Diabetes mellitus: diabetic retinopathy, diabetic macular edema: clinical guidelines

List of Abbreviations

BP — blood pressure

HIV — human immunodeficiency virus

WHO — World Health Organization

CS — corticosteroids

OD — optic disc

DME — diabetic macular edema

DR — diabetic retinopathy

IRMA — intraretinal microvascular abnormalities

ELISA — enzyme-linked immunosorbent assay

ICD-10 — International Classification of Diseases, 10th Revision

NPDR — non-proliferative diabetic retinopathy

OCT — optical coherence tomography — optical examination of the retina using a computer analyzer

OCT-A — optical coherence tomography angiography — optical examination of the retina using a computer analyzer in angiography mode

PPDR — pre-proliferative diabetic retinopathy

PDR — proliferative diabetic retinopathy

PRLP — panretinal laser photocoagulation

PCR — polymerase chain reaction

RNA — ribonucleic acid

DM — diabetes mellitus

FA — fluorescein angiography

FLKGD — focal laser photocoagulation of the fundus

CKD — chronic kidney disease

DCCT — Diabetes Control and Complications Trial

ETDRS — Early Treatment Diabetic Retinopathy Study

HbA1c — hemoglobin A1c, glycated hemoglobin A1c

ICAM-1 — intercellular adhesion molecule-1

PlGF — placental growth factor, placental growth factor

VCAM-1 — vascular cell adhesion molecule-1

VEGF — vascular endothelial growth factor

** — Vital and Essential Drugs

Terms and Definitions

Ocular biomicroscopy — a method of intravital visual examination of the optical media and tissues of the eye based on creating contrast between illuminated and non-illuminated areas, performed using a slit lamp and additional diagnostic lenses (in particular, for fundus biomicroscopy).

"Cotton wool" ("soft") exudate (cotton-wool spot) — a focus of focal ischemia of the inner retina due to a sharp disruption of retinal perfusion.

Hemophthalmus — vitreous hemorrhage, accumulation of blood in the vitreous body or vitreous cavity (in aphakia).

Intravitreal administration (intravitreal injection) — administration of a drug substance into the vitreous body or vitreous cavity (in aphakia).

Intraretinal microvascular abnormalities (IRMA) — branching vascular shunts located along the border of non-perfused retinal areas.

Microaneurysm — local dilation (outpouching) of the capillary wall.

Neovascular glaucoma — secondary glaucoma resulting from the proliferation of new vessels and fibrous tissue in the anterior chamber angle and on the iris surface.

Optical examination of the retina using a computer analyzer (optical coherence tomography (OCT)) — a diagnostic non-invasive contactless method for intravital visualization, qualitative and quantitative analysis of the morphological features of fundus structures, based on the principle of light interferometry.

Optical examination of the retina using a computer analyzer in angiography mode (optical coherence tomography angiography (OCT-A)) — a diagnostic non-invasive contactless method for intravital visualization, qualitative and quantitative analysis of microcirculation in fundus structures, taking into account fundus layer segmentation.

Preretinal hemorrhage (hemorrhage) — accumulation of blood in the retrohyaloid space.

Retinal neovascularization — a variant of the pathological proliferative response to retinal ischemia, manifested by the growth of newly formed vessels along the posterior surface of the vitreous body, originating from the retinal vessels themselves.

Rubeosis iridis — the growth of newly formed vessels in the iris, usually accompanied by neovascularization of the structures of the anterior chamber angle and is a consequence of severe retinal ischemia.

"Hard" (lipid) exudate — deposition of proteins and lipids in the layers of the neuroepithelium due to increased vascular permeability and the escape of blood plasma components beyond its limits.

Tractional retinal detachment — retinal detachment associated with the contraction of connective tissue within proliferative membranes and vitreous retraction, characterized by the accumulation of fluid between the neuroepithelium and the retinal pigment epithelium. When secondary retinal tears form, the detachment is classified as tractional-rhegmatogenous.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both [1, 2]. Chronic hyperglycemia in DM is accompanied by damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

Diabetic retinopathy (DR) – a specific late neuromicrovascular complication of diabetes mellitus, developing, as a rule, sequentially from changes associated with increased permeability and occlusion of retinal vessels to the appearance of newly formed vessels and fibroglial tissue. It is a manifestation of generalized microangiopathy.

Diabetic macular edema (DME) – retinal thickening associated with the accumulation of fluid in the intercellular space of the neuroepithelium due to a breakdown of the blood-retinal barriers and an imbalance between fluid transudation and its resorption capacity.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Diabetic retinopathy (DR) is a disease belonging to the group of ischemic retinopathies, which are characterized by significant impairment of capillary perfusion, the development of intraocular newly formed vessels, and retinal edema. Occlusion and edema are the main pathological manifestations of diabetic retinal damage, with occlusion mainly affecting the peripheral parts of the retina, while edema predominates in its central part — the macular zone. Vascular occlusion is the cause of non-perfused retinal areas, which stimulate the release of angiogenic factors and inflammatory cytokines.

Under conditions of hyperglycemia, a cascade of pathological biochemical processes occurs, resulting in the formation of advanced glycation end-products and reactive oxygen species, which cause vascular wall damage and endothelial cell death. Vascular endothelial damage is also promoted by a sharp increase in retinal blood flow occurring under hyperglycemic conditions (endothelial stress), as well as the action of free radicals. Oxidative stress, highly reactive oxygen compounds, and advanced irreversible glycation end-products induce the expression of inflammatory cytokines (such as interleukin-6, interleukin-8, interleukin-1β, and tumor necrosis factor), chemokines, and cell adhesion molecules (intercellular adhesion molecule-1 – ICAM-1, vascular cell adhesion molecule-1 – VCAM-1), which lead to leukocyte migration and leukostasis. Endothelial damage, increased blood element aggregation, and activation of coagulation factors lead to capillary occlusion and retinal ischemia, which triggers increased expression of vascular endothelial growth factor (VEGF), one of the most significant links in the pathogenesis of diabetic macular edema (DME) and diabetic retinopathy (DR). The opening of shunts—intraretinal microvascular abnormalities (IRMA)—in response to a significant decrease in blood supply only worsens the situation, as it redistributes blood flow bypassing the non-perfused retina [3, 4].

