Potential use of “Adaptive Optics Imaging to characterize Retinal Capillary Flow in Early Diabetic Retinopathy”

Ms. Srividya Neriyanuri

Diabetic Retinopathy – the big picture

Diabetic Retinopathy (DR), is a microvascular complication of the retina that results as a consequence of the most common hyperglycemic disorder - Diabetes. The early diagnosis, timely intervention, and regular follow up, each play an important role in controlling the progression of this sight threatening disease. It is one of the major causes of visual impairment with a prevalence of 35.3% worldwide (Yau et al., 2012). In developing countries like India,the prevalence is as high as about 18% in urban living population (Raman et al., 2009), whereas, in the western countries like Australia, the prevalence of sight threatening DR is as low as 4.5% (Keel et al., 2017). The major yet modifiable risk factors contributing to the development of DR include Hba1C (glycated hemoglobin), systolic blood pressure, hyperlipidemia and body mass index (Ting, Cheung, & Wong, 2016).

DR, the most common eye disease, is characterized by structural and physiological damage to the blood vessels, supplying inner retina, and may eventually result in severe vision loss due to the widespread disruption of retinal vascular and neural networks. Once established, DR changes are readily visible on routine clinical ophthalmoscopy, but the underlying vascular and neural damage begin well before these signs become clinically apparent. Insights into such “pre-clinical damage” in DR is of great research importance and interest as it helps unveil the complex pathophysiology of the disease; this knowledge may allow us in early detection of the disease and in designing appropriate clinical interventions.

Role of retinal blood circulation in DR pathophysiology

Retinal physiology and visual functions are maintained by a diversified vascular network comprising of large blood vessels – arteries and veins and small, thread like fine vessels known as capillaries. These smallest blood vessels called capillaries feed the underlying retinal tissue with necessary nutrients including oxygen and help maintaining a proper blood circulation between arteries and veins.

In healthy individuals, the capillaries deliver sufficient blood flow to meet the metabolic demands of the tissue, but conditions such as Diabetes (Type 1 & 2) & Hypertension, may result in altered capillary blood flow due to chronic hyperglycemia and rise in mean arterial pressure respectively. The resulting altered capillary flow acts as a trigger for the onset of structural damage and functional changes such as disrupted blood flow and oxygen supply in DR. Hence,evaluation of functional blood flow is as necessary as having the early structural damage detected in DR.

Advancements in retinal vascular flow imaging in Diabetic Retinopathy

Animal and human postmortem studies show that capillary degeneration marks the earliest signs of DR. Over years, routine clinical examination using ophthalmoscopy and fundus photography has been proven to be helpful in grading the severity of the disease. However, these techniques failed to detect early changes in capillary degeneration due to poor spatial and temporal resolutions. Fluorescein angiography (FA) imaging has been considered as a gold standard in detection and monitoring of the retinal capillary changes in DR. In addition to FA, Indocyanine green angiography provides dynamic visualization of blood with wide field of view, however, information obtained using these techniques is limited to only superficial (not deep) retina and the  segmentation of layers seems impossible with these methods.

Moreover, recent advancements in high resolution imaging techniques has now made it possible to image the microvasculature with better convenience. Optical Coherence Tomography Angiography (OCTA) is one of the imaging modalities that has gained significant popularity in the recent times; OCTA is a non-invasive technique and provides angiogram data using functional signals to generate a high resolution structural map without any contrast dyes. Advantage of OCTA is its depth imaging and was shown to highlight lesions better as compared to FA. However, OCTA is limited by the fact that it provides flow information only at a given point of time (example: highlights perfused capillaries) and cannot examine the flow dynamics (such as change in velocities with time).

On the other hand, Adaptive optics scanning laser ophthalmoscopy (AOSLO) offers better spatial resolution in imaging the retinal capillaries (figure1). Confocal nature of the AOSLO permits axial sectioning of the retina and visualization of different layers of the retina including blood vessels. Yet, AOSLO imaging is limited in quantifying speed of individual blood cells due to the errors caused by raster scanning and eye motion artifacts.

Figure 1:Comparison of capillary changes in a diabetic retina using different imaging modalities

A – Conventional fundus photograph (no lesions appreciated)

B – Intravenous fluorescein angiography (IVFA) showing numerous microaneurysms scattered around the macula (highlighted area indicates the region imaged with confocal AOSLO fluorescein angiography)

C – Magnified IVFA compared to the same region imaged with AOSLO in D which shows better contrast of microaneurysms (encircled). (Chui et al., 2016)

Current research to explore the characteristics of normal capillary blood flow 

As discussed above, disruptions in parafoveal capillary vascular network can happen early during diabetes, this may lead to leukocyte cell re-distribution (& stasis) and altered blood flow, eventually giving rise to damage seen as clinical cascades of DR. Before we can fully appreciate the role that altered capillary flow has in initiating the later structural and functional changes observed in DR, a clear understanding of the dynamics in capillary blood flow in normal human eyes is yet to be explored as not much is known about the heterogeneity of blood flow at these smallest capillary vessels.

