RU2749122C1 - Method for comprehensive treatment of macular edema associated with occlusion of branch of central retinal vein with oct control in real time - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to medicine, namely to ophthalmology. Treatment is carried out within one month from the moment of occlusion. At the first stage, a subthreshold micropulse laser exposure (SMILV) with a wavelength of 810 nm, low intensity or high density is carried out. Then, a panmacular operation is carried out 500 microns from the center of the macula, and an expanded paramacular operation is carried out in the upper or lower hemisphere, respectively, of the localization of the occluded branch of the CRV not reaching 500 microns to the optic disc and vascular arcade. In this case, the application of the applicates is carried out by the drain method without intervals, sector-by-sector, according to the "painting" technique, using subthreshold testing with OCT-dosimetric control in real time. At the second stage, after 50-60 minutes intravitreal administration of a VEGF inhibitor is performed. Repeated courses of complex treatment are carried out in 1.5-2 months or more.EFFECT: method makes it possible to treat macular edema in the early period from the moment of occlusion to the development of irreversible structural and functional disorders, allows to shorten the treatment time, to obtain an earlier, stable and effective restoration of the anatomy of the macula and visual functions; reduce the number of intravitreal injections of a VEGF inhibitor required.1 cl, 2 ex

Description

The invention relates to medicine, namely to ophthalmology, and is intended for effective and safe, organ-preserving treatment of macular edema (MO) of the retina with occlusion of the PCV branch. Being a serious complication of retinal venous occlusions, MO causes a decrease in visual functions, and in the absence of treatment, or late, ineffective treatment, pathological structural changes in the macular zone of the retina become partially irreversible, destruction and loss of photoreceptors occurs, and restoration of visual functions is no longer possible, and disability occurs. Prolongation of MR irreversibly changes the structure of the retina, so it is advisable to start its treatment as early as possible (Rotsos TG, Moschos MM Cystoid macular edema. Clin. Ophthalmol, 2008, Vol.2, No. 4; Astakhov Yu.S., Tultseva CH, Gatsu MB Retinal Vein Occlusions, 2017).

Analogs

Currently, VEGF (endothelial vascular growth factor) inhibitors are the first-line drugs for the treatment of MO in retinal vein occlusion, whose intravitreal injections (IVI) effectively reduce MO with restoration of visual acuity in a short time. At the end of the duration of their therapeutic action, the MO height and visual acuity return to the initial level, therefore IVI of the inhibitor is repeated monthly, then once every 2 months, then according to indications, up to a year or more (Campochiaro R.A. et al. BRAVO Investigators Ranibizumab for macular edema following branch retinal vein occlusion. Ophthalmology, 2010; Budzinskaya MB, Mazurina HK Algorithm for the management of patients with retinal venous occlusions. Communication 2. Macular edema. Bulletin of Ophthalmology, No. 6, 2015).

The use of IVI glucocorticoids for the treatment of MO in retinal venous occlusions, instead of VEGF inhibitors, takes place, especially in the case of resistance to inhibitors in some patients. Prolonged forms for intraocular administration of triamcinolone, dexamethasone with slow release have been created and are used, but they are not free from the negative side effects of prolonged steroid therapy, such as the development of cataracts and glaucoma, up to the operable stage in some patients, which is a significant drawback (Scott IU et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to BRVO / SCORE. Arch Ophthalmol 2009; Haller JA et al. GENEVA: Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion.Ophthalmology, 2010).

Studies CVOS, 1997, and SCORE / BRVO, 2009 confirmed the positive effect of laser coagulation (LC) in the "lattice" type in MO resorption in nonischemic occlusion of the PCV branch (PCVO), if after 3-6 months MO persists, visual acuity remains at 0 , 5 and below, with normal perfusion of the macular zone. The so-called "delayed" LK, in this case, is a component of the standard method of treatment of MO in RVCVO; in the form of monotherapy, it does not significantly increase visual acuity, but stabilizes visual functions. The technique consists in the application of coagulates with a diameter of 100 microns, in the form of a "lattice" in several rows on the macula area, retreating 1500 microns from the foveola (without affecting the foveolar avascular zone), in the peripheral rows - up to 200 microns in diameter, at a distance of 1-2 diameters coagulum (Central Vein Occlusion Study, 1997; Budzinskaya MB, Mazurina NK Algorithm for the management of patients with retinal venous occlusions. Communication 2. Macular edema. Bulletin of Ophthalmology, No. 6, 2015; Federal Clinical Guidelines for Ophthalmology, Ministry of Health of the Russian Federation, 2015; Sdobnikova S.V., Mirzabekova K.A., Seurguch V.K. Modern approaches and place of laser coagulation in the treatment of retinal vein occlusions. Bulletin of Ophthalmology, No. 3, 2017).