An increase in VEGF production above a critical level contributes to the development of the main clinical manifestations of diabetic retinal damage—macular edema and neovascularization [5, 6]. By acting on endothelial tight junction proteins, VEGF helps increase vascular permeability. This enhances the exudation and accumulation of extracellular fluid and proteins in the retinal tissue. Fluid that passes through the capillary wall should normally be reabsorbed by the retinal pigment epithelium (outer blood-retinal barrier) and adjacent retinal capillaries. When diffusion exceeds the potential capacity of the pigment epithelium and capillaries to reabsorb fluids, clinical signs of macular edema appear. A significant impact on the development of DME is exerted by an increase in the production of pro-inflammatory cytokines above the critical level and the activation of Müller cells.

Increased VEGF expression initiates the process of angiogenesis, which is an ordered sequence of complex processes:

– activation of endothelial cells and changes in their shape;

– pericellular secretion of proteases and degradation of the extracellular matrix;

– proliferation and migration of endothelial cells, and their invasion of the extracellular matrix;

– differentiation of migrating endothelial cell cords into newly formed vessels that have a lumen but lack a basement membrane.

New vessels grow along the posterior surface of the vitreous body. The wall of the newly formed vessel is defective, which leads to the leakage of both plasma components and whole blood beyond its limits. This stimulates connective tissue proliferation in areas of neovascularization. Since connective tissue always tends to contract, and the adhesion of the fibrovascular conglomerate to the posterior surface of the vitreous is very dense, a posterior vitreous detachment develops. As a rule, at this moment, the newly formed vessels rupture, leading to the development of preretinal (in front of the retinal surface) or vitreous (into the vitreous cavity) hemorrhages. Recurrent hemorrhages and scarring of the posterior vitreous lead to the formation of pathological vitreoretinal adhesions, which can cause tractional retinal detachment. Subsequently, the growth of new vessels along the iris (rubeosis) and in the anterior chamber angle is possible, leading to the development of neovascular glaucoma and unmanageable increases in intraocular pressure (IOP).

Thus, modern concepts of DR pathogenesis allow us to distinguish five main processes in its development:

– formation of microaneurysms;

– pathological vascular permeability;

– vascular occlusion;

– neovascularization and fibrous proliferation;

– contraction of fibrovascular tissue and the vitreous body.

1.3 Epidemiology of the Disease or Condition

DR is the leading cause of blindness in the working-age population of developed countries and is among the leading causes of vision loss in the age group over 65 years. It is estimated that blindness in patients with DM develops 25 times more often than in the general population [7]. Over the past three decades, the prevalence of DM (age-standardized) has increased significantly in countries of all income levels, reflecting the global rise in the number of overweight or obese people. The global prevalence of diabetes increased from 4.7% in 1980 to 8.5% in 2014 [2].

The main causes of vision loss in patients with DM are proliferative diabetic retinopathy (PDR) and DME [2]. The Wisconsin Epidemiologic Study showed a correlation between DR and the type, duration, and severity of DM [7 - 10]. In type 1 DM with a disease duration of more than 20 years, DR is diagnosed in more than 88% of patients [7]. In type 2 DM, the highest prevalence (65.2%) is observed in the group of patients with a 15–20-year history of diabetes [8]. In uncompensated DM, symptoms of DR occur almost twice as frequently as in compensated DM [7 - 9]. Regardless, at some point in life, more than a third of people with DM will develop DR [10]. No statistically significant difference in the incidence of DR between men and women has been identified. A slightly larger absolute number of women diagnosed with DR is due to their greater health-seeking behavior and self-care [7].

According to a global meta-analysis (in the USA, Europe, Australia, and Asia), it was shown that every third patient with DM (34.6%) had some form of DR, and every tenth (10.2%) had a vision-threatening form (PDR and/or DME) [11]. In 2010, there were more than 92 million adults worldwide with any retinopathy, 17 million with PDR, 20 million with DME, and 28 million with vision-threatening DR. In 2015, 145 million people had DR, including 45 million people at the vision-threatening stage [10, 11]. In the Russian Federation in 2016, the prevalence of DR was: in type 1 DM – 38.3% (3,805.6 per 10,000 adults), in type 2 DM – 15.0% (1,497.0 per 10,000 adults) [12]. The structure of new DR cases: non-proliferative stage in type 1 DM – 71.4%, in type 2 DM – 80.3%, pre-proliferative DR (NPDR) – 16.4% and 13.8% respectively, PDR – 12.1% and 5.8% respectively, end-stage – 0.2% and 0.1% respectively [12]. According to official statistics as of December 31, 2017, the number of patients with DR in the Russian Federation exceeded 580,000 people [12]. In most regions, the actual prevalence of DR exceeds that registered by medical visits by several times [12].

1.4 Features of Coding the Disease or Condition

H36.0 — Diabetic retinopathy

E10.3 — Insulin-dependent diabetes mellitus with ophthalmic complications

E11.3 — Non-insulin-dependent diabetes mellitus with ophthalmic complications

1.5 Classification of the disease or condition

The classification of DR proposed by Kohner E. and Porta M. (1991) identifies three main stages of the disease [13]:

1. non-proliferative DR;

2. pre-proliferative DR;

3. proliferative DR.

Clinical changes characteristic of each stage of DR are presented in Table 1.

Table 1. Characteristics of fundus changes in various stages of DR

The most comprehensive classification to date is that of the Early Treatment Diabetic Retinopathy Study (ETDRS) research group from 1991 (Table 2) [14], which can also be used in clinical practice.

Table 2. ETDRS classification and clinical manifestations of DR (1991)

Diabetic maculopathy, including DME, may occur at any stage of DR. Currently, there is no universally accepted classification of diabetic maculopathy and DME. At the same time, depending on which of the lesions listed below predominates, the main clinical forms of involvement are distinguished:

– DME or edematous maculopathy – local isolated breakdown of the inner blood-retinal barrier (group of microaneurysms) with impaired autoregulation (focal edema) or capillary hyperpermeability combined with a breakdown of the outer blood-retinal barrier (diffuse edema);

– tractional maculopathy – disruption of vitreoretinal relationships or density of the internal limiting membrane of the retina (tractional edema);

– ischemic maculopathy – capillary occlusion (ischemic edema).

