any new technology, the accuracy and reproducibility of AOSLO and OCTA must be tested in order to establish their validity and suitability for routine clinical implementation. These investigations are especially critical prior to initiation of cross-sectional or longitudinal studies of pathological microvascular change. Since accuracy and reproducibility have yet to be established, such studies must be conducted to define normative anatomic and physiologic standards before we can reliably assess disease states. In addition, comparative analyses between AOSLO and OCTA may be instructive regarding the significance of vascular patterns observed and their relationship to various vascular abnormalities.
Clinical applications of retinal microvascular imaging using AOSLO
Retinal vein occlusion
Retinal vein occlusion is second only to diabetic retinopathy as a cause of retinal vascular morbidity . Branch retinal vein occlusion has a prevalence of 5.20 per 1000, being more common than central retinal vein occlusion . Clinical presentations of retinal vein occlusion may range from asymptomatic to moderate or even severe loss of vision. Chronic vascular changes include abnormal or absence of perfusion distal to the point of occlusion, vessel leakage, dilated collateral vessels, and neovascularization [55, 57].
Sickle cell retinopathy
Longitudinal imaging of retinal microvasculature using AOSLO
Figure 10 shows fundus photographs and nonconfocal AOSLO structural images of a 55-year-old female with branch retinal vein occlusion of 4 years duration. She received segmental scatter photocoagulation in the left eye 4 years prior to her baseline AOSLO imaging session. Nonconfocal AOSLO structural images of the left eye were obtained at baseline, 2 months, and 7 months. During this period, her visual acuity in the study eye remained stable at 20/20. Baseline color fundus photography, IVFA, and spectral domain optical coherence tomography (SDOCT) images are shown in Fig. 10a–c, respectively. Nonconfocal AOSLO images at 2 months and 7 months show only minor microvascular changes as compared to baseline imaging (Fig. 10d, white arrows), suggesting that the BRVO is well-compensated with no progressive retinal microvasculature changes due to unresolved ischemia. The nonconfocal AOSLO images demonstrate the consistency and repeatability of the technique, and its ability to capture consistent images of the same retinal location over time.
Longitudinal vascular imaging of a 49-year-old female with proliferative diabetic retinopathy is shown in Fig. 11. This patient had a history of diabetes mellitus type 2 controlled with metformin and sitagliptin for 3 years duration. AOSLO imaging at 1° inferior retina of the right eye was done at baseline and 5 months. She received one bevacizumab injection to both eyes 2 months after baseline. During this period, her visual acuity changed from 20/15 to 20/20. Her hemoglobin A1c levels were not available at these times. Baseline color fundus photography, IVFA, and SDOCT images at baseline are shown in Fig. 11a–c, respectively. The fundus photograph and IVFA show evidence of dot-blot hemorrhages and fluorescein leakage with no significant changes in the OCT over the course of 5 months. Two distinct examples of vessel looping are evident at baseline in the confocal AOSLO FA and nonconfocal AOSLO images as revealed by the yellow arrows in Fig. 11d. Full structural regression and loss of capillary patency can be seen at 5 months as indicated by the yellow arrows in Fig. 11e. Neighboring vessels appear to remain intact in the structural images and persistently patent in the perfusion maps over the course of 5 months. Our preliminary results are consistent with a previous study that AOSLO imaging is repeatable and sensitive enough to detect changes such as capillary dropout .
Limitations of AOSLO for clinical use
Despite the AOSLO’s extraordinary ability to extend our view into the microworld, current instrumentation and protocols have limitations that prevent its widespread clinical use. It is very time-consuming to acquire images, due to its limited field of view, and can be very fatiguing for patients. Furthermore, the optics of the AOSLO exaggerates sensitivity to media opacities, higher refractive errors, fixation stability, and tear film quality, and demands exceptional subject cooperation. Image processing, montaging and analysis are also very labor intensive and time consuming due to lack of automated techniques. Hopefully future advances in speed and tracking will expand its ability to image more challenging eyes, and software advances will make results more rapidly available in a clinically relevant time course.
AOSLO provides unprecedented views of the retinal vascular network down to the capillary level, revealing microscopic vascular features that are not consistently visible with current clinical ophthalmic imaging instruments. This high resolution imaging technique also shows significant potential for studying physiological and pathological features of the retinal vasculature in the living human eye. Its ability to noninvasively track subclinical vascular changes over time opens new vistas onto the dynamic evolution of certain diseases and provides a more sensitive examination of clinical interventions.
adaptive optics scanning light ophthalmoscope
intravenous fluorescein angiography
optical coherence tomography angiography
spectral domain optical coherence tomography
TYC, SM, BK, NRM, NC, AP, and RBR drafted the article. TYC and RBR contributed to the conception and design of the article. TYC, AP, and RBR contributed to the interpretation of the data and images. All authors read and approved the final manuscript.
Funding for this research was provided by the Marrus Family Foundation, Bendheim‐Lowenstein Family Foundation, Wise Family Foundation, New York Eye and Ear Chairman’s Research Fund, Violett Fund, Milbank Foundation, Research to Prevent Blindness. The sponsors and funding organizations had no role in the design or conduct of this research. Research reported in this publication was also supported in part by National Eye Institute of the National Institutes of Health under award number P30EY001931 and U01EY025477. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Commercial Relationship(s): Richard B. Rosen: Clarity: (Consultant); Opticology: (Personal Financial Interest); OD-OS: (Consultant); Allergan: (Consultant); Carl Zeiss Meditech: (Consultant); Optovue: (Consultant); Advanced Cellular Technologies: (Consultant). NanoRetina: (Consultant) and Regeneron: (Consultant). No other competing relationships exist.
Ethics approval and consent to participate Written informed consent was obtained from each subject after the nature and potential risks of the procedure were explained. This study adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of the New York Eye and Ear Infirmary of Mount Sinai.
Consent for publication Consent to publish was obtained from all subjects presented in this review.
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