RU2815155C1 - Method for prediction of risk of developing low-tension glaucoma by optical coherence tomography with angiography - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely ophthalmology, and can be used to predict the risk of low-tension glaucoma (LTG). Patient is examined for optical coherence tomography with angiography of the macular region of the retina: vascular density values in the Fovea and Parafovea regions, in lower hemisphere and nasal sector of macula of superficial choroid plexus, thickness of retina in Fovea, lower hemisphere and lower sector of macula; optical coherence tomography indices: average thickness of the retinal ganglion cell complex in the lower sector, the level of focal losses. LTG risk coefficient is calculated. If the LTG risk coefficient is -158.0 and more, a high LTG risk is predicted.

EFFECT: method provides higher prediction accuracy by taking into account additional pathogenetic risk factors.

1 cl, 1 dwg, 1 tbl, 3 ex

Description

The invention relates to medicine, namely ophthalmology, and can be used to predict the risk of developing low-tension glaucoma.

Low-tension glaucoma (LPG) is a clinical form of primary open-angle glaucoma with a level of intraocular pressure (IOP) within the average statistical norm [National Guide to Glaucoma: for practicing physicians / ed. E.A., Egorova, V.P. Ericheva. - 4th ed., rev. and additional M.: GEOTAR-Media, 2019. 384 p.]. The pathogenesis of the disease has not been fully studied to date. One of the main theories of development is vascular [Kurysheva N.I. Vascular theory of the pathogenesis of glaucomatous optic neuropathy: the main aspects that form the vascular theory of the pathogenesis of glaucoma. Part 3. National Journal of Glaucoma. 2018; 17(1):101-112].

Particular attention is paid to the study of the macula, since this area is the most metabolically active and more than 50% of all retinal ganglion cells are concentrated in it [Hood DC, Slobodnick A, Raza AS, de Moraes CG, Teng CC, Ritch R. Early glaucoma involves both deep local, and shallow widespread, retinal nerve fiber damage of the macular region. Invest Ophthalmol Vis Sci. 2014 Feb 3; 55(2):632-49. doi: 10.1167/iovs.l3-13130. PMID: 24370831; PMCID: РМС3912939].

Involvement of the macula in the glaucomatous process, according to optical coherence tomography (OCT), can be realized by a decrease in the thickness of the retinal ganglion cell complex (RGC), most often in the lower parafoveal region [Hood DC, Raza AS, de Moraes CG, Liebmann JM, Ritch R. Glaucomatous damage of the macula. Prog Retin Eye Res. Jan 2013; 32:1-21. doi: 10.1016/j.preteyeres.2012.08.003. Epub 2012 Sep 17. PMID: 22995953; PMCID: РМС3529818]. When studying the parameters of the corticosteroids in the initial stage of glaucoma, a decrease in thickness in the lower and temporal sectors was revealed [Hou N, Moghimi S, Zangwill LM, Shoji T, Ghahari E, Penteado RC, Akagi T, Manalastas PIC, Weinreb RN. Macula Vessel Density and Thickness in Early Primary Open-Angle Glaucoma. Am J Ophthalmol. Mar 2019; 199:120-132. doi: 10.1016/j.ajo.2018.11.012. Epub 2018 Nov 26. PMID: 30496723; PMCID: РМС6382614].

Optical coherence tomography angiography (OCTA) is a modern non-invasive method for studying the blood flow of the retina and optic nerve at various levels [Spaide RF, Fujimoto JG, Waheed NK, Sadda SR, Staurenghi G. Optical coherence tomography angiography. Prog Retin Eye Res. May 2018; 64:1-55. doi: 10.1016/j.preteyeres.2017.11.003. Epub 2017 Dec 8. PMID: 29229445; PMCID: PMC6404988]. This method allows you to visualize the superficial and deep choroid plexuses of the macular region of the retina [Rao HL, Pradhan ZS, Suh MH, Moghimi S, Mansouri K, Weinreb RN. Optical Coherence Tomography Angiography in Glaucoma. J Glaucoma. 2020 Apr; 29(4):312-321. doi: 10.1097/IJG.0000000000001463. PMID: 32053551; PMCID: РМС7117982].

In patients with glaucoma, OCTA data revealed a decrease in vascular density in the superficial choroid plexus already in the initial stage of the disease [Nishida T, Oh WH, Moghimi S, Yarmohammadi A, Hou H, David RCC, Kamalipour A, Shoji T, El-Nimri N , Rezapour J, M Zangwill L, Weinreb RN. Central macular OCTA parameters in glaucoma. Br J Ophthalmol. Feb 2023; 107(2):207-214. doi: 10.1136/bjophthalmol-2021-319574. Epub 2021 Aug 23. PMID: 34426401; PMCID: РМС9368252].