When intraretinal fluid-filled spaces are large, the edema is referred to as cystoid.

The Early Treatment Diabetic Retinopathy Study (ETDRS) research group introduced the concept of clinically significant DME, the criteria for which are [15] (Appendix A3):

– retinal thickening and/or hard exudates involving the center of the macula;

– retinal thickening and/or hard exudates located within 500 µm of the center of the macula, but not involving it;

– retinal thickening with an area of 1 optic disc diameter or larger, located at least partially within 1 disc diameter of the center of the macula.

In addition, it is customary to distinguish DME with or without central involvement. Center-involving macular edema is defined as retinal thickening (retinal edema) affecting the central zone 1000 µm in diameter.

1.6 Clinical presentation of the disease or condition

Fundus changes in patients with diabetes mellitus develop sequentially from conditions associated with increased permeability and occlusion of retinal vessels to the appearance of new vessels and fibroglial tissue. A detailed description of the clinical picture depending on the stage of DR is presented in Tables 1 and 2.

Complicated forms of proliferative DR include the development of iris rubeosis and secondary neovascular glaucoma, preretinal and intravitreal hemorrhages, traction syndrome and/or tractional retinal detachment due to the formation of vitreoretinal fibroglial membranes.

Clinical presentation of diabetic maculopathy

At any stage of the disease, involvement of the macular area may develop, referred to as diabetic maculopathy and representing one of the main causes of vision loss. Fundus biomicroscopy reveals deformation or loss of the foveolar reflex, retinal thickening in the macular zone, and lipid exudate deposits. Long-standing macular edema can lead to cystoid, fibrotic, and atrophic changes in the retina.

Ischemic maculopathy is associated with a marked blood flow impairment in the perifoveal zone and is practically asymptomatic on ophthalmoscopy. Suspecting this variant of maculopathy is prompted by the discrepancy between low visual acuity and minor fundus changes in the macular region. Additional diagnostic methods, such as optical coherence tomography angiography (OCT angiography) and fluorescein angiography of the eye, allow reliable assessment of ischemic macular involvement. Ischemic maculopathy carries the worst visual acuity prognosis.

Tractional maculopathy may develop due to impaired vitreoretinal relationships (vertical tractions) or density of the internal limiting membrane of the retina (horizontal tractions). Fundus biomicroscopy reveals abnormal macular reflexes and deformation of retinal structures. Retinal edema (tractional edema) may appear.

Clinical presentation of transient diabetic retinopathy

Against the background of a rapid decrease in glycemia levels in patients with severe decompensation of diabetes mellitus, transient retinopathy is possible, which is characterized by a benign course. For the correct interpretation of the ophthalmoscopic picture and diagnosis of "transient retinopathy," a thorough history-taking is necessary to identify episode(s) of a sharp decrease in glycemia levels.

Clinical manifestations of transient retinopathy are quite variable and may manifest as either the appearance or increase of retinal hemorrhages, cotton-wool spots, and macular edema. Particular attention must be paid to the state of the optic disc, since diabetic papillitis (sometimes isolated) is a fairly frequent, but poorly documented manifestation of transient retinopathy. One of the severe manifestations of transient retinopathy is ischemic maculopathy, the treatment of which in the absence of retinal edema is inappropriate. Changes generally undergo spontaneous regression within a few months. Laser photocoagulation of the retina is usually not required [16].

Diabetic papillopathy (diabetic papillitis) is characterized by transient optic disc edema, the presence of soft exudates and retinal hemorrhages in the superficial retinal layers along the optic disc margin. The course is usually benign, and specific treatment is not required [16].

Other diabetic ocular disorders

In patients with diabetes mellitus (especially decompensated), metabolic disturbances lead to earlier onset and more intensive progression of cataracts.

The most common manifestation of mononeuropathy is involvement of the oculomotor and abducens nerves. Patients may complain of eyeball deviation, diplopia, and drooping of the upper eyelid, which is confirmed upon ophthalmological examination.

Due to impaired corneal innervation, corneal epitheliopathy may develop, which can lead to recurrent corneal erosions.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnosis of DR and DME should aim to detect early changes, which is especially important given the availability of effective vision-preserving methods for this disease in modern ophthalmology (Appendix A3).

Table 3. Main diagnostic criteria for establishing DR and DME

2.1 Complaints and Anamnesis

Comments: there may be an absence of symptoms for a long time despite disease progression. Patients with DR may complain of decreased visual acuity and floaters. In DME, patients note distorted vision (metamopsia), a "spot" in front of the eyes, and decreased visual acuity [17]. With complications of PDR (preretinal and intravitreal hemorrhages), patients may complain of decreased vision, a "spot", or a "veil" before the eyes; with retinal detachment, they may report decreased vision and a "curtain" in the visual field. Complaints of decreased visual acuity generally require immediate specialized treatment. When neuropathy develops with involvement of the III and VI cranial nerve pairs, patients may complain of ocular deviation, diplopia, and drooping of the upper eyelid. From the general anamnesis, it is important to clarify the duration of DM and the degree of disease control (blood sugar and glycated hemoglobin levels), the presence of arterial hypertension, lipid profile parameters, and the presence of macrovascular or other microvascular complications of DM [1, 2].

2.2 Physical Examination

Comments: a physical examination is recommended for all patients with DM as part of the management of the underlying disease (including assessing the risk of occurrence or progression of DR and DME) and is performed by a primary care physician (endocrinologist, therapist, or general practitioner (family doctor)) in accordance with clinical guidelines for the management of patients with various types of DM [10, 17, 18, 19]. It is also necessary to refer patients with other concomitant systemic diseases and risk factors for systemic complications for consultation with relevant specialists prior to laser or surgical treatment (including intravitreal drug administration) to identify potential contraindications to these types of treatment and minimize the risk of complications [19]. The choice of specialist profile (endocrinologist, therapist, otolaryngologist, dentist, etc.) is determined based on the course of DM, the planned treatment, and the presence of any concomitant systemic disease and risk factors for systemic complications in the patient.

