The Opthalmoscope a Monthly Review of Current Opthalmology 1904
J Ophthalmol. 2017; 2017: 8234186.
Update on Diagnosis and Treatment of Diabetic Retinopathy: A Consensus Guideline of the Working Grouping of Ocular Health (Spanish Society of Diabetes and Spanish Vitreous and Retina Society)
Borja Corcóstegui
iSpanish Retina and Vitreous Club (SERV), IMO (Institut Microcirurgia Ocular), Barcelona, Espana
Santiago Durán
2Spanish Guild of Diabetes (SED), Endocrinology Department, Valme University Infirmary and RAMSE Foundation, Sevilla, Spain
María Olga González-Albarrán
2Spanish Gild of Diabetes (SED), Endocrinology Department, Valme Academy Hospital and RAMSE Foundation, Sevilla, Espana
threeSpanish Society of Diabetes (SED), Endocrinology and Nutrition Department, Infirmary General Universitario Gregorio Marañón, Madrid, Espana
Cristina Hernández
ivSpanish Society of Diabetes (SED), Diabetes and Metabolism Research Unit and CIBERDEM (ISCIII), Vall d'Hebron Reseach Constitute (VHIR), Barcelona, Espana
José María Ruiz-Moreno
fiveSpanish Retina and Vitreous Society (SERV), Department of Ophthalmology, Castilla La Mancha University, Albacete, Spain
6University Hospital Puerta de Hierro-Majadahonda, Madrid, Spain
Javier Salvador
7Castilian Order of Diabetes (SED), Department of Endocrinology and Nutrition, Academy Clinic of Navarra, Pamplona, Spain
Patricia Udaondo
eightCastilian Retina and Vitreous Club (SERV), Section of Ophthalmology, Nuevo Infirmary Univeristario y Politécnico La Fe, Valencia, Spain
Rafael Simó
4Spanish Society of Diabetes (SED), Diabetes and Metabolism Inquiry Unit and CIBERDEM (ISCIII), Vall d'Hebron Reseach Establish (VHIR), Barcelona, Spain
Received 2016 Dec 30; Revised 2017 Apr twenty; Accustomed 2017 May 23.
Abstract
A group of members of the Spanish Retina and Vitreous Lodge (SERV) and of the Working Group of Ocular Health of the Spanish Society of Diabetes (SED) updated knowledge regarding the diagnosis and handling of diabetic retinopathy (DR) based on recent evidence reported in the literature. A synthesis of this consensus forms the basis of the nowadays review, which is intended to inform clinicians on current advances in the field of DR and their clinical applicability to patients with this disease. Aspects presented in this commodity include screening procedures of DR, new technologies in the early diagnosis of DR, control of hazard factors in the unlike stages of the disease, indications of panretinal laser photocoagulation, efficacy of intravitreal antiangiogenic agents and steroids, and surgical options for treating DR-related complications. Practical information regarding periodicity of screening procedures in patients with type 1 and type 2 diabetes, ophthalmological controls according to the stage of retinopathy and complications, and criteria and caste of urgency for referral of a DR patient to the ophthalmologist are also presented.
1. Introduction
According to the International Federation of Diabetes (IFD), there volition be 642 million people with diabetes in the world in 2040, with a foreseeable dramatic brunt of the illness, particularly worrisome in the most extreme population segments, that is, the immature people and the elderly subjects [1]. These alarming information accept an even greater impact on the possible furnishings of the numerous complications resulting from diabetes. From a traditional perspective, chronic complications of diabetes take been classified into microangiopathic or diabetes-specific (retinopathy, nephropathy, and neuropathy) and macroangiopathic frequently regarded every bit equivalent to atheromatosis. The three microvascular complications of diabetes show a complex interrelationship [2]. Also, microvascular and macrovascular complications frequently coexist [3].
The causative role of hyperglycemia in the development of complications is well established. Classical studies, such every bit the Diabetes Control and Complications Trial (DCCT) [4] and the United Kingdom Diabetes Study (UKPDS) [5] showed that early strict glycemic command, both in type 1 and type 2 diabetes, tin can delay the onset and progression of microvascular complications. Still, in addition to hyperglycemia, other factors, such as hypertension, dyslipidemia, hemorrheologic changes, and peculiarly the genetic load, take a remarkable influence on the severity and clinical course of diabetic retinopathy (DR).