There is a known method for diagnosing glaucoma based on changes in the linear velocity of blood flow in the superior orbital and internal carotid arteries on the affected side using Doppler ultrasound [Patent RU No. 2135087, 1999]. This method does not take into account changes in the microcirculation of the retina and optic nerve.

There is a known method for assessing hemodynamics in patients with GND using Doppler ultrasound of the internal carotid artery, ophthalmic artery, central retinal artery with determination of the volumetric blood flow index using the modified Poiseuille formula [Shmyreva V.F., Mostovoy E.N. “Hemodynamics of the optic nerve and retina in unstabilized glaucoma with normal intraocular pressure” // Bulletin of Ophthalmology. 1997. - No. 6. - Volume 113. - P. 7-9]. This method is based on the study of blood flow in large arteries supplying the optic nerve and retina, without taking into account microcirculation parameters in the posterior short ciliary arteries.

The closest analogue of the invention is a method for predicting the progression of optic neuropathy in primary open-angle glaucoma based on the thickness of the internal layers of the macula in the lower hemisphere, the relative density of the vessels of the superficial layer in the parafovea using OCTA, the pattern-ERG coefficient - PERG Ratio 2 (the ratio of the latency of stationary PERG to angular stimuli sizes 0.8° and 16°) [RU Patent No. 2706956, 2019]. When the thickness of the internal parts of the macula is less than 105 μm, the relative density of the vessels of the superficial layer in the parafovea is less than 45%, and the value of PERG Ratio 2≤1.12, the progression of glaucomatous optical neuroopticopia in POAG is predicted. This method requires the use of additional electrophysiological research methods, which are not available in all medical institutions.

The objective of the invention is to develop a method for predicting the risk of developing low-tension glaucoma with high sensitivity and specificity.

The technical result is to increase the accuracy of predicting the development of GND by taking into account additional pathogenetic risk factors.

The proposed method for predicting the risk of developing GND is carried out as follows. In a patient suspected of having this disease, the OCT parameters of the corticosteroids are determined: the average thickness of the corticosteroid complex in the lower sector, the level of focal losses; OCTA parameters of the macular region of the retina: indicators of vascular density in the Fovea and Parafovea, in the inferior hemisphere and nasal sector of the macula of the superficial choroid plexus, retinal thickness in the Fovea, inferior hemisphere and inferior sector of the macula.

After this, the obtained data is substituted into a mathematical model:

RFNTG = (-0.552)*GCCINF + 6.376*FLV - 0.258* SFOVEA - 0.121*SPARAFOVEA - 0.502*TINFHEMI - 0.213*TLNF - 1.236*SLNFHEMI - 0.223*SNASAL - 0.229*TFOVEA + 255.36,

Where:

RFNTG - risk coefficient for developing GND;

GCCINF - OCT indicator of the GCL complex Inferior GCC - average thickness of the GCL complex in the lower sector, µm;

FLV - OCT indicator of the GCS complex - level of focal losses of the GCS, %;

SFOVEA - OCTA indicator of vascular density in the Fovea region of the superficial choroid plexus, %;

SPARAFOVEA - OCTA indicator of vascular density in the Parafovea area of the superficial choroid plexus, %;

TINFHEMI - OCTA indicator of retinal thickness in the inferior hemisphere of the macula, µm;

TINF - OCTA index of retinal thickness in the lower sector of the macula, µm; SINFHEMI - OCTA indicator of vascular density in the inferior hemisphere of the macula of the superficial choroid plexus, %;

SNASAL - OCTA indicator of vascular density in the nasal sector of the macula of the superficial choroid plexus, %;

TFOVEA - OCTA index of Fovea thickness, µm;

255.36 is a mathematical constant.

With an RFNTG value of -158.0 or more, the development of low-tension glaucoma is predicted.

The invention is illustrated by a figure that shows a logit model of regression analysis indicating significant risk factors for the development of GND.

In order to develop a model for predicting the risk of developing GND, we analyzed data from 63 patients with GND in the initial and advanced stages aged from 45 to 65 (on average 55±2.7) years. Of these, 43 (68.2%) were women and 20 (31.7%) were men. The criterion for inclusion in the study was the diagnosis of “Primary open-angle glaucoma with low pressure” (H40.1), established on the basis of clinical, laboratory and instrumental research methods in accordance with modern diagnostic criteria (Federal clinical recommendations for ophthalmology, approved by the Ministry of Health of Russia, 2017. ). The control group included 50 individuals without glaucoma, comparable to GND patients by gender and age.