2.3 Laboratory Diagnostics

Comments: the choice of laboratory test is determined based on the characteristics of the course of DM and the presence of concomitant systemic disease and risk factors for systemic complications in the patient. It is also recommended to refer patients with concomitant systemic diseases and risk factors for systemic complications for laboratory testing prior to laser or surgical treatment (including intravitreal drug administration) to identify potential contraindications to these types of treatment [19, 20].

Comments: HIV testing is carried out on the basis of voluntary consent (Methodological Recommendations MR 3.1.5.0076/1-13 "Pre- and Post-Test Counseling as Prevention of HIV Transmission" and SanPiN 3.3686-21 "Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases"). The choice of laboratory test is determined based on the presence of concomitant systemic disease and risk factors for systemic complications in the patient [21 - 23].

2.4 Instrumental Diagnostics

Comments: biomicroscopy of the anterior segment of the eyeball must first be performed without mydriasis, since pupil dilation can make it difficult to detect "early" iris neovascularization. Vitreous biomicroscopy, conversely, is preferably performed after drug-induced mydriasis, which improves diagnostic quality.

Comments: Fundus biomicroscopy with aspheric lenses using a slit lamp (or ophthalmoscopy) is the primary diagnostic method for diabetic fundus changes during an ophthalmological examination across any care setting (primary health care, specialized care) and modality (inpatient, outpatient). In patients with diabetes mellitus, it must be performed exclusively with a dilated pupil (under drug-induced mydriasis). It is important to remember that anterior chamber depth must be assessed prior to pharmacological pupillary dilation.

Comments: The necessity and frequency of fundus photography using a fundus camera are determined by the ophthalmologist depending on the clinical course of DR, DME, and diabetes mellitus. Fundus photography must be performed with a dilated pupil. Numerous studies have demonstrated that pharmacological mydriasis significantly improves image quality. Therefore, fundus imaging should currently be performed under drug-induced mydriasis regardless of the type of retinal camera [10, 18, 19].

Comments: When evaluating the efficacy of treatment with intravitreal anti-vascular endothelial growth factor agents and topical corticosteroids, quantitative and qualitative tomogram parameters should be assessed. Anatomical parameters, along with visual acuity, are key factors of disease activity used to monitor treatment efficacy and make decisions regarding initiating or resuming treatment in patients with DME. Optical retinal imaging using a computerized analyzer must be performed under pharmacological mydriasis, as this significantly improves scan quality.

Comments: The necessity and frequency of OCT-A are determined by the ophthalmologist depending on the clinical course of the disease. Optical retinal imaging using a computerized analyzer in angiography mode should be performed under pharmacological mydriasis, as this significantly improves the quality of the study.

Comments: The decision to prescribe other additional diagnostic methods is made by the physician based on the results of the baseline examination.

2.5 Other Procedures

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Comments: At all stages of DR and DME, treatment of the underlying disease—diabetes mellitus—aimed at correcting metabolic disorders must be carried out [1, 2, 10, 18, 19, 29]. According to clinical and experimental studies, there is a clear correlation between the degree of glycemic control and the development of DR. The DCCT study showed that the better the glycemic control, the lower the risk and incidence of DR [29, 31]. Strict control of blood glucose, blood pressure, and lipid metabolism is associated with a lower likelihood of developing DR and a slower rate of its progression [17 - 19, 29 - 36].

3.1 Conservative Treatment

Comments: Lowering triglyceride levels may slow the progression of DR and DME [26, 34, 36].

3.2 Laser Treatment

Comments: standard PRP is usually performed over several sessions [10, 17, 18, 20]. Panretinal photocoagulation sessions can be performed both in inpatient and outpatient settings under maximal drug-induced mydriasis [37 - 40].

Comments: if HbA1c is greater than 10% and PDR is present, panretinal photocoagulation should be performed without waiting for substantial improvement in glycemic control.

Panretinal photocoagulation has certain side effects. Therefore, this laser treatment method is generally performed when new vessels are already present or the risk of their appearance is extremely high. The probability of blindness upon the appearance of new vessels is so high that it justifies the use of laser treatment despite the side effects [17, 37 - 41].

PRP usually begins in the inferior mid-peripheral regions, as these areas may become inaccessible in the event of vitreous hemorrhage. Laser application is then continued by placing burns across the entire surface of the mid-periphery of the fundus from the temporal vascular arcades. In the presence of PDR with iris neovascularization and/or anterior chamber angle neovascularization, it is also necessary to coagulate the far peripheral regions of the retina.

An indication for immediate panretinal photocoagulation is PDR combined with "high-risk characteristics for vision loss", which are defined as:

>– retinal neovascularization exceeding 1/2 of the optic disc area in size;

>– optic disc neovascularization exceeding 1/3 of the optic disc area in size;

>– vitreous or preretinal hemorrhage.

Comments: in the presence of DME, the greatest effect from laser treatment (focal (or grid) laser photocoagulation of the fundus is expected when the baseline central retinal thickness is no more than 350 µm. In other cases, laser treatment for DME is significantly inferior in functional outcome to treatment with anti-angiogenic agents (angiogenesis inhibitors) [42].

3.3 Surgical Treatment

3.3.1 Intravitreal administration of drugs

Comments: currently, intravitreal administration of anti-angiogenic agents (angiogenesis inhibitors) is the first-line therapy for DME involving the center of the macula. It should be taken into account, that when combining focal laser photocoagulation of the fundus and intravitreal administrations of anti-angiogenic agents, the functional effect of delayed laser treatment will be better [23, 51 - 57].

— Ranibizumab** is a humanized antibody fragment against vascular endothelial growth factor A (VEGF-A). It selectively binds to VEGF-A (VEGF110, VEGF121, VEGF165), preventing its interaction with receptors on the surface of endothelial cells, which leads to the suppression of neovascularization and endothelial cell proliferation [42, 58, 59].

