**3. Imaging and biomarkers**

**Stereoscopic examination** of the retina readily reveals signs predicting slow, limited visual response to treatment and tendency for recurrence:

Diffuse edema, ischaemic areas in the posterior pole, hard exudates close to the fovea and atrophic changes in the deep layers are often associated with **long-standing disease**. These changes persist if pharmacotherapy was provided occasionally and in long intervals.

**Previous laser treatment close to the macula** leaves chorioretinal scars that slowly progress towards the fovea, particularly if the photocoagulation spots were confluent and with high intensity.

**PDR** - active proliferative disease, signs of hypo- or nonperfusion and particularly the presence of retinal ischaemic areas in the equatorial zone and periphery indicate advanced microvascular damage and carry poor visual prognosis if left untreated. As noted in the secondary analysis of Protocol T patients, eyes with less than severe nonproliferative diabetic retinopathy (EDTRS severity levels 10 to 47) had 3.1 letters more visual acuity improvement after treatment for 2 years compared to patients with inactive advanced PDR and no prior panretinal photocoagulation [9].

**Panretinal photocoagulation (PRP)** for advanced PDR (EDTRS severity levels 61 to 75) at baseline in the same clinical trial was associated with approximately 3 letters less vision gain after 2 years [9]. This finding needs careful interpretation. Often, advanced PDR is associated with various stages of macular edema, and laser treatment that prevented the total blindness is such patients, was done years prior to the introduction of pharmacotherapy for the macular complication. On the other hand, confluent, high-intensity laser treatment applied over large areas in one or two sessions is associated with significant thermal trauma and can lead to inflammation, worsening of the macular edema, followed by atrophic changes and vision deterioration that may not respond to treatment.

Glistening, taut **epiretinal membranes** in the posterior pole with characteristic folds and retinal distortion require close monitoring - they may limit the vision gain in response to treatment, particularly in the presence of atrophic macular changes (**Figure 1**).

Anterior–posterior **vitreo-macular traction** can cause edema per se and will not respond to intravitreal treatment [10].

#### **Figure 1.**

*63 years old male, DM for 23 years, DME, PDR. a –VA decreased from 20/40 to 20/80 in two month during decompensation of CAD and CABG -epiretinal membrane, lamellar macular hole, severe recurrence of intraretinal edema with macrocysts, subsensory fluid collection; b -after 5 anti-VEGF injection –persistent intraretinaledema, resolved subsensoryfluid, VA 20/40, c* − *27 months and 9 anti-VEGF injections later – persistent intraretinal edema, hyperreflective foci, epiretinal membrane, lamellar macular hole, VA 20/40; d –persistent macrocysts, ischemic areas, hard exudates and microaneurisms.*