When developing the model, along with traditional clinical methods for diagnosing glaucoma (visometry, ophthalmoscopy), non-contact tonometry (Nidek, Japan) was used. OCT of the optic nerve head (Optovue Avanti RTVue XR, USA) was performed in a standard mode with analysis of the thickness of the retinal ganglion cell complex in the macular region. Additionally, using OCTA in Angio Retina mode with a scanning size of 3x3 mm, indicators of vascular density of the macula at the level of the superficial choroid plexus and retinal thickness by sector were determined.

Regression analysis was carried out using the binary regression method with a dichotomous conclusion (sick/healthy), in which the principle of reverse selection was used: all variables were included in the calculation of the regression equation, and then in the reverse order, insignificant variables were excluded.

Binary regressions were calculated (logit, probit, extreme-value), where the diagnosis of POAG was used as a binary outcome variable: “presence/absence of disease” (table). Based on the minimum values of the Akaike, Schwartz, and Khan-Queen information criteria, a selection of the calculated models was carried out. The relative quality of the model was determined by the minimum value of information criteria: Akaike, Shwarz and Hannah-Quinn criterion (Akaike, Shwarz, H-Q).

As a result of statistical analysis, a logit model was obtained that most accurately represents the existing regression. It was found that the following indicators were significantly associated with the disease (in descending order): OCT indicator of sGCs GCS Inferior GCC - average thickness of the GCS complex in the lower sector/GCCINF, OCT indicator of sGCs FEV - level of focal losses of sGCs/FLV, OCTA indicator of vascular density in the Fovea region of the superficial choroid plexus/SFOVEA, OCTA-indicator of vascular density in the Parafovea region of the superficial choroid plexus/SPARAFOVEA, OCTA-indicator of retinal thickness in the inferior hemisphere of the macula/TINFHEMt, OCTA-indicator of retinal thickness in the inferior sector of the macula/TINF, OCTA- indicator of vascular density in the inferior hemisphere of the macula of the superficial choroid plexus/SINFHEMI, OCTA indicator of vascular density in the nasal sector of the macula of the superficial choroid plexus/SNASAL, OCTA indicator of thickness Fovea/TFOVEA.

The final explanatory power of the regression model was R-square 0.882. Referring to this measure of goodness of fit (McFadden's QI), we can conclude that the regression equation explains 88.2% of the variation in the dependent variable “presence of GND” based on the identification of individual patient indicators.

The correspondence of the presented model to real data was verified using the Hosmer-Lemeshow test. As a result of the test, a point estimate of the parameters of interest to us was obtained, and their interval estimates were calculated.

Thus, the estimated linear regression logit model can be represented as:

RFNTG = (-0.552)*GCCINF + 6.376*FFV - 0.258* SFOVEA - 0.121*SPARAFOVEA - 0.502*TINFHEMI - 0.213*TINF - 1.236*SINFHEMI - 0.223*SNASAL - 0.229*TFOVEA + 255.36

Using this formula, you can calculate the risk of developing GND in patients with suspected disease. To do this, numerical values are substituted into the formula: the average thickness of the RGC complex in the lower sector (μm), the level of focal losses of the RGCs (%), the indicator of vascular density in the Fovea region of the superficial choroid plexus (%), the indicator of vascular density in the Parafovea region of the superficial choroid plexus ( %), retinal thickness in the inferior hemisphere of the macula (µm), retinal thickness in the inferior sector of the macula (µm), vascular density in the nasal sector of the macula of the superficial choroid plexus (%), index of Fovea thickness (µm). With an RFNTG value of -158.0 or more, the development of low-tension glaucoma is predicted.

Model sensitivity - 93.75; specificity - 97.96. Therefore, the model is suitable for wide use.

The essence of the invention is illustrated by the following clinical examples. Example 1. A 55-year-old patient was referred by an ophthalmologist from her local clinic to rule out low-tension glaucoma. She made no active complaints. There is no heredity for glaucoma. Denies concomitant chronic diseases. On examination: visual acuity in both eyes was 1.0. IOP level with non-contact tonometry is 18/18 mm Hg. The Criminal Procedure Code is open. Ophthalmoscopically, the right eye: the optic disc is pale, the boundaries are clear, the physiological excavation is widened. According to OCTA data, the vascular density of the superficial choroid plexus in Fovea is 8.7%, in Parafovea - 52.9%), in the lower hemisphere - 48.5%, in the nasal sector - 52.8%. The thickness of the retina in the lower hemisphere is 286 µm, in the lower sector of the macula - 296 µm, in the Fovea - 252 µm. According to OCT data, the thickness of the cGCL in the lower sector is 92 µm, the level of focal losses is 4.3%.

A diagnosis of “Suspected low-tension glaucoma of the right eye” was made and the integral risk coefficient for developing GND was calculated:

RFNTG OD=(-0.552)*92+6.376*4.3 - 0.258*8.7 - 0.121*52.9 - 0.502*286 -0.213*296 - 1.236*48.5 - 0.223*52.8 - 0.229* 252+255.36=-112.7.

