[Pathogenetic role of multifunctional protein alpha-2-macroglobulin and its activity in tears and serum in age-related macular degeneration and proliferative diabetic retinopathy]. / Patogeneticheskaya rol' polifunktsional'nogo belka α2-makroglobulina i ego aktivnost' v sleze i krovi pri vozrastnoi makulyarnoi degeneratsii i proliferativnoi diabeticheskoi retinopatii.

Alpha-2-macroglobulin (α2-MG) is a multifunctional protein involved in neurodegeneration, inflammation and neovascularization, which are key processes in the pathogenesis of age-related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR). AMD and PDR are two of the main causes of vision loss and blindness, are difficult to treat, and are generally diagnosed at the stage of irreversible changes. PURPOSE: This study estimates the activity of α2-MG in the blood serum and tears of patients with AMD and PDR in order to reveal the relation of its levels with the intensity of the pathological process in the retina. MATERIAL AND METHODS: The study included 17 patients (34 eyes) with AMD, 15 patients (30 eyes) with PDR, and 15 healthy adults (30 eyes) of the similar age. The activity of α2-MG in serum and tears was measured enzymatically using the specific substrate N-benzoyl-DL-arginine-p-nitroanilide (BAPNA). RESULTS: The activity of α2-MG in tears of patients with AMD was on the average 3.5 times higher than in healthy controls, and in patients with PDR - 1.5 times higher. Patients with AMD at the submacular fibrosis stage showed decreased α2-MG activity in tears. The activity of α2-MG in serum of patients with AMD and PDR was on the average 25% higher than in healthy persons. No correlation was revealed between serum and tear levels of α2-MG activity. CONCLUSION: This study revealed for the first time that in AMD and PDR the activity of α2-MG in tears is increased, and that in AMD the increase is higher than in PDR. An increase of α2-MG activity in serum confirms the presence of systemic inflammation. Absence of correlation between the serum and tear activity of α2-MG confirms its local origin. The high level of α2-MG activity in tears reflects the presence of an active destructive process in the retina, justifying its further investigation as a predictor of AMD and PDR course, as well as an indicator of therapy effectiveness.

[Current view on the issue of insufficient effectiveness of anti-VEGF therapy for age-related macular degeneration]. / Sovremennyi vzglyad na problemu nedostatochnoi effektivnosti antiangiogennoi terapii vozrastnoi makulyarnoi degeneratsii.

Due to the significant medical and social importance of neovascular (wet) age-related macular degeneration (wAMD), increasing the effectiveness of anti-VEGF therapy used to treat this disease is one of the high-priority problems in modern retinology. This article focuses on pathobiological aspects and clinical manifestations of incomplete responses to anti-VEGF therapy of wAMD, considers the proposed ways to improve the terminology and classification of responses to therapy, as well as the assessment of its correctness and effectiveness of the treatment. It also discusses the available ways to optimize anti-VEGF therapy and define the criteria of its termination in cases when the treatment proves to be futile.

[Anti-VEGF therapy for neovascular age-related macular degeneration: causes of incomplete response]. / Anti-VEGF-terapiya neovaskulyarnoi vozrastnoi makulyarnoi degeneratsii: prichiny nedostatochnoi effektivnosti.

Neovascular age-related macular degeneration (nAMD) is one of the leading causes of decreased vision in the elderly population in many countries, including Russia. Anti-VEGF therapy is undoubtedly the «gold standard¼ of treatment for the disease, but its use in different patients is known to produce results with significant interindividual differences. This article reviews modern ideas about the clinical assessment of the degree of response to anti-VEGF therapy, possible reasons for its insufficient effectiveness (clinical, pharmacological, or related to nAMD pathogenesis), discusses the potential applications of the existing therapeutic strategies, and considers the prospects for the emergence of new strategies that could be used for solving that problem.

[Bradykinin and angiotensin-converting enzyme in serum of patients with diabetic retinopathy and the prognosis of diabetic macular edema development (pilot study)].

BACKGROUND: Diabetic macular edema (DME) is a microvascular complication of diabetic retinopathy. One of the key roles in the pathogenesis of DME may belong to the components of rennin-angiotensin and kallikrein-kinin systems: bradykinin (Bk) and angiotensin-converting enzyme (ACE). PURPOSE: To determine the Bk and ACE concentration and ACE activity in serum of patients with proliferative diabetic retinopathy (PDR) and to estimate the significance of these parameters for the early diagnostic and prognosis of DMO. MATERIALS AND METHODS: Serum was collected from the 2 groups of patients with II type diabetes. Group I (n=9) had DME, group II (n=27) had PDR without DME. Control group (n=14) consisted of adult volonteers without diabetes and ophthalmic diseases. Concentration of Bk and ACE was measured using ELISA kits, ACE activity was determined enzymatically with specific fluorogenic substrate. RESULTS: Concentration of Bk in serum of patients without DME did not differ from one in controls (12,00 (9,70; 12,40) pg/ml) while all patients with DME had Bk level of 14,69 (13,68; 16,78) pg/ml that was significantly higher (p<0,01). In patients without DME ACE concentration (88,60 (77,30; 97,45) ng/ml) and ACE activity (6,8 (5,1;7,1) nmol/min·ml) were higher than normal (p<0,01) while in the case of DME concentration of ACE increased (77,36 (70,24; 86,29 ng/ml, p<0,01) and activity remained normal. The Bk/ACE concentrations ratio decreased in patients without DME and increased in those having DME. CONCLUSION: Patients with DME have increased Bk concentration along with nearly normal ACE concentration that indicate predominance of Bk synthesis over its degradation that may lead to the DME development. The Bk/ACE ratio decrease in patients with uncomplicated PDR and increase significantly in ones with DME. It means that determination of Bk in serum of patients with PDR may be used for the prediction of DME development. The Bk/ACE concentrations ratio may be even more informative.