In this newspaper, a console of members of the Working Group of Ocular Health, which consists of expert members belonging to the Spanish Retina and Vitreous Social club (BC, JMRM, and PU) and the Spanish Club of Diabetes (SD, MOGA, CR, JS, and RS) summarized the main conclusions of a workshop aimed at creating a consensus regarding the pathophysiology, diagnosis, and treatment of diabetic retinopathy (DR) based on recent evidence reported in the literature.
1.ane. Pathophysiology of DR and Diabetic Macular Edema
DR is the virtually frequent microvascular complication, the prevalence of which increases with the duration of diabetes, with an overall rate of upward to 30% and a high chance of severe visual impairment in 10% of subjects [6]. Diabetic macular edema (DME) is more frequent in blazon 2 diabetes, occurs in approximately 7.5% of diabetic patients, and is the principal cause of blindness in working-historic period adults in industrialized countries [7].
Elevated claret glucose levels per se and the metabolic pathways directly related to hyperglycemia, such as the polyol and hexosamine pathways, activation of the diacylglycerol-protein kinase C pathway, and accumulation of advanced glycation end products, are involved in the pathophysiology of DR [8]. Inflammation, alteration of retinal blood flow autoregulation, and hemorrheological factors also play an of import function in the pathogenesis of DR [8]. Thickening of the basement membrane, pericyte loss, and disruption of interendothelial tight junctions are characteristic pathophysiological mechanisms in early on stages of DR. Microaneurysm germination and fluid extravasation from the intravascular to the interstitial space can pb to retinal thickening and hard exudates [8]. This commencement phase is chosen nonproliferative diabetic retinopathy (NPDR), or the so-chosen groundwork DR (Figure 1).
Nonproliferative diabetic retinopathy showing microaneurysms, microhemorrhages, and hard exudates.
Loss of the capillary endothelium, thrombus formation, retinal leukostasis, and complete occlusion of the capillary lumen announced at later stages of the affliction. Cotton wool-wool spots or soft exudates, reflecting infarct zones and intraretinal microcirculatory alterations, are hallmark features of preproliferative DR [9] (Figure 2).
Proliferative diabetic retinopathy showing the presence of neovascularization.
Basement membrane digestion by proteolytic enzymes is essential for angiogenesis (neovascularization). Degradation products and hypoxia are strong activators of angiogenesis. Hypoxia promotes vessel growth by upregulating multiple proangiogenic pathways, peculiarly the vascular endothelial growth cistron (VEGF), which plays a pivotal function in the development of pathologic angiogenesis [x]. This stage known equally proliferative retinopathy (PDR) is characterized past growth of new vessels (Figure 3). The new vessels attached to the posterior hyaloid become fibrotic and may cause tractional retinal detachment. Vitreous hemorrhage may upshot from fragility and bleeding of neovascular vessels [9].
Proliferative diabetic retinopathy and tractional retinal detachment caused past fibrovascular tissue.
Rupture of the inner or the outer claret retinal barriers leading to extravasation of the intravascular content and increased intravascular colloid osmotic pressure are early events in the pathogenesis of diabetic macular edema (DME). Proinflammatory cytokines and VEGF are involved in the breakdown of blood-retinal bulwark [11].
In that location is growing evidence suggesting that retinal neurodegeneration is an early event in the pathogenesis of DR, which participates in the development of microvascular abnormalities [12]. This progressive degenerative process is characterized by neural apoptosis and reactive gliosis. Retinal neurodegeneration causes functional alterations, such as loss of colour bigotry and reduced contrast sensitivity. Electrophysiological evaluation is the most sensitive method for detecting neurodegeneration. It is worth mentioning that electrophysiological abnormalities can appear fifty-fifty before that whatsoever impairment can be detected in the fundoscopic examination. Also, treatment based on neuroprotection opens upwards a new approach for preventing or arresting DR development [13].