Retinal LC of the "lattice" type ("modified lattice"), 532 nm, is currently used as a complementary method for the treatment of MR in RVCVO after IVI of the drugs of these groups, providing combined treatment; LA is performed after anti-VEGF treatment, as it can increase MO and destructive macular disorders (Campochiaro R.A., BRAVO Investigators Ranibizumab for macular edema following branch retinal vein occlusion. Ophthalmology, 2010; Coscas G., Retreatment with Ozurdex for macular edema secondary to retinal vein occlusion. Ophthalmol, 2014; Budzinskaya MB, Mazurina NK Algorithm for the management of patients with retinal venous occlusions. Communication 2. Macular edema. Bulletin of Ophthalmology, No. 6, 2015; Astakhov Yu.S., Tulceva S. N., Gatsu M.V. Retinal vein occlusions, 2017).

Exerting its therapeutic effect aimed at reducing MO, LA thermally damages all layers of the retina, including the neurosensory layer that performs visual functions; causes side effects and complications: retinal scars leading to defects in the paracentral field of vision, decreased contrast sensitivity of the retina, expanding atrophy of RPE and choroid, subretinal fibrosis, neovascularization of the choroid (Lanzetta R., Dorin G., Theoretical bases of non-endpoint Ophthalmology, 2001; Kiire CA, Sivaprasad S., Chong V. Subthreschold Micropulse Laser therapy for Retinal Disorders. Retina Today, 2011); increases the amount of pro-inflammatory cytokines in the structures of the chorioretinal complex (CRC), causes reactive edema of the retina, which enhances the existing MO, leading to even greater destructive disorders of the macula with a decrease in visual functions (Er N., Doganay S., The levels of cytokines and nitric oxide in rabbit vitreous humor after retinal laser photocoagulation. Ophthalmic S Lasers, 2000; Khodjaev HC, et al. Effect of laser coagulation of the retina on clinical and laboratory parameters in patients with diabetic macular edema. Bulletin of NSU, 2011; Deschler EK et al. Side-Effects and Complications of Laser Treatment in Diabetic Retinal Disease. Sem. Ophthalmol. 2014).

Subthreshold micropulse laser exposure (SMILV) with a wavelength of 810 nm, selectively at the level of RPE-choriocapillaris, is maximally absorbed by RPE melanin, passes through the internal media of the eye, the neurosensory layer of the retina, blood hemoglobin (in post-occlusive hemorrhages), without being absorbed by them; pathogenetically substantiated, its therapeutic effect of MO resorption is comparable to the effect of threshold LA, without its inherent complications (Luttrull JK, Long-term safety, high-resolution imaging, and tissue temperature modeling of subvisible diode micropulse photocoagulation for retinovascular macular edema. Retina, 2012; Volodin P.L., Doga A.V. Appendix No. 2 to the order of the Ministry of Health of the Russian Federation No. 433n, 2015; Izmailov A.S., Kotsur T.V. Use of 0.81 μm diode laser in high-density microphotocoagulation mode for the treatment of macular edema . Ophthalmology, 2016). As a result of stimulation of RPE cells, their production of anti-inflammatory factors, the antiangiogenic factor of the pigment epithelium (PEDF), with neuroprotective and neurotrophic properties increases (Duh EJ, Yang HS, Campochiaro PA et al. Pigment epithelium derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced retinal neovascularization migration and growth. Ophthalmol, 2002; Takhchidi Kh.P., Gavrilova HA, Comparative characteristics of the effect of PEDF and Avastin. Ophthalmosurgery. 2009).

