*3.6.1 The classification of diabetic retinopathy (DR) and DME*

The classification of diabetic retinopathy (DR) and DME have evolved over the years. About five decades ago, experts in ophthalmology gathered in Airlie House for a symposium to review the state of knowledge of DR; an outcome from that meeting was developing a standardized classification of DR [68–70]. Afterward, this classification was modified for use by the Diabetic Retinopathy Study (DRS) [69, 70]. The modified Airlie House classification of diabetic retinopathy used in the DRS was further developed for the Early Treatment Diabetic Retinopathy Study (ETDRS). This randomized, prospective study evaluated the efficacy of laser treatment for macular edema [68]. It became the gold standard for many years. The ETDRS introduced the term clinically significant macular edema (CSME). CSME was defined using slit-lamp biomicroscopy, when it met any of the three criteria viz. "(1) thickening of the retina at or within 500 μm of the center of the macula; or (2) hard exudate at or within 500 μm of the center of the macula associated with thickening of the adjacent retina; or (3) a zone of retinal thickening one disc area or larger, any part of which is within one disc diameter of the center of the macula" [71]. After that, fluorescein angiography was used to guide laser treatment [72]. The ETDRS found that macular laser photocoagulation effectively reduced moderate visual loss by at least 50% in laser-treated eyes with CSME compared to untreated eyes [68, 70]. In 2003, an international classification called the Diabetic macular edema disease Severity Scale with greater simplicity was proposed [29, 73]. The DME disease severity scale put forward that DME is 'apparently present' when some apparent retinal thickening or hard exudates exist in the posterior pole; DME is proposed to be 'absent' otherwise [29, 70]. When DME is present, it is classified

into mild, moderate, or severe if the retinal thickening or hard exudate is distant from the center of the macula, approaching the center of the macula but not involving the center and involving the center of the macula, respectively [29, 70]. Ten years after ETDRS, Optical Coherence Tomography (OCT) became the new imaging modality that enabled ophthalmologists to utilize the qualitative and quantitative measurement of central subfield macular thickness (CSMT) and visual acuity to diagnose and determine the response of DME to treatment [29, 72]. OCT is invaluable due to its reliability and reproducibility; its importance in evaluating and monitoring DME cannot be over-emphasized [41, 74].

A classification based only on slit-lamp biomicroscopic evidence of retinal thickening is grossly insufficient to precisely describe DME and determine the appropriate therapeutic modalities for the various morphologies [72, 75].

#### *3.6.2 DME classification based on OCT*

DME classification based on OCT is described using various morphology (1) diffuse edema type (sponge-like diffuse retinal thickening), (2) cystoid macular edema (CME) type (thickening of the fovea with intraretinal cystoid change), (3) serous retinal detachment (SRD) type (thickening of the fovea with subretinal fluid) and (4) vitreomacular interface abnormalities as seen in incomplete or complete posterior vitreous detachment and epiretinal membrane (ERM) formation or vitreomacular traction or both [74–76].

Other parameters deployed by the OCT in DME diagnosis include retinal thickness, volume (quantitative data), and inner and outer layers of the retina [72, 74].

#### **3.7 Clinical presentation (symptoms and signs)**

Patients with DME may be asymptomatic if the macula center is not involved. However, some eyes having center involving DME (CI-DME) have been seen to have no visual disturbance, presumably because of the recent involvement of the center [32]. Depending on the degree of fovea involvement and the chronicity of the edema, patients may present with an array of visual symptoms [32]. These include gradual progressive diminution and distortion of central vision over some time (usually moderate, unlike the severe loss after vitreous hemorrhage or retinal detachment involving the macula in proliferative diabetic retinopathy), metamorphopsia, and loss of color vision. They may also experience poor night vision and 'washing-out of vision in bright sunlight with poor dark–light adaptation [32, 77, 78].