[Bilateral occlusion of retinal vessels in Waldenstrom's disease (a case study)]. / Dvustoronniaia okkliuziia retinal'nykh sosudov pri bolezni Val'denstrema (klinicheskoe nabliudenie).

The article describes a clinical case of bilateral occlusion of retinal vessels in a patient with Waldenstrom's disease - a rare lymphoplasmocytic tumor of the bone marrow characterized by a complex of syndromes, among which the syndrome of blood hyperviscosity dominates. Comprehensive clinical, instrumental and laboratory examinations revealed that besides the syndrome of blood hyperviscosity the patient also had loci of cerebral ischemia (according to magnetic resonance imaging), ocular hypoperfusion with severe deficiency of retinal and choroidal blood flow (according to Doppler methods) indicating the presence of ocular ischemic syndrome. Since bilateral occlusion of retinal vessels without concomitant vascular and/or systemic pathology is rare, patients with such diagnosis should be referred to a hematologist.

[The effect of intravitreally administered angiogenesis inhibitor on the concentration of angiotensin-converting enzyme in the blood serum and lacrimal fluid in patients with diabetic macular edema].

BACKGROUND: Diabetic retinopathy (DR) is one of the more serious complications of diabetes and the main cause of blindness among working-age individuals. In recent years, information has emerged on the possible role of the renin-angiotensin system (RAS) in the pathogenesis of DR, and DR's possible connection with the system of pro-angiogenic factors. AIM: To study the impact of anti-angiogenic therapy on systemic and local concentrations of angiotensin-converting enzyme (ACE), a key component of RAS, for patients with diabetic macular edema (DME). MATERIAL AND METHODS: The concentration of ACE in the lacrimal fluid and blood serum in 10 patients (20 eyes) with DME was determined before and after intravitreal injection (IVI) of ranibizumab. The comparison group consisted of 7 patients (14 eyes) with age-related macular degeneration (AMD). The control group consisted of 10 healthy individuals (20 eyes). All groups were comparable in age and sex. The concentration of ACE was determined by enzyme immunoassay. The main group was examined four times: before IVI of ranibizumab, and then one week, two weeks and one month after IVI of ranibizumab. The comparison group was examined before, and then one week after, IVI of ranibizumab. RESULTS: In patients with DME, there was an initial 1.8-fold increase in the concentration of ACE in the lacrimal fluid of both eyes. A week after IVI of ranibizumab, the concentration of ACE in the lacrimal fluid began to decrease, reaching the control level after two weeks, and remaining there one month after IVI of ranibizumab. Initially, the concentration of ACE in the blood serum in patients with DME was 2.2 times lower than the control level. After IVI of ranibizumab there was an increase in the concentration of ACE in the blood serum, but by the end of the observation, the indicators continued to remain well below the control level. In patients with AMD, the initial concentration of ACE in the lacrimal fluids was not elevated; the concentration of ACE in the lacrimal fluids decreased 1.4 times one week after IVI of ranibizumab. The concentration of ACE in the blood serum of the patients with AMD was initially 25% lower than the control level, and essentially did not change after IVI of ranibizumab. СONCLUSIONS: Changes in the concentration of ACE in patients with DME may be a new prognostic criterion for the development of DME for patients with diabetes. These changes in the concentration of ACE, in the context of antiangiogenic therapy, indicate an interaction between the renin-angiotensin and angiogenic systems. Similar changes that were observed after IVI of ranibizumab in patients with AMD confirm the mutual influence of these two systems. The data presented in this study open up prospects for finding new pathways of pathogenic therapy for diabetic macular edema and diabetes.

[Possibilities of multicolor confocal scanning laser ophthalmoscopy in complex diagnostics of severe proliferative diabetic retinopathy]. / Lazernaia mul'tikolor-oftal'moskopiia v kompleksnoi diagnostike tiazheloi proliferativnoi diabeticheskoi retinopatii.