— Aflibercept** is a recombinant fusion protein consisting of extracellular domain fragments of human VEGF receptors fused to the Fc portion of human immunoglobulin G. It acts as a soluble decoy receptor that binds VEGF-A and placental growth factor with higher affinity than their natural receptors, and also binds Gal-1 and VEGF-B, thereby inhibiting the binding and activation of VEGFR-1 and VEGFR-2 receptors by multiple growth factors, which reduces vascular permeability, decreases inflammation, suppresses pathological angiogenesis, and has the potential to reduce the number of injections [41, 43, 54 - 56, 60 - 65]. Aflibercept** has a higher affinity for VEGF-A compared to native receptors, which positively affects its duration of action [64]. According to clinical trial results, the intervals between aflibercept** injections can be extended up to 16-24 weeks (depending on dosage) while maintaining the achieved visual acuity [41, 65 - 66].

— Brolucizumab** is a humanized single-chain antibody fragment (ScFv, single-chain variable fragment) with a molecular weight of 26 kDa, which is the smallest functional unit of an antibody, allowing a greater number of moles of the substance to be administered in a single dose compared to previously registered anti-VEGF antibodies, with the potential for longer duration of action and higher tissue penetration [44]. Brolucizumab** binds with high affinity to various isoforms of VEGF-A (specifically VEGF110, VEGF121, and VEGF165), thereby preventing the binding of VEGF-A to its receptors VEGFR-1 and VEGFR-2.

— Faricimab is a humanized bispecific immunoglobulin G1 (IgG1) antibody that acts by inhibiting two distinct pathways, neutralizing both angiopoietin-2 (Ang-2) and vascular endothelial growth factor A (VEGF-A). Ang-2 and VEGF-A act synergistically to increase vascular permeability and stimulate neovascularization. Dual inhibition of Ang-2 and VEGF-A by faricimab reduces vascular permeability and inflammation, suppresses pathological angiogenesis, and may provide greater vascular stability compared with anti-VEGF therapy, with the potential for a longer duration of action and extended dosing intervals [45 - 47]. Dual inhibition of Ang-2 and VEGF-A with faricimab led to a reduction in macular leakage [48], hyperreflective focus volume [49], and epiretinal fibrosis [50], and improved vascular morphology in patients with diabetic macular edema [51].

In each clinical case, the final decision on the indications for treatment with anti-angiogenic agents and the choice of injection regimen is made by the physician based on an assessment of the clinical features and disease course.

Contraindications to intravitreal administration of ranibizumab**, aflibercept**, brolucizumab**, or faricimab:

— hypersensitivity to the components of the drug,

— active confirmed or suspected ocular infections or periocular infections,

— active intraocular inflammatory process,

— pregnancy and breastfeeding.

A topical corticosteroid (dexamethasone** intravitreal implant) provides sustained (up to 6 months) release of the active substance in the vitreous cavity. Dexamethasone**, as a potent corticosteroid, suppresses inflammation by reducing edema severity, fibrin deposition, capillary permeability, and phagocyte migration to the site of inflammation. Corticosteroids suppress the expression of vascular endothelial growth factor and prevent the release of prostaglandins, some of which are mediators of cystoid macular edema [52, 67 - 69].

Intravitreal administration of a dexamethasone** intravitreal implant is advisable in patients with DME resistant to anti-angiogenic therapy and laser treatment, particularly in cases of aphakia, in patients with high cardiovascular risk [26], and in those patients who cannot adhere to the frequent clinic visit schedule required during anti-angiogenic treatment [70].

The use of a dexamethasone** intravitreal implant requires prolonged, regular IOP monitoring. Re-administration of the intravitreal implant is possible approximately 6 months later in the event of decreased visual acuity and/or increased retinal thickness.

Contraindications to intravitreal administration of the dexamethasone** intravitreal implant:

— hypersensitivity to the components of the drug;

— active confirmed or suspected ocular infections or periocular infections;

— advanced glaucoma with IOP decompensation uncontrolled by medical therapy;

— aphakia with posterior lens capsule rupture;

— presence of an anterior chamber intraocular lens (IOL), iris-clip IOL, or posterior chamber IOL with transscleral fixation in the presence of a posterior lens capsule rupture.

When intravitreally administering anti-angiogenic drugs or the dexamethasone** intravitreal implant, potential risks of complications such as infectious and non-infectious endophthalmitis, iatrogenic cataract, hemophthalmus, retinal detachment, and others must be considered [19, 71].

When using anti-angiogenic drugs or the dexamethasone** intravitreal implant, preventing a decline in visual acuity, even in the absence of improvement, should be considered a positive response compared to the natural course of the disease.

Contraindications to intravitreal administration of prourokinase**:

– individual hypersensitivity to the drug components;

– conditions with a high risk of bleeding, including blood disorders;

– active confirmed or suspected ocular infections or periocular infections;

– active intraocular inflammatory process;

– pregnancy and breastfeeding;

– chronic renal failure (serum creatinine > 0.02 g/L, urea > 0.5 g/L);

– severe hepatocellular failure (blood albumin < 30 g/L).

Comments: the duration of antimicrobial drop instillations (ATC S01AX) before and after intravitreal administration of any medicinal product is determined by the physician based on a comprehensive assessment of the risk of infectious complications and the condition of the ocular surface.

3.3.2 Vitreoretinal surgery

Comments: during microinvasive vitrectomy or vitreo-schwartrectomy, when indicated, membrane peeling, retinotomy, endolaser photocoagulation, endodiathermocoagulation, endotamponade with ophthalmic gas, perfluorocarbon liquid ophthalmic material for temporary use in vitreoretinal surgery, silicone oil, and other manipulations may be performed. Patient preparation for surgery is carried out in conjunction with an endocrinologist and general practitioner. If necessary, consultations with a nephrologist (in case of renal impairment), cardiologist (in case of cardiovascular complications), endocrinologist and/or surgeon (for diabetic foot syndrome) are prescribed.