1.2. Nomenclature
Definitions used in the Early Treatment Diabetic Retinopathy Study (ETDRS) [xiv, fifteen] accept provided uniform criteria for the terminology and classification of DR and DME, which have been included in the 2016 preferred do pattern guidelines for DR issued by the American University of Ophthalmology [16]. DR is classified into two basic stages: NPDR and PDR. NPDR is divided into mild, moderate, and severe co-ordinate to affliction severity level. DME is defined equally apparently absent-minded and apparently nowadays. It is important to remember that visual acuity (VA) is not included in the definition of DME. Clinically significant DME is nowadays when the post-obit 3 criteria are met: retinal thickening at or within 500μthou of the center of the macula; difficult exudates at or within 500μm of the center of the macula, if associated with thickening of the adjacent retina; and/or a zone (or zones) of retinal thickening one disc surface area in size at least office of which is within one disc diameter of the center [sixteen]. According to the morphology of the macula on Oct, DME is divided into three groups: spongiform, cystoid, and neuroepithelial retinal detachment (Figure 4). Fundus fluorescein angiography identifies focal (or multifocal), diffuse, ischemic, and mixed DME.
Diabetic macular edema (DME). (a) We can detect the presence of DME with intraretinal cysts. (b) Autonomously from cysts, neuroretinal detachment can be noticed (SS-October images).
In recent years, OCT has revolutionized the diagnoses and monitoring of DME, thus facilitating its management (see Department 2.iii).
2. Prevention of DR
2.ane. Hazard Factors
Duration of diabetes, poor control of blood glucose, and hypertension are major risk factors for rapid progression of RD [8]. A rapid lowering of blood glucose levels [17, 18] and hypoglycemia [19] may aggravate preproliferative DR and precipitate vitreous hemorrhage in patients with PDR. Insulin-dependent blazon one diabetes is associated with a higher risk of DR and severe forms (PDR) as compared with type 2 diabetes. The percentages of DR may vary from 85% for insulin-dependent patients to 58% for non-insulin-dependent patients for more than xv years after diagnosis [20]. Dyslipidemia [21], puberty [22], pregnancy [23], diabetic nephropathy [24, 25], and obesity [26] take also been reported equally risk factors for DR.
Tight metabolic control, command of gamble factors, and shut monitorization of progression of preexisting DR are indispensable measures to maximally prevent vision loss. A recommended approach for the control of patients with RD is shown in Table 1.
Table 1
Recommended strategy for the control of DR taking into account the feel of the physician in performing funduscopic examinations and clinical status and comorbidities of diabetic patients.
| Recommended action |
| (i) The doctor (eastward.yard., general practitioner) has experience in fundus test: systematic fundus test to all diabetic patients at each consultation, with referral to the ophthalmologist once a year. |
| (2) The doctor has no experience in fundus test: referral to diabetic patients to the ophthalmologist afterwards 5 years of diagnosis in type i diabetes and immediately after diagnosis in type 2 diabetes. |
| (iii) Increased controls in patients at take chances: hypertension, proteinuria, dyslipidemia, and pregnancy. |
| (4) Metabolic control of diabetes every bit strict equally possible. |
| (5) Treatment of associated high blood pressure level. |
| (vi) Healthy lifestyle, diet, and physical exercise. |
| (vii) Avoid tobacco and alcohol. |
2.2. Screening for DR
Early diagnosis of DR is the best strategy to foreclose or filibuster loss of vision. Although regular fundus exam is widely recommended in screening protocols for early treatment of retinal lesions prior to the appearance of visual difficulties, dissimilar studies take shown that, in daily practice, only a small percentage of diabetic subjects underwent fundus exam with the recommended periodicity [27]. Directly ophthalmoscopy requires pupillary dilation and skills for the process. Even so, general practitioners tin can screen for DR with a loftier level of accurateness using nonmydriatic retinography. This cost-effective diagnostic tool is used to obtain digital photographs of the retina (retinographies), which can exist stored in the reckoner and efficiently send by the family unit physician to the ophthalmologist for assessment. Although full general practitioners should play a pivotal role in the screening of DR, this will depend on their skillfulness in performing fundus examination (Table 1), as well as the availability of nonmydriatic retinal cameras.