To address these drawbacks, my research aims at exploring the normal behavior of capillary blood flow as a basis to understanding the altered dynamics in early DR using high resolution adaptive optics that does non-invasive imaging of the living cells. Previous work from our lab highlight the importance of improved spatial and temporal resolution in adaptive optics system that allows better visualization and quantification of red blood cells in the capillary vessels. (Bedggood & Metha, 2012).  

Figure 2: Our lab set-up at The University of Melbourne

We use a flood–illuminated adaptive optics ophthalmoscope system with a near-infrared (750 nm) imaging light to document the capillary flow around the foveal microvascular network in small patches of about 1.5° in diameter (figure 3). The blood flow is recorded at a frame rate of 200-300 frames/second for about three cardiac cycles (~3 secs), the information is then extracted into MATLAB to analyze the capillary cell flow velocities with time. By understanding the variability of patterns in blood flow in the healthy retina, we will be able to present evidence as in to what extent these parameters change contributing to an altered blood flow in early DR.

Figure 3: Fundus photograph with inset of adaptive optics imaged parafoveal capillary network montage on the left projected to a magnified view showing the arrangement of arteries, veins (bright thick segments) and intervening fine capillaries (indicated by stars) in a healthy human eye (pic courtesy: Imaging retinal cells human unit, Department of Optometry and Vision sciences, The University of Melbourne).

To summarize, advancements in retinal imaging using adaptive optics system could provide a wide scope to study and understand the cellular level hemodynamics. This understanding may offer early detection of the disease and/or possibly arrest the onset of pathologies that are triggered by altered blood flow.

If you are interested in knowing about my research or have any queries, please feel free to drop me an email at srividya.optometrist@gmail.com. 

Ms. Srividya Neriyanuri is a postgraduate (PhD) student at The University of Melbourne. She graduated from Bausch and Lomb School of Optometry in the year 2010 and worked as a clinical Optometrist at Jasti V. Ramanamma centre for children’s eye care (Department of Strabismus and Neuro-ophthalmology), LVPrasad Eye Institute (LVPEI) until 2013. During her tenure at LVPEI, she carved a niche by excelling in pediatric eye care and have presented her clinical research work in various symposiums. She holds an MPhil in Optometry (2013-2015) from the Elite school of Optometry, Chennai (& BITS, Pilani). She later worked as a research fellow at Sankara Nethralaya, Chennai (on a collaborative DR project with Anglia Ruskin University, Cambridge) before starting her PhD journey at The University of Melbourne. Srividya has selective publications on Diabetic neuropathy and X-linked Retinoschisis in national and international peer reviewed journals. Her current research interests include use of adaptive optics for imaging retinal capillary blood flow, pathogenesis of diabetic retinopathy, and genetic studies on retinal disorders. She aspires that her current and future research unveils better understandings into basic mechanisms of our retinal physiology. Apart from science being an interest, Srividya has a strong passion and respect for Indian culture and is a student of classical dance, she aims to get skillful in different dance forms and believes by the fact that art form helps an individual to evolve and find their true self.

References:

Bedggood, P., & Metha, A. (2012). Direct visualization and characterization of erythrocyte flow in human retinal capillaries. Biomed Opt Express, 3(12), 3264-3277. doi:10.1364/BOE.3.003264.

Chui, T. Y. P., Mo, S., Krawitz, B., Menon, N. R., Choudhury, N., Gan, A., Rosen, R. B. (2016). Human retinal microvascular imaging using adaptive optics scanning light ophthalmoscopy. International Journal of Retina and Vitreous(1). doi:10.1186/s40942-016-0037-8.

Keel, S., Xie, J., Foreman, J., Van Wijngaarden, P., Taylor, H. R., & Dirani, M. (2017). The prevalence of diabetic retinopathy in Australian adults with self-reported diabetes: the National Eye Health Survey. Ophthalmology, 124(7), 977-984.

Raman, R., Rani, P. K., Rachepalle, S. R., Gnanamoorthy, P., Uthra, S., Kumaramanickavel, G., & Sharma, T. (2009). Prevalence of diabetic retinopathy in India: Sankara Nethralaya diabetic retinopathy epidemiology and molecular genetics study report 2. Ophthalmology, 116(2), 311-318.

Ting, D. S. W., Cheung, G. C. M., & Wong, T. Y. (2016). Diabetic retinopathy: global prevalence, major risk factors, screening practices and public health challenges: a review. Clinical and Experimental Ophthalmology(4), 260. doi:10.1111/ceo.12696.

Yau, J. W., Rogers, S. L., Kawasaki, R., Lamoureux, E. L., Kowalski, J. W., Bek, T., Orchard, T. J. (2012). Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care, 35(3), 556-564.

 

Acknowledgements:

  1. Australian Government Research Training Program Scholarship

  2. Principal supervisor: A/ Prof Andrew Metha, Department of Optometry and Vision Sciences, The University of Melbourne

Edited by 

Mr. Vinay Nilagiri &

Ms Deepika Kommanapalli

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