**3. The identification of lesions in the retinal periphery**

in diseased retinas [62–64]. Furthermore, there have already been a number of approaches to compile normative databases for retinal oximetry measurements in Caucasian [61] and multiethnic populations [65], to set a basis for comparability for future clinical trials. Age is the most important factor that should be accounted for in the interpretation of retinal oximetry measurements. Beside age and ethnicity, other demographic factors do not seem to influence retinal oximetry results markedly [61, 65, 66]. Additionally, no statistically significant difference in SO2 levels between patients with type 1 and type 2 diabetes could be observed [61]. Oxygen saturation levels in retinal vessels seem to steadily increase with progressing severity of DR, even if it is not fully elucidated if both, arterioles and venules [67, 68], or solely venules are affected by this increase [69]. Compared with healthy individuals, the change in SO2 levels only becomes statistically significant at more advanced stages of severe NPDR or PDR. Some investigators support the concept that in earlier stages of DR, increased levels of SO2 are detected in retinal venules only, which stands for a decreasing oxygen extraction in these patients, whereas in patients with PDR, SO2 levels are also increased in retinal arteri-

The metabolic results reflected by retinal oximetry also seem to correlate with the extent of

At first, the findings of increased oxygen saturation levels in patients with diabetes with or without DR seem to conflict with the traditional concept of DR being an ischemic disease. However, this observation can be explained by at least three mechanisms: (1) capillary nonperfusion and shunting (2) thickening of the basement membrane of capillary vessel walls, and (3) greater affinity of hemoglobin for oxygen [71]. Capillary non-perfusion in conjunction with the formation of shunt vessel is already known from histologic studies in the diabetic retina. In capillary shunting, while some vessels dilate, others constrict, leading to blood flow bypassing parts of the capillary network. Blood is then transported faster through these dilated preferential channels, resulting in a shortened arterio-venous passage time and therefore a reduced oxygen extraction time [72]. Further, with thickening of the capillary basement membranes, inevitably, oxygen diffusion from the blood to the retinal tissue is hindered as the transport distance increases [73]. All these mechanisms lead to a maldistribution of oxygen. Oxygen cannot be delivered to the retinal cells in these ischemic areas, which makes venular blood relatively hyperoxic and retinal tissue relatively hypoxic. As a compensatory response, oxygen demand will increase, and more blood will be directed to the tissue. Therefore, oxy-

Intraocular injections of substances inhibiting the production of vascular endothelial growth factor (VEGF), as well as laser treatment and vitrectomy are therapeutic for complications in

The vitreous cavities of patients with PDR who have undergone vitrectomy have lower oxygen tension than those who do not have diabetes [74]. Anti-VEGF injections can reduce diabetic macular edema and retinal neovascularization leading to a gain in visual acuity in patients with diabetic maculopathy and/or PDR. The introduction of this treatment modality has considerably improved the visual rehabilitation for patients with DR, but still, some

advanced DR and all of them influence retinal oxygen metabolism.

oles, resulting in unchanged levels of oxygen extraction [70].

retinal ischemia measured in FA [67].

16 Early Events in Diabetic Retinopathy and Intervention Strategies

genation in arterioles increases too [68].

Increasing evidence from research suggests that the first lesions in DR develop in the periphery of the retina and that these lesions are potentially associated with DR progression [79, 80]. The gold standard for determining the severity of DR is the extended modified Airlie House classification, which was first used in the Early Treatment Diabetic Retinopathy Study (ETDRS) in 1991 [81]. This rigorously standardized grading scale comprises 13 distinct levels, ranging from the absence of DR to the most severe manifestations of the disease localized in the central posterior 90° of the retina, representing approximately 30% of the entire retinal surface. The ETDRS grading scale is an established measure of disease activity and predictive of the risk of DR progression and visual loss over time [82]. However, due to imaging limitations, a systematic assessment of the retinal periphery was not feasible when the original ETDRS criteria were created. Therefore, the presence of pathologic features outside the 7-fields of ETDRS photography was not accounted for in this grading scale. With the advent of commercially available high-resolution ultrawide-field (UWF) scanning laser ophthalmoscopes, peripheral retinal lesions within and outside the area of the 7-standard ETDRS fields can now be evaluated [83]. Instead of 30° captured by a single ETDRS photo, these UWF imaging systems cover up to 200° in a single image, representing approximately 82% of the retinal area. Combining low-powered green (532 nm) and red (633 nm) laser light, a composite color image with a resolution of 14 μm can be acquired in just a quarter of a second. The high-resolution scanning laser ophthalmoscopy UWF technique allows improved imaging through media opacities such as cataracts, and images can even be acquired without pupillary mydriasis.

