in RBX-treated group). At least, even if focal/grid laser therapy for macula edema became necessary during the follow-up, the study reported a lower severe and moderate visual loss in patients receiving RBX despite of patients who had received laser but were receiving placebo.

In both these studies, RBX showed an excellent safety profile [92]: it was well tolerated by patients and only few side effects were reported, such as mild gastrointestinal symptoms.

Thus, the positive effects of oral ruboxistaurin in patients with non-proliferative diabetic retinopathy consisted in reducing vision loss and macular edema progression and needing for laser treatment while increasing the chance of visual improvement.

In an open-label extension (OLE) of PKC-DRS2 trial [93], some authors studied the effect of ruboxistaurin on visual acuity decline after a period of 6 years: at this time, over the 3-year follow-up of the placebo-controlled trial, all patients remained 1 year without any treatment and then were equally treated for 2 years with RBX. This analysis reported a reduction in the rate of severe and moderate visual loss in the patients that had a longer RBX exposure (5 years), compared to those that have received a shorter RBX therapy (only 2 years).

Ruboxistaurin was named as Arxxant (Eli Lilly) by the FDA. Nowadays some additional studies are underway and a further phase 3 trial is necessary for the FDA marketing approval.

Summary 2.4

Diabetic retinopathy is still now the most frequent cause of preventable blindness, involving patients of working age. There are many preventive and secondary interventions useful in limiting visual loss. Sure enough, data from well-conducted studies demonstrated that a slight control of blood glucose level, hypertension, and dyslipidemia could significantly delay the onset and slow the progression of NPDR.

2.4Evolving Algorithms

2.4.1Screening

The role of screening eye evaluation in the early detection of DR occurrence and progression has been clearly documented [94] (Figs. 2.25, 2.26, 2.27, and 2.28). Nevertheless nowadays almost 50 % of people with diabetes did not perform routinely dilated fundus examination and still 50 % of diabetics went blind without any treatment [95–97]. The recommendations of the American Academy of Ophthalmology (AAO), the American Diabetes Association (ADA), and the American Optometric Association (AOA) suggested an annual dilated fundus examination for all diabetic patients by an eye-care professional. Other works suggested that annual screening is an expensive procedure and that less frequent examinations (such as biennial evaluations) could provide an effective solution at lower costs [98]. Nevertheless, annual screening seemed to create less risk of noncompliance, and this practice is suggested as the diabetic patients have often any other

Fig. 2.25 FA frames of an area of peripheral retina in a diabetic patient at baseline (a), and respectively after 18 (b) and 24 (c) months. It is possible to clearly detect the progression of perfusion defects and of microvascular abnormalities

c

Fig. 2.26 Panretinal FA image of mild NPDR in a young female with a long history of poorcontrolled diabetes (a, baseline). Perivascular leakage is present in the areas of non-perfusion. (b) Panretinal FA image after 2 years shows an increasing of retinal ischemia and the progression to PDR, with the occurrence of epiretinal neovascularization (arrow). (c) In the follow-up, the OCT scan reveals a normal retinal profile, without any macular involvement

ocular comorbidities [99, 100]. Timing strategies have been proposed according to age of the patients, type of diabetes, disease duration, property of glycemic control, and the additional status of pregnancy.

In pediatric patients, the proliferative complications of DR have been reported rarely, while the most frequent findings consisted in NPDR [101]. Published data reported in several studies revealed a rate of background retinopathy in children that ranged from 4.5 % in France to 22 % in Tanzania [102–104]. Based on that information, the International Society for Pediatric and Adolescent Diabetes suggested an annual screening in diabetic children aged >11 years old with disease duration of 2 years and in >9-year-old patients with 5 years of duration of DM (Table 2.3). Other works suggested a different timing in the routine evaluation of the fundus oculi, including different ages for the initial check and, in other reports, a 2-year screening frequency [40, 105]. Thus, a regular monitoring of the biomicroscopic findings, including counseling and lifestyle education, is mandatory in the pediatric diabetics.

Adults with type 2 DM should perform the first screening examination as soon as the disease is diagnosed and a following annual control is warranted if no signs of

f

h

Fig. 2.27 Progression to PDR (e–h) with NVD (neovascularization of the disk) and NVE (neovascularization elsewhere) (black arrow, g) after 30 months in a male diabetic patient with NPDR at baseline (a–d). Despite the hemorrhages (black arrow, a), hard exudates (white arrow, a), and cotton wool spots (gray arrow, a) previously detectable in red-free image (a) regressed in the fol- low-up picture (e), the OCT horizontal scans show an increase of the edema (d, h)

DR have been identified [94]. In case of diagnosis of DR, the timing of the further follow-up could be suggested at the discretion of the ophthalmologist.

Pregnancy can lead to progression of DR. Female projecting pregnancy should perform a screening evaluation just before getting pregnant. During pregnancy, diabetic women should undergo dilated fundus examination every 3 months if the DR is absent, while in case of detection of DR, monthly controls are suggested [94]. In case of occurrence of any new symptoms, diabetic pregnant female should be examined immediately [106].

Fig. 2.28 FA photographs of posterior pole and infero-nasal sector of retinal periphery of a diabetic patient at baseline (a, b) and after 8 months (c, d), which show an increased area of ischemia in the infero-nasal sector (arrows, a, c) associated with the onset of neovascularization at the optic disk (d). A macular “grid” laser photocoagulation has been performed some years before (b, d)

Table 2.3 Frequency of screening, according to the different types of diabetes, age, duration of the disease, and possible status of pregnancy

Modified from the International Society for Pediatric and Adolescent Diabetes, the American Academy of Ophthalmology (AAO), the American Diabetes Association (ADA), and the American Optometric Association (AOA)