An ophthalmologist referring a patient for vitreal surgery should consider several factors:

- the severity of pathological changes to predict the functional outcome of the surgery;

- in case of vitreous hemorrhage, the severity of the hemorrhage must be assessed (a minor hemorrhage that does not impede laser treatment and does not lead to disability is not an indication for surgery);

- the adequacy of previously performed panretinal laser photocoagulation of the retina (hemorrhages may occur due to insufficient photocoagulation);

- visual acuity of the fellow eye (vitreoretinal surgery may be recommended earlier if the patient is disabled due to low visual acuity in the fellow eye);

- severity of general comorbidities, estimated life expectancy of the patient, and anesthesia risk.

Comments: the duration of silicone oil endotamponade of the vitreous cavity is determined by the physician based on the results of patient monitoring. The decision on the need for repeated endotamponade of the vitreous cavity is made by the physician based on the evaluation of the patient's ocular status, the risk of recurrent hemorrhage, retinal detachment, etc.

Comments: the duration of instillation and injection of medicinal products before and after vitreoretinal surgery is determined by the physician based on a comprehensive assessment of the clinical presentation, the course of the surgery, and the postoperative period.

3.4 Dietary Therapy

Diet therapy is carried out in accordance with the Clinical Guidelines "Type 1 Diabetes Mellitus in Adults".

Comments: it is necessary to perform a quantitative assessment of digestible carbohydrates using the carbohydrate unit system for all patients with type 1 DM to adjust the dose of insulin and its analogs before meals [1, 79 - 83]. Total intake of proteins, fats, and carbohydrates in type 1 DM should not differ from that of a healthy individual. The correspondence between the dose of insulin and its analogs and carbohydrate intake, pre-prandial blood glucose levels, and expected physical activity is determined for patients with type 1 DM to improve glycemic control [1].

Diet therapy is carried out in accordance with the Clinical Guidelines "Type 2 Diabetes Mellitus in Adults".

Comments: it is necessary to view nutrition as part of the therapeutic plan in all type 2 diabetes patients, regardless of the glucose-lowering drug regimen, in order to achieve metabolic goals [84, 85]. There is no ideal percentage ratio of proteins, fats, and carbohydrates for all patients with diabetes. Recommendations are developed based on an analysis of the current dietary pattern and metabolic goals. All patients with overweight/obesity need a calorie-restricted diet to achieve moderate weight loss. Achieving weight loss is most effective when combining physical activity and educational programs. Drastic unphysiological dietary restrictions are contraindicated. As a rule, maximum restriction of fats (primarily animal-derived) and sugars, and moderate restriction of foods consisting of complex carbohydrates (starches) and proteins can be helpful for weight loss. Carbohydrate intake should be encouraged as part of vegetables, whole grains, and dairy products, as opposed to carbohydrate sources that additionally contain saturated or trans fats, sugars, or sodium. It is important to include foods rich in mono- and polyunsaturated fatty acids (fish, vegetable oils) in the diet. Nutrition must be a part of the therapeutic plan and should contribute to achieving metabolic goals with any option of glucose-lowering pharmacotherapy. Dietary recommendations are provided by a primary care physician (an endocrinologist, general practitioner, or family physician) as part of the management of the underlying disease. Assessment of digestible carbohydrates using the bread unit system is recommended for all type 2 diabetes patients receiving therapy with short-acting insulins and their injectable analogs to adjust the dose of insulins and their analogs before meals [1].

3.5 Anesthesia

Pain relief methods are not applied, as DR and DME are not accompanied by pain syndrome. Anesthesia during various treatment options is discussed in the relevant chapters (3.2 "Laser treatment" and 3.3 "Surgical treatment").

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

Table 4. Target glycated hemoglobin (HbA1c) levels in patients with DM [1]

Comments: these target values do not apply to children, adolescents, and pregnant women. Cardiovascular diseases: coronary artery disease (history of myocardial infarction, coronary artery bypass grafting/stenting, angina pectoris), history of cerebrovascular accidents, history of lower extremity arterial disease (symptomatic). The main criteria for the risk of severe hypoglycemia are: history of severe hypoglycemia, asymptomatic hypoglycemia, long duration of DM, chronic kidney disease (CKD stage 3–5), dementia.

Table 5. Blood pressure target levels [1]

Comments: the lower limit of target BP values applies to individuals receiving antihypertensive therapy.

Table 6. Target lipid profile levels in patients with diabetes mellitus [1]

Comments: reducing HbA1c to 7% and below decreases the risk of microvascular complications. Stricter glycemic control (HbA1c less than 6.5%) may be recommended for individual patients if achievable without hypoglycemic states and other undesirable effects [1]. Endocrinologists currently use an algorithm for the individualized choice of HbA1c treatment targets (Table 3). However, when intensive treatment is initiated in patients with a long-standing history of poor glycemic control, especially if retinopathy is at the moderate non-proliferative DR stage or worse, an ophthalmologist examination is necessary prior to starting intensive treatment and at 3-month intervals for 6–12 months.

Table 7. Initiation and frequency of ophthalmologist examinations in patients with diabetes mellitus [1]

Comments: the implementation of screening programs is essential for the prevention of blindness and low vision due to diabetic eye disease. The ideal screening method for DR and DME is fundus biomicrophotography using a fundus camera (stereoscopic photography of standard retinal fields). The procedure is performed by technical staff, and the evaluation of photographs is subsequently performed by an ophthalmologist specializing in retinal pathology [13]. In type 1 diabetes, the risk of developing DR within the first 5 years of the disease is negligible; therefore, an ophthalmologist examination must be performed no later than 5 years from the onset of the disease.

Due to the specific features of the disease and the absence of an acute onset, type 2 diabetes may remain undiagnosed for several years, which significantly increases the risk of DR. About 20% of patients with type 2 diabetes have signs of DR at the time of diabetes diagnosis. Therefore, patients must undergo a comprehensive ophthalmologist examination immediately upon the diagnosis of type 2 diabetes.

Pregnancy is associated with the potential for rapid progression of DR in type 1 and type 2 diabetes. Therefore, ophthalmological examination of women with diabetes planning pregnancy should be performed at the pregnancy planning stage, during the first trimester, and subsequently every 3 months. The woman must also undergo a comprehensive ophthalmological examination within the first year after childbirth.