Different studies have shown that the frequency of screening tests can be modified according to the stage of DR. In a dynamic cohort study of 20,686 people with type 2 diabetes who had annual retinal photography upwardly to fourteen times between 1990 and 2006, after 5 years of follow-up, few patients without retinopathy at baseline developed preproliferative retinopathy or sight-threatening maculopathy, whereas patients with NPDR at baseline were 5 times more likely to develop preproliferative, PDR, or maculopathy [28]. Screening intervals at 2 years may be appropriate for subjects without DR at the initial screening examination. Other studies have also shown that the strategy of biannual screening is safe and cost-constructive for subjects who have not developed DR [29, 30].
The periodicity of screening for DR is summarized in Table two. In type 1 diabetes, beginning of screening is recommended afterward five years of diagnosis and in people older than 15 years. Subjects with type two diabetes should start screening immediately after diagnosis and earlier the end of the first trimester in pregnant women with diabetes. The periodicity of screening is recommended annually except for type 2 diabetes without signs of DR with adequate metabolic command and brusk duration of the illness.
Table 2
Recommended periodicity of screening procedures for DR.
| Recommendation | Type of diabetes | Action |
|---|---|---|
| Starting screening | Type 1 | (i) 5 years later diagnosis |
| (2) In people older than 15 years of age | ||
| Type ii | (i) At the fourth dimension of diagnosis | |
| Pregnancy in a diabetic woman | (i) Earlier the end of the first trimester of gestation | |
| | ||
| Periodicity of screening | Type ane | (i) Annual |
| Type two without signs of DR, adequate metabolic command, and brusque duration of the affliction | (i) Every 2 years | |
| Blazon 2 without signs of DR, poor metabolic command or >10 years since diagnosis | (i) Every year | |
| Blazon 2 diabetes and mild NPDR | (i) Every yr | |
Recommendations of ophthalmological examinations in patients with DR according to complications and stages of DR are shown in Table 3. In patients with the presence of central-involved DME (CIDME), or edema affecting the ane mm in bore retinal central subfield, intravitreous therapy with a careful follow-up every 1–four months is recommended. When non-CIDME is present, controls should be scheduled every 6 months in mild NPDR and every 3-four in moderate and severe NPDR. In the absence of DME, patients should be visited annually when NPDR is mild, every 6–12 months if NPDR is moderate, and every 6 months if NPDR is severe. Patients with PDR should exist controlled at 3-month intervals. Apart from ophthalmological examinations, a tight control of blood glucose levels, claret pressure, and serum lipids are recommended.
Table 3
Recommended ophthalmological controls∗ in patients with DR according to stage and complications.
| DR stage | Control periodicity |
|---|---|
| Nonproliferative diabetic retinopathy (NPDR) | |
| Mild | |
| Diabetic macular edema (DME) | |
| Nowadays | |
| (i) Non-CIDME | Every 6 months |
| (two) CIDME | Every 1–iv months∗∗ |
| Absent | Every 12 months |
| Moderate | |
| Diabetic macular edema (DME) | |
| Nowadays | |
| (i) Not-CIDME | Every 3-4 months |
| (ii) CIDME | Every 1–4 months∗∗ |
| Absent-minded | Every half dozen–12 months |
| Severe | |
| Diabetic macular edema (DME) | |
| Present | |
| (i) Not-CIDME | Every 3-4 months |
| (ii) CIDME | Every 1–4 months∗∗ |
| Absent-minded | Every 6 months |
| Proliferative diabetes retinopathy (PDR) | Every iii months |
The criteria adopted by the panel for either full general screening follow-up of patients in whom DR was already diagnosed are similar to other guidelines such every bit the recently reported position statement of the American Diabetes Association [31].
Finally, criteria and level of urgency according to ophthalmologic findings for referral of patients with DR to the ophthalmologist are detailed in Table iv.
Table 4
Criteria and degree of urgency for referral of a patient with DR to the ophthalmologist.