evaluated the association between peripheral retinal ischemia of UWF FA images and central ischemia in DR, and observed a moderate correlation between the peripheral ischemic index and FAZ area, as well as peripheral leakage index and FAZ area in eyes which have not been treated with laser yet [44]. Similarly, 3.9 times more non-perfusion, 1.9 times more neovascularization, and 3.8 times more panretinal photocoagulation scars could be detected in UWF FA compared with the 7-standard field ETDRS images [93]. An increase in retinal non-perfusion was associated with worsening DR [94]. As peripheral non-perfusion probably underlies the development of PPL [80], the identification of PPL may be a potential surrogate marker

Potential Imaging Biomarkers in the Development and Progression of Diabetic Retinopathy

http://dx.doi.org/10.5772/intechopen.71747

19

Current study results assessing the value of UWF FA in eyes with diabetic macular edema

Besides the paramount advantages of incorporating UWF imaging into the diagnosis and management of DR, certain limitations including low portability and the need for extensive imager training to obtain high quality images must be acknowledged [95]. UWF imaging systems are still expensive but their cost is likely to decrease over time with further technological

In summary, peripheral lesions identified in UWF imaging may substantially alter the risk of DR onset, progression and outcome. Currently a new DR severity grading scale will be established combining clinical with imaging information from UWF photographs and angiograms. A large longitudinal multicenter study sponsored by the Diabetic Retinopathy Clinical Research Network (DRCR.net) has been designed to assess the relation between baseline variables on UWF color fundus photographs and UWF FA with long-term DR outcomes [95].

Diabetic macular edema (DME) is one of the most vision-threatening manifestations of DR, affecting almost 30% of patients with a duration of diabetes mellitus of more than 20 years [96]. Elevated levels of vascular endothelial growth factor (VEGF) are a major contributor to retinal microvascular dysfunction and the development of DME. VEGF interferes with tight junctions of the vascular endothelium, leading to a breakdown of the blood retinal barrier and consequently leakage into the retinal tissue [97]. Therefore, repetitive intraocular injections of anti-VEGF agents are a first-line therapy among the currently available treatments for DME. These injections have demonstrated efficiency in reducing macular thickness and improving best-corrected visual acuity (BCVA) [98]. However, while beneficial for some patients, others do not respond to intraocular drug injections. Furthermore, the resolution of DME may not be followed by a recovery in visual function. To date, no reliable methods exist to determine which individuals with DME will or will not respond to available treatments. The implementation of predictive biomarkers would guarantee an efficient therapeutic selection to identify patients with a limited prognosis of visual recovery despite ongoing

**4. Disorganization of the retinal inner layers for diabetic macular** 

for estimating the location and extent of peripheral non-perfusion [94].

(DME) are still contradictory [28, 93, 94].

innovations and market competitions.

**edema prediction**

There are a number of examples in the literature showing that UWF imaging is comparable to conventional retinal imaging techniques for DR grading. In these studies, images were evaluated for the presence of predominantly peripheral lesions (PPLs), defined as lesions with more than 50% of the lesion located outside one of the ETDRS fields. Compared with eyes without PPL, it is estimated that eyes with PPL at baseline have a 3.2-fold increased risk of a 2-step or more DR progression and a 4.7-fold increased risk for progression to PDR over 4 years, independent of baseline DR severity and HbA1c levels [84].

Identification of DR lesions with non-mydriatic UWF imaging has been compared with standard non-mydriatic multifield fundus photography (NMFP) in large population-based DR teleophthalmology programs. Determining the risk for DR progression associated with an individual's retinal findings in imaging is fundamental in such programs for appropriate risk assessment as well as timing of screening intervals. Ungradable images generally result in referral for comprehensive eye examination because the severity of DR cannot be ascertained. The efficiency of DR teleophthalmology programs could be improved by reducing the unnecessary referrals due to ungradable images, which would lead to considerable savings in logistical complexities, travel arrangements, and time burdens for patients and the healthcare system [83]. UWF imaging can reduce the ungradable image rate by 71% and image evaluation time by 28% compared with NMFP [85]. UWF imaging additionally resulted in a more severe DR level in 9–15% of eyes [84, 86]. Non-mydriatic UWF images were shown to compare favorably with dilated ETDRS photography in determining DR severity, and discrepancies between ETDRS and UWF images were found to be mostly attributable to hemorrhages or microaneurysms [83, 87]. Silva et al. suggested that approximately one third of lesions including hemorrhages, microaneurysms, IRMA, and neovascularization were found predominantly outside the ETDRS fields, being more frequent in temporal than nasal fields [83]. Furthermore, UWF imaging substantially increases the identification of peripheral non-diabetic lesions such as lattice and other retinal degenerations, retinal tears and holes, and choroidal lesions [88]. The utility of UWF imaging has also been demonstrated in comparison with conventional slit-lamp biomicroscopy in a "real-life" clinical setting [89], and in comparison with the gold standard dilated fundus examination with scleral indentation, where Optomap showed high specificity and moderate sensitivity for lesions posterior to the equator, but low sensitivity for lesions anterior to the equator [90]. It was even proposed that assessing of UWF combined with OCT images allows more eyes with higher grades of DR to be detected than in a clinical examination alone or combined with imaging in a clinical setting [91].