Prototype

The prototype is "Method of modified subthreshold panmacular microphotocoagulation of the retina in diabetic macular edema" (RF patent No. 2308920), it consists in subthreshold micropulse laser exposure. Testing in the areas of the retina farthest from the center of the macula is carried out with a packet of impulses with a duration of 0.2 s, selecting the power until a barely noticeable trace of laser exposure appears, after which the exposure is reduced to 0.1 s. Subthreshold microphotocoagulation is carried out concentrically around the source of leakage, in two or more rows, within the zone of local retinal edema, the intervals between coagulates are equal to the diameter of the coagulum; then - on the entire area of the macula, excluding the foveal avascular zone, with radial rows of coagulates, at intervals equal to the diameter of the coagulum, with the capture of the edge of the avascular zone.

Disadvantages of the prototype

In the prototype method, a partial pathogenetic effect on the retina is performed. Increased expression of VEGF, which contributes to the preservation of MO, occurs not only in the macular zone and around the source of local extravasation, where laser exposure is performed, but also in the entire paramacular zone of the retina, corresponding to the thrombosed branch of the PCV. Performing laser exposure only on the area of retinal edema is not effective enough for a long-term lasting treatment result. Pathological changes that contribute to the preservation of MO occur in the entire corresponding paramacular zone, from where fluid seeps out and re-accumulates in the macula.

The technique is somewhat laborious for practical use, since not all microaneurysms and local extravasation zones are detected ophthalmoscopically for their targeted patrolling, which requires preliminary fluorescence angiography followed by mapping on the fundus.

During testing, a "barely noticeable tissue trace" is achieved on the retina, that is, a threshold laser coagulum is applied, then the laser intensity is reduced to a subthreshold level; the technique of the prototype method cannot be considered completely safe for the retina, completely subthreshold, especially taking into account possible repeated courses; threshold test coagulates can be a source of subsequent cattle and other complications.

The aim of the invention is to increase the effectiveness of treatment of MO with occlusion of the branch of the PCV due to the complex simultaneous use of SMILV, 810 nm, low intensity / high density and IVI of the VEGF inhibitor - in the early periods from the moment of occlusion (up to 1 month), until the development of destructive changes in the macula with irreversible loss of vision; with a possible repetition of the course of complex treatment in 1.5-2 months or more; ensuring an earlier stable structural and functional restoration of the macula, using a safe, organ-saving treatment method; decrease in the frequency of IVI of the VEGF inhibitor.

The essence of the proposed method

The method is intended for the treatment of macular edema with occlusion of a branch of the central retinal vein in the early period from the moment of occlusion (up to 1 month), and is a complex technique consisting of two successive stages, with a time interval between them of 50-60 minutes.

Stage 1 - SMILV, 810 nm, infrared diode laser (IRIS Medical IQ 810, IRIDEX, USA) using safe effective parameters recommended for practical use based on the results of domestic and foreign studies (Doga A.V., Zhuravleva E.S. Infrared micropulse diode laser radiation in the treatment of macular pathology, 2011; Izmailov A.S., Kotsur T.V.The use of a 0.81 micron diode laser in high-density microphotocoagulation mode for the treatment of macular edema.Ophthalmology, 2016; Luttrull JK Low-intensity / high -density subthreshold diode micropulse laser for central serous chorioretinopathy. Retina. 2016; others). The maximum dilatation of the pupil with mydriacil 1%, local anesthesia with alkaine 0.5%, application of a contact lens Reichel-Mainster 1x (0.95x) on the anterior segment of the eye with preliminary application of corneregel 5% is performed. Parameters used: applicate diameter 125 μm, micropulse duration 25-50 μs, duty cycle 2-5%, pulse packet duration 0.1-0.2 s, power 850-1500 mW, - were selected individually, depending on the degree of eye pigmentation. bottom, MO height, transparency of the eye media.