| Lesions requiring immediate assessment past the ophthalmologist | Proliferative retinopathy | (i) New vessels on the optic disc or at any location in the retina |
| (ii) Preretinal hemorrhage | ||
| Advanced diabetic retinopathy | (i) Vitreous hemorrhage | |
| (two) Fibrotic tissue (epiretinal membrane) | ||
| (iii) Recent retinal detachment | ||
| (iv) Iris neovascularization | ||
| | ||
| Lesions that should be referred to the ophthalmologist for assessment as soon every bit possible | Preproliferative retinopathy | (i) Venous irregularities |
| (ii) Multiple hemorrhages | ||
| (iii) Multiple cotton-wool exudates | ||
| (iv) Intraretinal microvascular abnormalities (IRMA) | ||
| Nonproliferative retinopathy with macular involvement | (i) Decreased visual vigil uncorrected with a pinhole occluder (suggestive of macular edema) | |
| (ii) Microaneurysms, hemorrhages, or exudates within less than one disc bore of the centre of the macula (with or without vision loss) | ||
| Nonproliferative retinopathy without macular interest | (i) Hard exudates with a circinate or plaque pattern in the major temporal vascular arcades | |
| Any other finding that the observer could non exist interpreted with a reasonable degree of certainty | ||
| | ||
| Lesions requiring follow-up control (every vi–12 months) just should not exist referred to the ophthalmologist | Nonproliferative retinopathy | (i) Hemorrhages or microaneurysms occasionally or hard exudates beyond i disc diameter of the centre of the macula |
| (ii) Isolated cotton wool-wool exudates without preproliferative associated lesions | ||
2.3. Early Diagnosis of DR
Ophthalmoscopy with or without the pupil dilated is the standard procedure in the screening for DR, in which detection of microaneurysms in the posterior pole is the primeval clinical sign [32, 33]. Fluorescein angiography is an invasive, costly, and time-consuming technique merely is a sensitive method to detect vascular changes due to rupture of the inner and outer claret retinal barrier in the course of an established DR [34]. In contrast to retinography or fluorescein angiograms, October provides high-resolution images of the retinal layers, choroid, vitreous gel, and the vitreoretinal interface and has become the gold standard for the diagnosis, treatment approach, prognosis, assessment of handling response, and command of patients with DME (Figure 5). Because of the advantages of the speed and ease of prototype conquering as compared to other examinations, the association of October to retinography may increase the sensitivity of early diagnosis/screening in the diabetic patient.
OCT in good for you patient showing in high resolution the different structures: choroid, retina layers, and vitreous gel.
Oct angiography (OCTA) is a new noninvasive imaging technique that employs movement dissimilarity imaging to loftier-resolution volumetric blood flow information generating images similar to angiographic images in a matter of seconds [35, 36]. Information technology provides a highly detailed view of the retinal vasculature, which allows for accurate delineation of the foveal avascular zone (FAZ) and detection of subtle microvascular abnormalities, including FAZ enlargement, areas of capillary nonperfusion, and intraretinal cystic spaces [37]. The possibility of detecting microvascular changes in diabetic eyes before the presence of visible microaneurysms may have important implications in the future. Equally OCTA is fast and noninvasive, it can provide a sensitive method for detecting early changes in DR, constituting a very promising technique for early diagnosis and control of treatment in patients with DR [38–xl]. In this sense, OCTA could be able to speedily place diabetic individuals at take a chance for developing retinopathy, which in turn would require more frequent examinations and a higher optimization of metabolic command.
three. Treatment of DR
3.one. Control of Adventure Factors in Different Stages of DR
Numerous studies have confirmed the relationship between glycemic command and DR likewise as the efficacy of reduction of glycated hemoglobin (HbA1c) in the appearance and progression of DR. In patients with type ii diabetes, the risk of diabetic complications is strongly associated with the degree of metabolic control. Each 1% reduction in HbA1c reduces whatsoever endpoint related to diabetes past 21% [41]. There is level 1 prove (grade A recommendation) for intensive glycemic control for reducing the progression of DR [42, 43]. In the DCCT written report of patients with type ane diabetes, intensive therapy to maintain normal glucose claret levels and HbA1c < vi.v% reduced the risk for the evolution of retinopathy by 76% and the progression of retinopathy by 54% [4]. In patients with type 2 diabetes, results of the UKPDS report were similar [5]. In add-on, this written report showed that tight command of blood pressure level was associated with a risk reduction of 34% in the proportion of patients with deterioration of retinopathy and 47% with deterioration in VA by three lines of ETDRS nautical chart [44]. Also, in hypertensive patients with diabetes, a decrease in systolic blood pressure of x mmHg was associated with 35% reduction of the risk of progression of DR, 35% of the need of retinal photocoagulation, and a twofold reduction of the risk of vision loss. However, a very strict control of blood pressure level (systolic claret pressure < 120 mmHg) did non show additional benefits [45].