On dilated biomicroscopic examination, retinal thickening may be observed in commonly identified patterns. Focal edema often occurs in association with a cluster of microaneurysms, sometimes surrounded by an incomplete ring of hard exudates. Diffuse DME may be very difficult to identify clinically if the retina is uniformly thickened due to the lack of reference landmarks. Clues include the height of the retinal blood vessels over the pigment epithelium, cystoids spaces, or even loss of the foveal depression. Other features that are sometimes seen with macular edema include variable loss of retinal transparency, a significant number of microaneurysms, intraretinal hemorrhages, and dispersed areas of hard exudates [32].

#### **3.8 Evaluation of DME**

#### *3.8.1 The control of systemic metabolic abnormalities*

The control of systemic metabolic abnormalities observed in diabetes mellitus has a significant effect on the development and progression of

*Current Management of Diabetic Macular Edema DOI: http://dx.doi.org/10.5772/intechopen.100157*

diabetic microvascular complications, including DME [79]. The United Kingdom Prospective Diabetes Study (UKPDS) and the Diabetes Control and Complications Trial (DCCT) did demonstrate that optimal metabolic control could reduce the incidence and progression of DR [50, 80]. To achieve good management of a patient with DME, a multidisciplinary approach involving different medical subspecialists such as ophthalmology, endocrinology, nephrology, neurology, cardiology, orthopedics is key [29]. Systemic workup involving blood investigations helps monitor the systemic status of these patients. These investigations including fasting blood glucose (FBG), glycosylated hemoglobin levels (HbA1C), serum electrolyte, urea, creatinine, and fasting lipid profile. Other investigations that may be required would be based on systemic complaints, examination findings, and other suspected comorbidities [29]. The recommended values for HbA1c, blood pressure, and LDL cholesterol are < 6.5–7%, <130/<85 mmHg, and < 100 mg/dl, respectively [81]. However, many patients fail to achieve or maintain these levels of metabolic control. In patients who significantly reduce HbA1c, there is an associated increased risk of severe hypoglycemia [33, 50, 80]. Managing physicians must recognize correctable risk factors of DR and DME, such as hyperglycemia, hypertension, and/or hyperlipidemia, to ensure appropriate monitoring and referral for eye care.

## *3.8.2 Ophthalmic evaluation*

I. Over the last two decades, a wide range of imaging modalities, including fundus photography, fluorescein angiography (FA), optical coherence tomography (OCT), and OCT-Angiography (OCT-A), have been utilized not only for the diagnosis and classification of disease but also to monitor disease progression and treatment [82]. **Figures 1**–**5** illustrate the significance of these imaging technologies in DR and DME. DME is diagnosed clinically with the slit-lamp biomicroscopy or indirect ophthalmoscopy with features such as visible microaneurysms, hard exudates, cysts, and retinal thickening. However, stereoscopic fundus photography and fluorescein angiography have greater sensitivity in detecting DME than ophthalmoscopy because of superior optics of the former, the enhanced contrast of fluorescein angiography, ability to make confirmation of vascular leakage, and the ability of the observer to evaluate magnified images without the interference of patients moving or blinking [83].

#### **Figure 1.**

*OCT image of both eyes of a patient who suffers from DME in the left eye. The right eye shows typical retinal microstructure, while the left eye shows thickening in the foveomacula area from intraretinal cystic spaces due to diabetic macular edema. Notice that the posterior vitreous membrane is "partly" attached to the retina in both eyes.*

#### **Figure 2.**

*(a) Right eye fundus photograph, with the star shaped appearance of hard exudation, the nasal portion of which involves the fovea. There are dot hemorrhages and microaneurysms involving the temporal macula and superiorly within the superotemporal arcade. Notice the arteriovenous nipping (broken yellow arrows) suggestive of co-existing hypertensive retinopathy. There are opacities within the vitreous. (b) Left eye fundus photograph, a ring of fibrovascular tissue extends from the retina into the pre retinal space and vitreous cavity. Hard exudates, hemorrhages, and microaneurysms are present within the temporal macula beneath the fibrovascular tissue. Contraction of fibrovascular proliferative tissue creates a tractional effect on the inferotemporal arcade (broken yellow arrows).*