Preliminary testing is performed by a packet of impulses in the most pigmented retinal area remote from the macula, near the vascular arcade, by a stepwise increase in the power of invisible applications from 700 mW, adding 100 mW each, with OCT dosimetry control (on a spectral optical coherence tomograph RTVue XR Avanti, Optovue, USA). When a barely noticeable hyperreflective spot appeared on the OCT scan in the photoreceptor layer in the projection of the last applied test patch, testing ended with the selection of the power of the previous applicator corresponding to the true subthreshold one (Lavinsky D. et al. Subvisible retinal laser therapy. Titration Algorithm. Retina. 2014; Steiner P . et al. Time-Resolved Ultra-High Resolution Optical Coherence Tomography for Real-Time Monitoring of Selective Retina Therapy. Ophthalmol. 2015; Kaufmann D. et al. Selective retina therapy enhanced with optical cogerence tomography for dosimetry control and monitoring. Biomed Opt Express. 2018). The applicability determined on OCT corresponded to the clinical subthreshold (Framme C. et al. Structural Changes of the Retina After Conventional Laser Photocoagulation and Selective Retina Treatment in Spectral Domain OCT. Curr Eye Res. 2009; Luttrull JK, Dorin G. Subthreshold diod micropulse laser photocoagulation (SDM) as invisible retinal phototherapy for diabetic macular edema. Current diabetes reviews. 2012), which does not leave laser-induced retinal damage after 30 days. Damaged photoreceptors and RPE cells are completely restored after 30 days, since their coagulation "burning" did not occur, the state of CRC structures returns to the initial state (Fedoruk N.A., Fedorov A.A., Bolshunov A.V. Ultrastructural changes in the chorioretinal complex during exposure to subthreshold laser radiation at wavelengths 0.81 and 0.532 microns. Experimental study. Ophthalmology. 2014).

Therapeutic laser exposure: panmacular and expanded paramacular - in the upper or lower hemisphere, depending on the localization of the occluded branch of the PCV. Since laser applicators are invisible and control of the treated area of the retina is difficult, it is more convenient to apply sector-by-sector for a more thorough treatment of the entire targeted area (Doga A.V., Kachalina G.F., Kuranova O.I., 2014). The laser exposure area was divided into 4 quadrants, according to the vertical and horizontal axes; the applications were applied in turn in each quadrant: from one axis to the other, according to the "paint over" technique, low intensity / high density (Luttrull JK, 2005, Lavinsky D. et al, 2011, Luttrull JK, Dorin G., 2012), starting from the macular area, 500 microns away from the center of the macula, and one row outward from the borders of the MO, then to the paramacular region, in the upper or lower hemisphere, not reaching 500 microns to the boundaries of the optic nerve head and vascular arcade. To exclude repetitive processing of the same quadrant in "invisible retinal therapy", the established definite sequence was used: upper hemisphere - left, then right quadrant (left to right), lower hemisphere - left, then right quadrant (left to right), with application of applicators almost draining (almost without intervals). After removing the contact lens - a topical antiseptic for the prevention of infectious and inflammatory complications.

Stage 2 - intravitreal administration of the VEGF inhibitor ranibizumab (lucentis 0.5 mg / 0.05 ml) or aflibercept (eilea 2 mg / 0.05 ml) in the operating room, under aseptic conditions. Local anesthesia with alkaine 0.5%, antiseptic treatment of the operating field with betadine, chlorhexidine 0.05%, blepharostat imposition. 4 mm from the limbus in the upper-outer quadrant, in the pars plana projection, having previously slightly displaced the conjunctiva from the sclera above the injection site, puncture the conjunctiva and sclera in the perpendicular direction with a thin needle (30 G) and injected into the vitreous towards the center of the eyeball with the introduction of an inhibitor solution, removing the needle perpendicular to the plane of the sclera; at the end - topical antibiotic, antihypertensive, antiseptic dressing; antibiotic and antihypertensive topically for 2 weeks.

The complex method can be used again after 1.5-2 months or more for the treatment of MO with RVCVO with the aim of complete resorption of MO with maximum restoration of visual acuity.

Features of the invention that differ from the prototype

Prototype features

In the prototype method, panmacular subthreshold microphotocoagulation is performed in radial rows, and the distance between the coagulates can be different. It is necessary to patrol around each microaneurysm - the source of extravasation. Preliminary testing with a packet of impulses with a duration of 0.2 s, selecting the power until a barely noticeable trace from the laser exposure appears, then the exposure is reduced to 0.1 s.