The show regarding control of dyslipidemia and its effect on progression of DR is less than solid [46, 47]. However, the employ of fenofibrate as a specific treatment for dyslipidemia has been associated with a reduction of the risk of progression of DR in clinical trials [48, 49]. Therefore, fenofibrate may have a relevant role in the prevention of DR in clan with intensive treatment of traditional risk factors, such every bit hyperglycemia and hypertension [l, 51]. In improver to the lipid-modifying activeness, fenofibrate has as well numerous pleiotropic effects, which seem to accept a more relevant role than the lipidic mechanisms in its beneficial effects on DR and DME [52].
In patients with DME, besides the control of chance factors identified for DR, a complete study of the renal office is recommended because of the well-established relationship between subclinical diabetic nephropathy (microalbuminuria/albuminuria) and the risk of DME [53].
A multidisciplinary arroyo including treatment of risk factors, particularly metabolic control and reduction of blood pressure, too as the implementation of an acceptable screening plan seems the most effective intervention to preclude DR or to human action on the early stages of retinopathy when AV is even so unaffected.
3.2. Current Indications of Laser Photocoagulation
Once DR has been diagnosed, ophthalmological treatment with laser photocoagulation is specially directed to treat ii cardinal complications: retinal neovascularization and severe or clinically significant macular edema [31, 54].
Panretinal laser photocoagulation can be performed in a unmarried or various sessions (availability of the laser equipment, severity of the retinopathy, patient's full general condition, travel distance for treatment, etc.). In patients with regression of new vessels within the first three months of photocoagulation, the visual prognosis is usually excellent.
Handling with panretinal photocoagulation is not indicated in mild and moderate NPDR [xvi] because the risk of progression to proliferative stages is very low. In patients with severe NPDR, the use of laser photocoagulation should be cautiously evaluated. It may exist indicated in the presence of intraretinal signs suggestive of the evolution of PDR, such every bit venous beading, intraretinal microvascular abnormalities (IRMA), and an increasing number of microaneurysms and hemorrhages. On the other hand, early on panretinal photocoagulation should be considered in those patients at a higher adventure of progression, including patients with long-standing diabetes and poor metabolic control, presence of hypertension or advanced renal disease, noncompliance with scheduled visits, PDR in the fellow center, cataracts with significant visual impairment limiting light amplification by stimulated emission of radiation photocoagulation in the future, prior to cataract surgery, pregnancy or intention to become meaning, and detection of generalized ischemic areas in the angiogram. In addition, laser treatment should exist considered as an adjunctive therapy in eyes with persistent primal-involved DME despite anti-VEGF therapy [31].
It is important to explicate to the patient the following points: (a) panretinal photocoagulation can terminate the progression of PDR, but not in all cases; (b) the adventure of bleeding persists later on treatment because the regression of neovascularization is slow; and (c) panretinal photocoagulation may produce a moderate decrease in vision, visual field or dark-adapted threshold, but the benefit far outweighs the side effects.
3.three. Current Treatment of DME: Role of Intravitreal Antiangiogenic Agents and Steroids
Intravitreal therapies with anti-VEGF agents, especially aflibercept, ranibizumab, and bevacizumab, accept substantially improved the prognosis of potentially severe ocular diseases, including DME. A recent study on the guidance for the management of DME has been recently published past the European Club of Retina Specialists [55].
Anti-VEGF handling has superseded macular laser treatment and is now the first-line therapy for DME involving the central macula [56, 57]. Level 1 evidence from large, multicenter clinical trials has established the benign upshot of anti-VEGF agents in patients with DME [49–55]. Intravitreal anti-VEFG handling was associated with sustained EDTRS letter gains of best-corrected visual acuity (BCVA) and reduction of central retinal subfield thickness on OCT as compared to command groups (sham injections or laser photocoagulation) [58–64]. Handling regimens subsequently an initial load of intravitreal injections depend on each drug, but in the case of aflibercept, a regimen of 2 mg every viii weeks (later on five monthly doses) is a therapeutic option that tin can reduce substantially the number of intravitreal injections and visits and, consequently, the workload in ophthalmology do [65]. In addition, there is a lower cost associated with fewer intravitreal injections. Also, up to ane-3rd of eyes treated with aflibercept achieved a regression equal or greater than 2 steps in EDTRS score of the diabetic retinopathy severity scale (Diabetic Retinopathy Severity Score (DRSS)) at calendar week 100, which should be considered not only a great achievement from a functional perspective but also a differential characteristic as compared to the remaining anti-VEGF drugs [62].