#### **Figure 3.**

*OCT images of both eyes as in Figure 2a and b. There is intraretinal cluster of hard exudates and intraretinal cystoid spaces, worse in the right eye (correlating with the fundus photographs). Epiretinal membrane is present in both eyes (broken yellow arrows).*

Stereoscopic fundus photographs provide an opportunity to evaluate and document long-term changes in the retina [32, 82]. The ETDRS study used the 7 standard fields (7SF) 30° photographs of the retina (three horizontally across the macula and four around the optic nerve). This combination gave nearly 75° of visualization [29]. Mydriatic or nonmydriatic fundus imaging with ≥300 mono- or stereo photography is used with or without OCT [84]. Ultra-wide-field imaging is currently used for the screening and detection of DR, as is ultra-wide-field angiography [83].

Fundus fluorescein angiography (FFA) visualizes the retinal vasculature. It identifies lesions of diabetic retinopathy, patchy areas of hypo fluorescence representing ischemia as demonstrated by capillary dropout, areas of impaired BRB function, and microaneurysms manifest as areas of hyper fluorescence demonstrated by leakage of dye and visualize expansion of the foveal avascular zone (FAZ) [59, 82].

#### **Figure 4.**

*Left eye fundus photograph showing extensive fibrovascular tissue proliferation across the macula and optic disc. There is a faint view of retinal hemorrhages in the temporal macula.*

#### **Figure 5.**

*The OCT image of the left eye fundus photograph in Figure 4. Tangential (yellow star) and vertical (yellow dotted arrow) tractional elements in the preretinal space extend into the vitreous. This thick taut hyaloid creates foveomacular traction-induced macular edema (evident as the large cystoid spaces within the macula).*

Previously FFA helped predict prognosis and response to treatment in DME [59]. A case of diffuse DME was defined by fluorescein leakage involving most of the macula. This form of DME is more challenging to treat than focal DME involving

leakage from identified lesions [85]. FFA also revealed the degree of capillary non-perfusion and macular ischemia, shown by an enlarged foveal avascular zone [59]. With the development of ultra-widefield imaging, FFA can now be performed with visualization of up to 200° of the retina. Extensive ischemia in the retinal periphery has been associated with recalcitrant disease, and the ultra-widefield FFA may help identify DME that is likely to be treatment-resistant [59]. It reveals areas of peripheral ischemia and non-perfusion, which can be promptly treated with pan-retinal laser photocoagulation. The significant advantage of FFA is that it was the only imaging modality commonly used in DR that provides information on vascular flow and vessel permeability over time by visualizing leakage and pooling [82]. The disadvantage of FFA is that it is an invasive procedure that involves the administration of intravenous dye. It should be performed carefully, especially in patients with severe DR and associated systemic vascular complications such as severe renal disease and clinical or subclinical cardiovascular disease [29, 82, 86, 87]. The most common adverse reactions are nausea and vomiting, but more severe side effects include localized reactions, urticaria, seizures, and, very rarely, anaphylaxis [29, 82]. Before performing FFA, the ophthalmologist must carefully consider whether the information provided is necessary to make therapeutic decisions and whether the same or equivalent information can be provided by OCT which is noninvasive [83].

II. Since its first introduction, OCT has become the most frequently used diagnostic tool in ophthalmology for the past two decades and has revolutionized clinical imaging for diagnosis and disease management in most retinal diseases, including DME [78, 82]. The diagnostic utility of the OCT can be seen in the case illustrated by **Figures 6** and **7**. The fast, non-invasive, high-resolution imaging available with OCT of the posterior segment allows for close study of the retinal anatomy and assessing retinal thickness profile and morphology in DME [82, 83]. A significant advantage of OCT is that it can be easily repeated several times, within the same day, with a high degree of reproducibility. Therefore, it can be used to monitor the effect of therapy, e.g., intravitreal anti-VEGF given the same day or shortly after, to detect or objectively quantify response to therapy [82, 83]. This value of the OCT to monitor treatment is illustrated with **Figures 8** and **9**.