Women with gestational diabetes do not require an ophthalmologist examination for the diagnosis of DR, as they are not at risk of developing DR [7, 10].

Subsequent examinations in adults with type 1 and type 2 diabetes are performed in accordance with the stage of DR, but at least once a year.

Table 8. Frequency of ophthalmological examinations in patients with diabetes

Comments: when planning the frequency of ophthalmologist examinations, it should be taken into account that the risk of development and progression of DR and DME increases in certain patient conditions associated with hormonal status disorders (pregnancy, status post artificial abortion, puberty, and others).

In the event of an unexpected decrease in visual acuity or the appearance of any visual symptoms, an examination by an ophthalmologist should be performed as soon as possible, regardless of the scheduled visit date.

6. Organization of Medical Care

Primary specialized health care is provided by an ophthalmologist in the outpatient department of a medical organization.

Treatment (laser interventions, intravitreal drug administration, or vitreous surgery) is performed by an ophthalmologist on an outpatient basis, in a day hospital setting, or in an inpatient setting.

Indication for planned hospitalization in a medical organization:

• the need for intravitreal drug injections or vitreoretinal surgical interventions if outpatient treatment is not feasible.

Indication for emergency hospitalization in a medical organization:

• endophthalmitis as a complication of intravitreal drug administration [38].

Indication for patient discharge from a medical organization:

1) completion of treatment or a stage of specialized, including high-tech, medical care in an inpatient or day-care setting, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day-care setting;

3) need to transfer the patient to another medical organization.

7. Additional Information

The patient must be informed about the need to normalize glycemia, blood pressure, and lipid profile parameters. The patient should also be encouraged to strictly comply with all specialist appointments (endocrinologist, ophthalmologist, nephrologist, cardiologist, therapist, general practitioner/family physician, etc.).

It is important to emphasize to the patient with diabetes the necessity of an ophthalmologist examination at least once a year (in the case of type 1 diabetes, 5 years from disease onset) even in the absence of visual symptoms, as well as the urgency of consulting an ophthalmologist if visual symptoms appear.

If diabetic eye changes are present, the patient should be informed of the recommended frequency of ophthalmologist examinations depending on the severity of the changes, as well as the need for unscheduled examinations if any new visual disturbances occur.

It is necessary to discuss the ocular changes identified by the ophthalmologist with other specialists managing the patient (endocrinologist, nephrologist, cardiologist, general practitioner/family physician, etc.).

Patients must be informed that the efficacy of treatment for diabetic retinopathy (DR) and diabetic macular edema (DME) depends on its timely initiation, even in the absence of subjective visual symptoms.

In cases of irreversible blindness or low vision, the patient must be fully informed about the opportunities for vocational, social, and psychological rehabilitation.

When intravitreal drug administration is used, the following points must be discussed with the patient:

– the prospects for treatment with intravitreal drug administration in patients with DME depend on the timely initiation of treatment and compliance with the optimal injection regimen in accordance with the product labeling and clinical guidelines based on regular monitoring data;

– it is important to warn patients receiving intravitreal injections of the need to immediately report symptoms that may suggest intraocular inflammation (endophthalmitis): eye pain or increased discomfort in the eye, increased eye redness, blurred or decreased vision, increased light sensitivity, or an increase in the number of "floaters" in the visual field.

When performing retinal laser photocoagulation (PRP or focal laser photocoagulation), the following points must be discussed with the patient:

– the need for follow-up examinations and additional laser treatment;

– PRP reduces the risk of low vision and blindness, but may have side effects;

– laser treatment often worsens peripheral vision and may moderately reduce central vision; however, these side effects of laser photocoagulation are offset by the long-term reduction in the risk of low vision and blindness;

– in some patients, despite ongoing laser treatment, a vitreous hemorrhage may occur, which is a consequence of the course of DR rather than caused by the laser (in such cases, the patient may require additional laser or surgical treatment).

Criteria for Evaluating the Quality of Medical Care

Table 9.

References

Appendix A1. Working Group Composition

1. Astakhov Yu.S., Group Leader, Doctor of Medical Sciences, Professor at the Department of Ophthalmology with Clinic, Pavlov First Saint Petersburg State Medical University, Vice-President of the Association of Ophthalmologists;

2. Neroev V.V., Doctor of Medical Sciences, Academician of the Russian Academy of Sciences, Director of the National Medical Research Center for Eye Diseases named after Helmholtz of the Ministry of Health of the Russian Federation, Honored Doctor of the Russian Federation, Honored Scientist of the Russian Federation, President of the Association of Ophthalmologists;

3. Shestakova M.V., Co-Group Leader, Doctor of Medical Sciences, Academician of the Russian Academy of Sciences, Deputy Director of the National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Ministry of Health of the Russian Federation, Honored Scientist of the Russian Federation, Scientific Secretary of the Russian Association of Endocrinologists;

4. Zaytseva O.V., Candidate of Medical Sciences, Deputy Director for Organizational and Methodological Work, National Medical Research Center for Eye Diseases named after Helmholtz of the Ministry of Health of the Russian Federation, Leading Researcher, Executive Director of the Association of Ophthalmologists;

5. Okhotsimskaya T.D., Candidate of Medical Sciences, Physician at the National Medical Research Center for Eye Diseases named after Helmholtz of the Ministry of Health of the Russian Federation, Member of the Association of Ophthalmologists;

6. Ryabina M.V., Candidate of Medical Sciences, Senior Researcher at the National Medical Research Center for Eye Diseases named after Helmholtz of the Ministry of Health of the Russian Federation, Member of the Association of Ophthalmologists.