The DRCR.net Protocol T study [66] compared aflibercept, ranibizumab, and bevacizumab. The loading stage and subsequent flexible retreatment stage regimen were the same for all iii study drugs. The interim results after 1 year showed a mean gain that was +2.one letters college for aflibercept 2 mg than for ranibizumab 0.iii mg (the approved dose in the US; 0.five mg is the approved dose in Europe) (p = 0.03). Patients were monitored as often as every 4 weeks. A subgroup assay showed that the superior outcome of aflibercept was driven by the study participants with poorer baseline BCVA (<69 messages). Of a maximum possible number of injections of thirteen in the commencement yr, the aflibercept arm received a median of 9 injections; the bevacizumab and ranibizumab arms received a median of 10 injections. Intravitreal bevacizumab was junior to both aflibercept and ranibizumab in virtually comparisons. Serious agin result rates were comparable between study arms. The two-twelvemonth results [67] of the Protocol T study slightly changed this scenario. The departure in BCVA gain between aflibercept and ranibizumab for optics with poorer baseline BCVA that was noted at i year decreased at 2 years. Nevertheless, the first-twelvemonth beliefs and the slightly better mean BCVA gain confirmed the superiority of aflibercept over ranibizumab in patients with poorer baseline BCVA when considering the expanse nether the curve. Information technology remains unclear if the 0.v mg dose that is approved in Europe would have led to dissimilar results in the first year of Protocol T in favor of ranibizumab 0.v mg.
It is worth mentioning that in the classical study of Aiello et al. [68] more half of patients with PDR did not bear witness increased VEGF levels in the vitreous fluid, which may explain why approximately 50% of patients with DME do non reply to anti-VEGF treatment. In this subgroup of patients, proinflammatory cytokines probably play a more than relevant pathogenic office and intravitreal steroid injections may be a more plausible therapeutic choice.
With regard to intravitreal steroids, there is level one evidence that intravitreal triamcinolone is inferior to laser treatment at 3-year follow-up [69]. Sustained corticosteroid delivery systems such as the dexamethasone delivery system (DDS) and the fluocinolone acetonide insert have both been canonical for the treatment of DME. The DDS was originally approved for use in presudophakic eyes or phakic eyes scheduled to undergo cataract removal, simply approval for the use in phakic optics followed inside months. Unfortunately, neither drug has been directly compared to anti-VEGF therapy in prospective, masked, randomized, multicenter trials. Visual acuity improvements for these sustained commitment systems average + 7 letters [70, 71], generally less than +eight to +12, achieved with anti-VEGF therapy [72]. The high rate of increased intraocular pressure level (IOP) and cataract needs to exist considered when using intravitreal steroid preparations. For these reasons, intraocular corticosteroids may be constructive second-line therapy but are usually not used as first-line therapy. Nonetheless, intravitral corticosteroids may be suitable for pseudophakic patients and in particular when chronic DME exists [69, 72, 73].
3.4. Intravitreal Antiangiogenic Agents for PDR Handling
The Diabetic Retinopathy Clinical Research Network (DRCR.net) recently published the two-yr results of Protocol S, which was designed as a noninferiority written report to compare panretinal photocoagulation (PRP) and intravitreal ranibizumab (Lucentis, Genentech) for patients with high-risk PDR. Protocol S randomized eyes to receive one to three sessions of PRP treatment (203 eyes) or ranibizumab 0.5 mg intravitreal injection at baseline and then every four weeks (191 optics). A structured retreatment protocol determined repeat injections based on SD-October and clinical findings. It is worth mentioning that eyes with DME received ranibizumab in both groups. The primary findings were that vision outcomes and surgery rates were not junior in the injection group. At 2 years, visual acuity improved by ii.viii messages from baseline in the ranibizumab group compared with an improvement of 0.2 messages from baseline in the PRP group, with a mean difference of two.2 letters betwixt treatment groups (p < 0.001) [74].