#### **Figure 6.**

*(a and b) The left eye fundus photograph shows dot hemorrhages, microaneurysms, and few hard exudates, over the macula (a) and extending to the temporal retina (b). This is a clinical diagnosis of non-proliferative diabetic retinopathy and DME.*

#### **Figure 7.**

*OCT of fundus image in Figure 6 showing intraretinal cystoid spaces and a few hard exudates clustering around the cystoid (broken yellow arrows). Hyper reflective digitations are extending into the outer nuclear layer (broken red line).*

#### **Figure 8.**

*This is the OCT image of the same eye as in Figure 7 after intravitreal injection of Bevacizumab. Notice the reduction in intraretinal cystoid space size. The foveomacular retina is no longer thickened, as in Figure 7.*

There are three types of OCT: time-domain (TD), spectral-domain (SD), and swept-source (SS) [82]. Spectral-domain OCT is the most commonly used, allowing three-dimensional raster scans of up to a few hundred B-scans, also creating highresolution images. It supersedes time-domain (TD)-OCT, the first generation that allowed imaging of 6 radial cuts only [78, 83]. The most recent third-generation OCT technology uses a swept-source (SS) light source that allows high-speed imaging and provides three-dimensional raster images of high microstructural resolution, also referred to as optical histology [78]. OCT is highly sensitive and more accurate in

**Figure 9.**

*This serial OCT shows longitudinal follow-up of a case of recurrent macular edema, which resolves after initial treatment with intravitreal Ranibizumab. However, recurrence of edema (broken yellow arrow) occurs after an attempt at extending the injection interval from monthly to two monthly, then three monthly (treat and extend protocol). The resolution of edema (broken red arrow) occurs again after repeating intravitreal injection of Ranibizumab. The macula remains dry at subsequent visits.*

diagnosing DME when compared to fundus stereo photography and biomicroscopy [78], see **Figures 1, 3** and **5**. It is currently the gold standard for the diagnosis and monitoring of DME.

It is used to determine whether DME is center-sparing or center -involving, an essential criterion in determining treatment [78]. A limitation noted is that image segmentation could be a problem in eyes with marked DME and dome-shaped macula [88].

OCT not only identifies the presence or absence of disease activity such as the intra-retinal fluid (IRF) and the sub-retinal fluid (SRF) as seen in DME, it localizes them in the retina. It allows for quantification to assess the disease's response to anti-VEGF therapy [89], as demonstrated in **Figure 9**. It has been demonstrated that OCT using microstructural changes seen in IRF and SRF at baseline can prognosticate response to intravitreal treatments [90].

III. Certain features of retinal morphology seen on the SD-OCT, such as central subfoveal thickness (CST), vitreoretinal interface abnormalities, and the epiretinal membrane (ERM), can be used as surrogate markers and act as predictive factors for visual acuity (VA) outcomes in the treatment of DME [91–93]. CST was initially used as a predictor of visual outcome after treatment due to the ease of identifying and obtaining this parameter, but this had limitations [92]. Consequently, other aspects of OCT have been investigated to determine their usefulness as possible biomarkers and correlations for VA and treatment outcomes. These include an external limiting membrane (ELM) and ellipsoid zone (EZ) disruption, and disorganization of retinal inner layers (DRIL) [91, 92]. Sun et al. described an OCT feature termed disorganization of the inner retinal layers (DRIL) [94]. It was observed that an improvement in DRIL following treatment for DME was predictive of better VA outcomes. There was an association with VA after the resolution of centre-involving DME [95, 96]. An association between DRIL, the disruption of the outer retina, and increasing DR severity have been observed [91].