7. Shadrichev F.E., Candidate of Medical Sciences, Head of the Ophthalmological Consultative and Diagnostic Department, Regional Endocrinological Center, City Consultative and Diagnostic Center No. 1, Assistant at the Department of Ophthalmology with Clinic named after Professor Yu.S. Astakhov, Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation, Member of the Association of Ophthalmologists;

8. Grigorieva N.N., PhD in Medicine, Assistant Professor at the Department of Otorhinolaryngology and Ophthalmology, Saint Petersburg State University, member of the Association of Ophthalmologists;

9. Korchuganova E.A., DSc in Medicine, Head of the Department of Diabetic Retinopathy and Ophthalmic Surgery, Academician I.I. Dedov National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation, member of the Russian Association of Endocrinologists and the Association of Ophthalmologists;

10. Bessmertnaya E.G., PhD in Medicine, Leading Research Scientist at the Department of Diabetic Retinopathy and Ophthalmic Surgery, Academician I.I. Dedov National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation;

11. Kononenko I.V., PhD in Medicine, Endocrinologist, Associate Professor at the Department of Diabetology and Dietetics, Institute of Higher and Continuing Education, Academician I.I. Dedov National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation, member of the Russian Association of Endocrinologists;

12. Shklyarov E.B., PhD in Medicine, Ophthalmologist at the Ophthalmic Consultative and Diagnostic Department, Regional Endocrinological Center, City Clinical Diagnostic Center No. 1, member of the Association of Ophthalmologists.

No conflict of interest is declared.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• Ophthalmologists;

• Endocrinologists;

• General practitioners (family physicians).

Methods used for collecting/selecting evidence: searching electronic databases; analysis of current scientific developments on DR and DME in Russia and abroad; synthesis of practical experience of Russian and foreign specialists. Description of methods used for collecting/selecting evidence: the evidence base for the guidelines includes publications from the Cochrane Library, EMBASE, and MEDLINE databases, as well as monographs and articles in leading specialized peer-reviewed domestic medical journals on this topic. Methods used for assessing the quality and strength of evidence: expert consensus, significance assessment according to the rating scheme.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Current package leaflets for the drugs mentioned in these clinical guidelines can be found on the website http://grls.rosminzdrav.ru

2. International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). World Health Organization.

3. Nomenclature of Medical Services. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."

4. Order of the Ministry of Health of the Russian Federation No. 205n dated May 2, 2023, "On Approval of the Nomenclature of Positions of Medical and Pharmaceutical Workers" (as amended on August 1, 2014)

5. Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on January 15, 2025), "On Approval of the List of Vital and Essential Medicines, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for Medical Care."

6. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Health Protection of Citizens in the Russian Federation."

7. Rules for the Provision of Medical Care to the Adult Population for Diseases of the Eye, Its Adnexa, and Orbit. Order of the Ministry of Health of the Russian Federation No. 633n dated October 24, 2025, "On Approval of the Rules for the Provision of Medical Care to the Adult Population in the Profile 'Ophthalmology'."

8. Order of the Ministry of Health of the Russian Federation No. 203n dated April 14, 2025, "On Approval of Criteria for Assessing the Quality of Medical Care."

9. Resolution of the Government of the Russian Federation No. 1940 dated December 24, 2024, "On the Program of State Guarantees of Free Medical Care to Citizens for 2025 and for the Planning Period of 2026 and 2027."

10. Sanitary and Epidemiological Rules and Regulations SanPiN 2.1.3678-20 "Sanitary and Epidemiological Requirements for the Operation of Premises, Buildings, Structures, Equipment, and Transport, as well as the Working Conditions of Economic Entities Engaged in the Sale of Goods, Performance of Work, or Provision of Services" (Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 44 dated December 24, 2020).

11. Sanitary and Epidemiological Rules and Regulations SanPiN 3.3686-21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" (Decree of the Chief State Sanitary Doctor of the Russian Federation No. 2 dated January 28, 2021). (In Russ.)

12. Sanitary and Epidemiological Rules SanPiN 3.1.5.2826-10 "Prevention of HIV Infection" (Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 1 dated January 11, 2011).

13. Pre- and Post-Test Counseling as HIV Prevention: Methodological Recommendations MR 3.1.5.0076/1-13. Moscow: Federal Center for Hygiene and Epidemiology of Rospotrebnadzor; 2014. 26 p. (In Russ.)

14. Order of the Ministry of Health of Russia No. 1129n dated October 20, 2020, "On Approval of the Rules for Conducting Mandatory Medical Examinations to Detect the Human Immunodeficiency Virus (HIV Infection)" (Registered with the Ministry of Justice of Russia on November 11, 2020, No. 60847)

15. Management of Planned Hospitalization in a Multidisciplinary Hospital. Methodological Recommendations No. 2001/144 (approved by the Ministry of Health of the Russian Federation on November 9, 2001).

Table 1. Main diagnostic criteria for DR and DME

Table 2. ETDRS diabetic retinopathy staging criteria (1991)

Table 3. Criteria for selecting management tactics for patients with DR and DME

Appendix B. Physician Action Algorithms

Diabetic retinopathy

Appendix C. Patient Information

To prevent blindness and low vision due to diabetic eye complications, all prescriptions from the endocrinologist and general practitioner must be followed to achieve glycemic control, blood pressure control, and target lipid profile values.

Even in the absence of visual symptoms, every patient with diabetes mellitus must undergo an ophthalmological examination at least once a year (in type 1 diabetes mellitus — 5 years after disease onset). If any visual symptoms appear, an immediate visit to an ophthalmologist is required.

If diabetic eye changes are present, the required frequency of ophthalmological examinations must be followed, depending on the severity of the changes established by the physician. If new visual symptoms appear, an immediate visit to an ophthalmologist is required.

Diabetic retinopathy may remain asymptomatic for a long time. The effectiveness of DR treatment depends on the timeliness of its initiation, even in the absence of subjective visual symptoms.

Laser treatment generally requires repeated treatment sessions, the frequency and scope of which are determined by the physician. Intraocular hemorrhages occurring during or after laser photocoagulation are associated with the presence of diabetes mellitus, rather than the laser treatment itself, and may require additional retinal laser photocoagulation.

Intravitreal drug injections require regular ophthalmological examinations and, as a rule, repeated injections, the frequency of which is determined by the physician. If symptoms likely indicating inflammation (eye pain or increased discomfort in the eye, increased eye redness, increased blurring or further vision loss, increased light sensitivity, an increase in the number of "floaters" in the visual field) appear within a few days after the injection, they must be reported to the physician immediately.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not used.