Signs of invention

1. According to the proposed method, a subthreshold micropulse drug, 810 nm, low intensity / high density is performed sector by sector, according to the "painting" technique, almost confluent (almost without intervals) application of laser applications: panmacular and expanded paramacular in the upper or lower hemisphere, depending on localization of occlusion (in the upper or lower branch of the PCV), on the entire retinal zone involved in the pathological process, which increases the area of therapeutic effect: absorption at the RPE-choriocapillary level increases, VEGF production decreases, the expression of its own anti-angiogenic and anti-inflammatory factors increases, which causes resorption of MO.

2. Testing for selecting the intensity of SMILV is subthreshold, thanks to OCT dosimetric control, it does not leave tissue traces in the neurosensory retina, which makes the SMILV technique completely subthreshold, safe, in contrast to the prototype method.

3. The proposed complex method for the treatment of MO with RVCVO, in contrast to the prototype, includes SMILV, 810 nm, low intensity / high density and simultaneous IVI of the VEGF inhibitor - in the early periods from the moment of occlusion (up to 1 month), with a possible repetition of the course of complex treatment , which allows you to summarize both therapeutic actions and get a faster, more stable and long-term restoration of the anatomy of the macula with the maximum possible restoration of visual functions.

Clinical examples

Patient T., 68 years old, complaints of a sharp decrease in vision of the right eye after a hypertensive crisis a few days ago; examined on an outpatient basis, DS: occlusion of the inferior temporal branch of the PCV of the right eye, initial cataract in both eyes; accompanying diagnosis: hypertension II degree, arterial hypertension 3 degree, risk 3. Passed a 10-day course of early conservative pathogenetic therapy, corrected antihypertensive therapy.

When applied, the maximum corrected visual acuity (MCVA) OD = 0.2, OS = 0.9; IOP OU = 20 mm Hg Stereoscopic ophthalmoscopy OD: expansion and tortuosity of the inferior temporal branch of the PCV, edema and hemorrhages in the inferior temporal segment; biomicroscopy OD: transparent lens, slight opacities in the cortical layers. OCT of the retina OD: rarefaction of the retinal layers in the region of the macula with an area of serous detachment of the neuroepithelium, the central retinal thickness (CTS) - 392 μm. The proposed complex method of treatment of MO OD: SMILV, 810 nm, according to the described method was carried out; after 50-60 minutes. in the operating room, under aseptic conditions - IVI of the VEGF inhibitor ranibizumab (lucentis) 0.5 mg / 0.05 ml, then a topical antibiotic, aseptic dressing; within 2 weeks: floxal 1 to 3 r, betoptic 0.5% 1 to at night.

After 1.5 months of observation after treatment with BCVA OD = 0.4, OS = 0.9; IOP OU = 20 mm Hg OCT of the retina OD: the profile of the macula is closer to normal, the rarefaction of the retinal layers in the macular zone has significantly decreased, the CTS is 298 μm. Computer static perimetry (CP) OD: an increase in the average central photosensitivity (CSP) of the retina (MS) from 16.4 dB to 17.8 dB, not detected in cattle. With ophthalmoscopy: there is a resorption of hemorrhages. A repeated course of complex treatment was carried out. After 1.5 months. after a repeated course of MCVA OD = 0.6; OS = 0.9; on OCT, the profile of the macula OD is close to normal, the CTL of the macular zone is 267 µm; with CP, the average CPF of the retina increased to 18.4 dB. 2.5 months after the repeated course of treatment, ICVA OD = 0.7; OS = 0.9; on OCT OD, the macula profile is normal, PZT - 252 μm; with CP, the average CPR of the retina is 18.7 dB, not found in cattle; with ophthalmoscopy, significant resorption of hemorrhages; during the entire observation period, there was no deterioration of the listed indicators.