The costs of PRP versus intravitreal ranibizumab for PDR have recently been evaluated. PRP compared with intravitreal ranibizumab as primary treatment for PDR is less expensive over 2 years, but both autumn well below the accustomed cost per QALY upper limit [75].
Overall, these results back up the intravitreal injections of ranibizumab as a possible alternative treatment for PDR.
3.v. Surgical Treatment of RD-Related Complications
Main indications of vitrectomy in patients with DR include tractional retinal detachment, tractional macular edema, and vitreous hemorrhage [76, 77].
Vitreous hemorrhage is one of the most frequent complications of DR. Surgical treatment is indicated for patients with DR without previous laser photocoagulation. If a previous panretinal photocoagulation has been performed, a waiting time of 3 months for reabsorption of the hemorrhage can be established, only surgery is indicated in the presence of unresolved bleeding after this interval [76, 77]. The surgical technique is usually a posterior pars plana vitrectomy with 3-port sclerotomy arrangement of 23 or 25 approximate. Endo-ocular laser during surgery can be applied. Information technology is important to remove membranes or fibrovascular tissue that may cause retinal traction and subsequent retinal disengagement. Staining of the vitreous with triamcinolone helps surgeons to reach a complete removal of the vitreous from the retina, besides acting as anti-inflammatory agent at the end of the procedure.
Pars plana vitrectomy is likewise the surgical selection in diabetic patients with tractional retinal detachment. Technical details regarding triamcinolone injection, application of perfluorocarbon liquid, endo-ocular panretinal photocoagulation, or preoperative or perioperative anti-VEGF handling depend on the surgeon'due south criteria according to individual characteristics of the patient [76, 77].
Surgical handling of neovascular glaucoma would be indicated in the presence of new vessels and no decrease of IOP after extensive panretinal photocoagulation or intravitreal handling with anti-VEGF drugs. Glaucoma surgery involves aqueous humor bleed using different valve devices [76, 77].
Complications of vitrectomy include new hemorrhages, cataract (peculiarly in patients over fifty–55 years, which justifies combined cataract surgery and vitrectomy), and other complications as in any endo-ocular surgery such every bit retinal detachment and endophtalmitis [74, 75].
4. Concluding Remarks
DR is i of the nearly common microvascular complications of diabetes with the potential to cause severe vision loss and blindness and a devastating effect on quality of life. Despite a solid trunk of evidence regarding the importance of strict metabolic control and treatment of associated risk factors especially hypertension, failure to maintain target HbA1c levels is a major contributing cause of development and progression of DR. Screening protocols using mydriatic and, preferable, nonmydriatic retinography should be implemented in the primary care setting. Family physicians should take adequate cognition of the different stages of DR and the current international classification systems of DR and DME to follow recommendations for acceptable screening schedules and referral, including urgency of referral to the specialized ophthalmologist. Panretinal photocoagulation should be used to treat ii key complications of DR: retinal neovascularization and macular edema. Laser photocoagulation is non indicated in mild and moderate NPDR but it may exist indicated in the presence of suggestive signs of development of PDR. Anti-VEGF handling is now the first-line therapy for DME involving the central macula. Aflibercept, ranibizumab, and bevacizumab are effective antiangiogenic agents, but aflibercept is probably the well-nigh price-constructive option, with a lower cost associated with fewer intravitreal injections needed and a reduced workload in daily do.
Fluocinolone slow release implant is constructive in DME and is a promising culling due to the reduced frequency of treatment required, just long-term follow-up information is still lacking. Patients with tractional retinal detachment, tractional macular edema, and vitreous hemorrhage are candidates for vitrectomy. In the presence of new vessels and no subtract of intraocular pressure after all-encompassing panretinal photocoagulation or intravitreal anti-VEGF therapy, surgical treatment of neovascular glaucoma should be considered.
Finally, a fluent and robust communication between the diabetologists and the retinologists seems crucial for absorbing the progression of this devastating complexity of diabetes.
Acknowledgments
Thanks are due to Marta Pulido, Dr., for editing the paper and for the editorial assistance.
Conflicts of Involvement
The authors declare that there is no conflict of interests regarding the publication of this paper.
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