Multicolor scanning laser ophthalmoscopy (multicolor SLO) is a new informative method of eye fundus visualization. The method is based on synchronously obtaining three separate confocal images with monochromatic laser sources - blue (488 nm), green (515 nm) and infrared (820 nm), which are then combined into one in the Multicolor mode. PURPOSE: To evaluate the informative value of multicolor SLO in a complex examination of patients with severe proliferative diabetic retinopathy (PDR). MATERIAL AND METHODS: A total of 46 patients (62 eyes) aged 19 to 75 years with severe PDR was examined. All patients had massive growth of proliferative tissue on the eye fundus, which caused traction deformation and/or retinal detachment in the posterior pole. Optical mediums of the eyes were sufficiently transparent to obtain high quality images. All patients underwent color photo-registration of the fundus, fluorescein angiography (FA), optical coherence tomography (OCT) and multicolor SLO under drug-induced mydriasis. RESULTS: Pseudo-volumetric images obtained with multicolor SLO allow visualization of of preretinal proliferative membranes and their structure, the degree of their vascularization, the anatomical features of their attachment to retina, and the occluded vessels on fundus periphery. Being an additional option on scanning laser ophthalmoscope, the technique does not require special equipment, which enables several separate examinations, including OCT and FA, to be performed on a single device. CONCLUSION: Multicolor SLO is a promising new method of visualizing structures of the eye fundus and can be successfully used in complex diagnostics, monitoring and preoperative preparation of patients with severe PDR.

[Impact of antiangiogenic therapy on ocular blood flow and microcirculation in diabetic macular edema]. / Vliianie antiangiogennoi terapii na glaznoi krovotok i mikrotsirkuliatsiiu pri diabeticheskom makuliarnom oteke.

Today, diabetic macular edema (DME) is still one of the main causes of vision loss in patients with diabetes. PURPOSE: To identify changes in the ocular blood flow and microvascular network of the macular zone in patients with DME after antiangiogenic therapy. MATERIAL AND METHODS: In the course of the study, 25 patients (50 eyes) with monolateral clinically significant DME aged 67.5±3.85 years were examined. Control group consisted of 75 healthy subjects (150 eyes). All patients underwent ultrasound examination of the eyes and orbits (in Color Doppler Imaging (CDI) and Pulse-Doppler modes) and OCT-angiography (OCT-A) before the intravitreal injection of ranibizumab, as well as 3 days, 2 weeks, and 1 month after the treatment. RESULTS: According to OCT-A, the initial values of microvascular network parameters were significantly below the norm (p<0.05). After intravitreal ranibizumab injection (IRI), no significant changes in the density of microcapillaries or in the parameters of foveal avascular zone (FAZ) were recorded. However, a transient increase of the FAZ area was revealed 2 weeks after the injection, as well as an increase of microcapillaries density in the central quadrant together with a decrease of density in the peripheral quadrants 1 month after IRI. By the end of the follow-up period, a decrease in the initially raised maximum systolic velocity (Vsyst) and resistance index (RI) in the ophthalmic artery (OA) of the affected eye were documented. Additionally, an increase in Vsyst and 2-fold increase in end-diastolic velocity (Vdiast), as well as a decrease in RI in the central retinal artery (CRA) on the affected and paired eyes were detected. CONCLUSION: The study revealed no negative effects of the angiogenesis inhibitor ranibizumab on retinal microcirculation or ocular blood flow. The registered changes in blood flow may indicate improvement of hemodynamic parameters after resorption of macular edema.

[Role of optical coherence tomography angiography in diagnostics of early choroidal melanoma and circumscribed choroidal hemangioma]. / Opticheskaia kogerentnaia tomografiia-angiografiia v diagnostike nachal'noi melanomy i otgranichennoi gemangiomy khorioidei.

Small choroidal melanoma is a malignant tumor that is prone to early metastasis, its amelanotic form is often similar to circumscribed choroidal hemangioma. The main attribute for tumor identification is its vascularization, which is the target of various examination methods. Optical coherence tomography angiography (OCTA) has not been previously used in complex diagnostics of early choroidal melanoma and circumscribed choroidal hemangioma for detection of tumor vessels and the nature of their branching, as well as for vessel caliber comparison. Purpose to examine vascularization of early uveal melanoma and circumscribed choroidal hemangioma by optical coherence tomography angiography. MATERIAL AND METHODS: The study included 23 patients with early choroidal melanoma (13 subjects) and circumscribed choroidal hemangioma (10 subjects) that were examined by optical coherence tomography angiography. According to ultrasound investigation, mean tumor prominence was 1.1±0.3 mm, mean base diameter - 8.1±0.6 mm. RESULTS: Optical coherence tomography angiography in 13 patients with small choroidal melanoma revealed presence of a neovascular component localized under retinal pigment epithelium (RPE) that had marginal avascular zone corresponding to the tumor slope. The loop-like shape of tumor vessels with numerous twists and interweaving was noted under retinal vessels. A tree-shaped neovascular component with large-caliber vessels in the form of a tree trunk with multiple branches extending from it was seen under RPE in 4 cases with circumscribed choroidal hemangioma; diffuse vascularization in the form of numerous tiny tortuous vascular branches was seen in 6 patients. CONCLUSION: Optical coherence tomography angiography allows detection of tumor`s own vessels with characteristics of their vascularization in early choroidal melanoma and circumscribed choroidal hemangioma. Increasing the frequency of detection of tumor`s own vessels will make possible early differential diagnostics of a malignant or benign tumor and will help establish adequate conserving therapy.