Patient M., 69 years old, complaints of a sharp decrease in vision in the left eye after a prolonged uncorrected rise in blood pressure a week ago; examined, DS: occlusion of the superior temporal branch of the PCV of the left eye; conn. diagnosis: hypertension II degree, arterial hypertension 3 degree, risk 3. Passed a 10-day course of early conservative therapy, correction of antihypertensive therapy. MCVA OD = 0.8; OS = 0.3. With ophthalmoscopy OS: expansion and tortuosity of the superior temporal branch of the PCV, edema and hemorrhages in the superior temporal segment of the fundus; on OCT OS: rarefaction of the retinal layers in the macula with an area of serous detachment of the neuroepithelium, CTS OS -387 microns; at the CP, the average CPR of the retina OS (MS) is 17.2 dB. The proposed complex method of OS treatment was carried out: SMILV, 810 nm, according to the described method, after 50-60 minutes. - IVI VEGF inhibitor aflibercept (eilea) 2 mg / 0.05 ml.

1.5 months after the treatment, the MCVA OS increased to 0.5; on OCT of the retina OS: the macular profile changed closer to normal, the rarefaction of the retinal layers in the macular region decreased, the MO height in the central zone decreased to 288 µm; on CP OS: the average CSF of the retina increased to 18.3 dB, not found in cattle; with ophthalmoscopy OS: resorption of hemorrhages. A second course of complex treatment was carried out 2 months after the treatment. 1.5 months after the repeated course of MCVS OS = 0.7; The OCT OS on OCT decreased to 242 µm, the rarefaction of the retinal layers in the macular zone has almost completely passed, the macular profile is close to normal; on the CP, the average CPR of the retina was 18.8 dB, not found in cattle; with ophthalmoscopy: postocclusive hemorrhages have significantly resolved; during the entire observation period, there was no deterioration of the listed indicators.

Method advantages

1. SMILV, 810 nm, low intensity / high density on the entire retinal area involved in the pathological process: panmacular and expanded paramacular, on the entire hemisphere corresponding to the occluded branch of the CVS, with almost confluent application of laser applications, increases the area of the therapeutic effect and its effectiveness: improves chorioretinal metabolism, absorption of intra- and subretinal fluid, reduces retinal ischemia and VEGF production; increases the production of anti-angiogenic and anti-inflammatory factors (PEDF, etc.) by cells of the pigment epithelium, which promote MO resorption.

2. The use of subthreshold testing with OCT-dosimetric control "in real time" in the proposed complex method of treatment of MR makes it possible to make the SMILV technique completely safe for the neurosensory layer of the retina, in contrast to the applied testing with the achievement of the threshold exposure level and subsequent decrease to the subthreshold level, when which is inevitable thermal burns of the retina, the death of photoreceptors, a decrease in the photosensitivity of the retina, the formation of cattle, etc., taking into account the need for repeated courses of complex treatment in the same patient.

3. The proposed complex method for the treatment of MO in RVCVO includes the simultaneous SMILV, 810 nm, low intensity / high density and IVI of the VEGF inhibitor, which allows you to summarize both therapeutic effects. The VEGF inhibitor helps in a short time to achieve a decrease in MO while maintaining visual functions, while SMILV has a gradual therapeutic effect on the retina. The use of two therapeutic strategies simultaneously allows achieving a more complete and stable anatomical and functional restoration of the macula in the early stages, providing a more long-term result; reduce the number of intraocular injections of VEGF inhibitors.

4. Early, before the development of irreversible structural and functional changes in the macula, the use of a complex method of treatment contributes to a faster and more stable resorption of MR in RVCVO, earlier restoration of the integrity of photoreceptors and visual functions, a stable result of treatment; allows you to shorten the treatment time.

Claims (1)

A method of complex treatment of macular edema with occlusion of a branch of the central retinal vein, including the conduct of subthreshold micropulse laser exposure (SMILV), characterized in that the treatment is carried out within one month from the moment of occlusion, at the first stage, SMIL is performed with a wavelength of 810 nm, low intensity and high density, including panmacular exposure, retreating 500 microns from the center of the macula, and expanded paramacular in the upper or lower hemisphere, respectively, the localization of the occluded branch of the CVS, not reaching 500 microns to the optic nerve disc and the vascular arcade, confluent application of applicators without intervals, sector by sector, according to the method " painting ", with the use of subthreshold testing with OCT dosimetry control in real time during SMILV, at the second stage, after 50-60 minutes, intravitreal administration of a VEGF inhibitor is carried out; repeated courses of complex treatment are carried out in 1.5-2 months or more.