IV. The role of OCT-A is evolving as a tool in the evaluation of DME. OCT-A is an imaging technique that uses motion contrast and faster scan speeds, including spectral-domain (SD) and swept-source (SS), to obtain three-dimensional cubes, which then undergo automated segmentation into layers [82], as seen in **Figure 10**. In DME, as with FFA, OCTA can visualize the increase in the size of the fovea avascular zone (FAZ) and perifoveal intercapillary area [97], seen in **Figure 11**. It can also *Current Management of Diabetic Macular Edema DOI: http://dx.doi.org/10.5772/intechopen.100157*

#### **Figure 10.**

*A normal OCT-Angiography (OCT-A) scan of the right eye, showing the four segmented layers, including superficial and deep plexi, outer retina and the choriocapillaris layers. Also shown are the cross sectional OCT scans, highlighting the borders and planes of tissue segmentation.*

#### **Figure 11.**

*OCT-A, showing a well perfused macular and what looks like shunt vessels within the foveal avascular zone. The en face OCT images show radiating hard exudates centered on the fovea. The cross sectional OCT shows large intra retinal cystic space in the fovea, and there is aggregation of hard exudates observed within the retina (outer nuclear layer) microstructure.*

study the retinal vascular plexuses in layers, determine microvascular parameters, and correlate them with functional and morphological data [98].

The advantages of OCT-A are: It provides "3-D" imaging information of the macula and visualizes peripapillary capillaries [99]. It is dye-free, thereby suitable for patients with adverse reactions to the dyes and poor intravenous access or renal failure [100]. It is reproducible with a faster acquisition time [99, 101]. An advantage of OCT-A over conventional FA is that the absence of dye leakage using OCT-A enables visualization of the distinct margins and sizes of neovascularization since there is no leaking of dye to obscure the neovascularization complex's margins seen in the later frames of the FFA [33]. The disadvantages of OCT-A include its inability to visualize leakage of dye in the retina, a common feature of inflammatory vascular pathology, and a sign of blood-retinal barrier breakdown [100]. Limitation to detecting peripheral retinal ischemia as it can scan mostly the posterior pole [100]. Studies suggest that in the future management of DME, OCT-A could be used to prognosticate the evolution of visual acuity with the help of biomarkers such as low vascular density (VD) and enlargement of the foveal avascular zone (FAZ) [102– 104]. OCT-A could also be used to aid in the monitoring of the response of DME to anti-VEGF treatment such as Ranibizumab since poor responders show significant damage to the DCP, but not SCP [105, 106].

Initially, the major limitation of OCTA was the small field of view, with the greatest resolution achieved at smaller scanning sizes such as the commonly used 3 × 3 mm scan [33, 82]. Wider field OCTA scans are already available such as the 9 × 9 mm and 12 × 12 mm. Experimental wide-field OCTA using faster scanning OCTA is being researched and could be available in the future [102, 103, 107].

Other drawbacks noted are that OCTA is subject to projection artifacts. Vasculature from outer layers is projected onto the deep plexuses and choriocapillaris, affecting the accurate interpretation of vascular pathology in the deeper layers. It is also prone to movement artifact; patient movement presents as horizontal white lines, and artifact blinking appears as black lines across the image [83]. Solutions to artifacts include the incorporation of software to correct the motion artifacts [108].

Visual acuity is still viewed as the gold standard in clinical settings for assessing vision using the Snellen or ETDRS charts, but it does not entirely reflect functional vision [109, 110]. Functional vision depicts the impact of sight on the quality of life as expressed by the patient [109]. Various visual function disturbances such as waviness, relative scotoma, and reduction in contrast sensitivity are known to precede loss of visual acuity in patients with DME. However, they are not assessed and quantified during a routine eye examination. For assessing these abnormalities, microperimetry is used to identify vision-threatening retinopathy before visual acuity is affected. Microperimetry is a diagnostic tool used to assess retinal sensitivity while the fundus is directly examined; it enables exact topographic correlation between macular pathology and corresponding functional abnormality [109, 110]. It is rapid, safe, and non-invasive [110]. Microperimetry is of value in prognosticating the functional outcome as foveal thickness returns to normal following the treatment of DME [109]. Microperimetry has been used to demonstrate low retinal sensitivity present in the areas of capillary drop out in eyes with ischemic DME [111].

Multifocal electroretinogram is an electrophysiologic test. It is used to objectively identify functional changes of the retina in the early phases of DR and DME [112] and is also helpful for objectively monitoring eyes on intravitreal antiVEGF treatment such as Ranibizumab for DME [113].