The ETDRS extensively evaluated FA but did not provide evidence for a substantially improved ability to predict subsequent DR progression applying this technique. However, due to the limited field of view, traditional FA may miss major areas of peripheral capillary non-perfusion and neovascularization. The advent of UWF FA has provided the opportunity to visualize both the central and peripheral retina in a single examination [92]. Sim et al. evaluated the association between peripheral retinal ischemia of UWF FA images and central ischemia in DR, and observed a moderate correlation between the peripheral ischemic index and FAZ area, as well as peripheral leakage index and FAZ area in eyes which have not been treated with laser yet [44]. Similarly, 3.9 times more non-perfusion, 1.9 times more neovascularization, and 3.8 times more panretinal photocoagulation scars could be detected in UWF FA compared with the 7-standard field ETDRS images [93]. An increase in retinal non-perfusion was associated with worsening DR [94]. As peripheral non-perfusion probably underlies the development of PPL [80], the identification of PPL may be a potential surrogate marker for estimating the location and extent of peripheral non-perfusion [94].

high-resolution scanning laser ophthalmoscopy UWF technique allows improved imaging through media opacities such as cataracts, and images can even be acquired without pupil-

There are a number of examples in the literature showing that UWF imaging is comparable to conventional retinal imaging techniques for DR grading. In these studies, images were evaluated for the presence of predominantly peripheral lesions (PPLs), defined as lesions with more than 50% of the lesion located outside one of the ETDRS fields. Compared with eyes without PPL, it is estimated that eyes with PPL at baseline have a 3.2-fold increased risk of a 2-step or more DR progression and a 4.7-fold increased risk for progression to PDR over

Identification of DR lesions with non-mydriatic UWF imaging has been compared with standard non-mydriatic multifield fundus photography (NMFP) in large population-based DR teleophthalmology programs. Determining the risk for DR progression associated with an individual's retinal findings in imaging is fundamental in such programs for appropriate risk assessment as well as timing of screening intervals. Ungradable images generally result in referral for comprehensive eye examination because the severity of DR cannot be ascertained. The efficiency of DR teleophthalmology programs could be improved by reducing the unnecessary referrals due to ungradable images, which would lead to considerable savings in logistical complexities, travel arrangements, and time burdens for patients and the healthcare system [83]. UWF imaging can reduce the ungradable image rate by 71% and image evaluation time by 28% compared with NMFP [85]. UWF imaging additionally resulted in a more severe DR level in 9–15% of eyes [84, 86]. Non-mydriatic UWF images were shown to compare favorably with dilated ETDRS photography in determining DR severity, and discrepancies between ETDRS and UWF images were found to be mostly attributable to hemorrhages or microaneurysms [83, 87]. Silva et al. suggested that approximately one third of lesions including hemorrhages, microaneurysms, IRMA, and neovascularization were found predominantly outside the ETDRS fields, being more frequent in temporal than nasal fields [83]. Furthermore, UWF imaging substantially increases the identification of peripheral non-diabetic lesions such as lattice and other retinal degenerations, retinal tears and holes, and choroidal lesions [88]. The utility of UWF imaging has also been demonstrated in comparison with conventional slit-lamp biomicroscopy in a "real-life" clinical setting [89], and in comparison with the gold standard dilated fundus examination with scleral indentation, where Optomap showed high specificity and moderate sensitivity for lesions posterior to the equator, but low sensitivity for lesions anterior to the equator [90]. It was even proposed that assessing of UWF combined with OCT images allows more eyes with higher grades of DR to be detected than in a clinical examination alone or combined with imaging

The ETDRS extensively evaluated FA but did not provide evidence for a substantially improved ability to predict subsequent DR progression applying this technique. However, due to the limited field of view, traditional FA may miss major areas of peripheral capillary non-perfusion and neovascularization. The advent of UWF FA has provided the opportunity to visualize both the central and peripheral retina in a single examination [92]. Sim et al.

4 years, independent of baseline DR severity and HbA1c levels [84].

lary mydriasis.

18 Early Events in Diabetic Retinopathy and Intervention Strategies

in a clinical setting [91].

Current study results assessing the value of UWF FA in eyes with diabetic macular edema (DME) are still contradictory [28, 93, 94].

Besides the paramount advantages of incorporating UWF imaging into the diagnosis and management of DR, certain limitations including low portability and the need for extensive imager training to obtain high quality images must be acknowledged [95]. UWF imaging systems are still expensive but their cost is likely to decrease over time with further technological innovations and market competitions.

In summary, peripheral lesions identified in UWF imaging may substantially alter the risk of DR onset, progression and outcome. Currently a new DR severity grading scale will be established combining clinical with imaging information from UWF photographs and angiograms. A large longitudinal multicenter study sponsored by the Diabetic Retinopathy Clinical Research Network (DRCR.net) has been designed to assess the relation between baseline variables on UWF color fundus photographs and UWF FA with long-term DR outcomes [95].