The resulting integral coefficients make it possible to predict a high risk of developing GND. The patient was offered a dynamic examination. During the follow-up examination, progression of disturbances in hemodynamic and morphometric parameters was observed. Despite the IOP level of 15 mm Hg, the vascular density of the superficial choroid plexus in Fovea was 7.6%), in Parafovea - 51.8%, in the lower hemisphere - 48.0%, in the nasal sector - 50.8 %). The thickness of the retina in the lower hemisphere is 280 µm, in the lower sector of the macula - 291 µm, in the Fovea - 249 µm. According to OCT data, the thickness of the cGCL in the lower sector is 89 µm, the level of focal losses is 5.1%. A diagnosis of primary open-angle glaucoma with low pressure was made in the right eye. Local antihypertensive treatment was prescribed.

Example 2. A 50-year-old patient was referred by an ophthalmologist from her local clinic to rule out low-tension glaucoma. She made no active complaints. There is no heredity for glaucoma. Denies concomitant chronic diseases. On examination: visual acuity in both eyes was 1.0. IOP level with non-contact tonometry is 16/17 mm Hg. The Criminal Procedure Code is open. According to OCTA data, the vascular density of the superficial choroid plexus in the Fovea for the right eye was 17.9%, in the Parafovea - 51.8%, in the lower hemisphere - 48.9%, in the nasal sector - 54.8%. The thickness of the retina in the lower hemisphere is 306 µm, in the lower sector of the macula - 319 µm, in the Fovea - 256 µm. According to OCT data, the thickness of the kGCL in the lower sector is 97 µm, the level of focal losses is 0.55%

A diagnosis of “Suspected low-tension glaucoma of the right eye” was made and the integral risk coefficient for developing GND was calculated:

RFNTG OD = (-0.552)*97+6.376*0.55 - 0.258*17.9 - 0.121*51.8 - 0.502*306 - 0.213*319 - 1.236*48.9 - 0.223*54.8 - 0.229* 256 + 255.36=-158.407

The resulting integral coefficients make it possible to predict a low risk of developing GND. The patient was offered a dynamic examination. When examined after 6 months, no significant deterioration in hemodynamic and morphometric parameters was revealed; the IOP level was 18/18 mm Hg.

Example 3. A 56-year-old patient was referred by an ophthalmologist from her local clinic to rule out low-tension glaucoma. She made no active complaints. My mother has a hypertensive form of primary open-angle glaucoma. He is registered with a neurologist with a diagnosis of “Vegetative-vascular dystonia”. On examination: visual acuity in both eyes was 1.0. IOP level with non-contact tonometry 15 mm Hg. The Criminal Procedure Code is open. Ophthalmoscopically, the left eye: the optic disc is pale, the boundaries are clear, the physiological excavation is widened. According to OCTA data, the vascular density of the superficial choroid plexus in Fovea is 17.85%, in Parafovea - 51.70%, in the lower hemisphere - 48.8%, in the nasal sector - 54.5%. The thickness of the retina in the lower hemisphere is 306 µm, in the lower sector of the macula - 319 µm, in the Fovea - 256 µm. According to OCT data, the thickness of the kGCL in the lower sector is 97 µm, the level of focal losses is 0.58%

A diagnosis of “Suspected low-tension glaucoma of the left eye” was made and the integral risk coefficient for the development of NHL was calculated:

RFNTG OS=(-0.552)*97 + 6.376*0.58 - 0.258*17.85 - 0.121*51.70 - 0.502*306 - 0.213*319 - 1.236*48.8 - 0.223*54.5 - 0.229* 256+255.36=-158.0.

The resulting integral coefficients make it possible to predict a high risk of developing GND. The patient was offered a dynamic examination. During the follow-up examination, progression of disturbances in hemodynamic and morphometric parameters of the left eye was observed. Despite the IOP level of 14 mm Hg, the vascular density of the superficial choroid plexus in Fovea was 16.9%, in Parafovea - 50.4%, in the lower hemisphere - 48.1%, in the nasal sector - 53.4% . The thickness of the retina in the lower hemisphere is 305 µm, in the lower sector of the macula - 315 µm, in the Fovea - 251 µm. According to OCT data, the thickness of the cGCL in the lower sector is 92 µm, the level of focal losses is 0.63%. A diagnosis of primary open-angle glaucoma with low pressure was made in the left eye. Local antihypertensive treatment was prescribed.

Claims (14)

A method for predicting the risk of developing low-tension glaucoma (LTH) according to optical coherence tomography with angiography (OCTA), including determination of vascular density in the Parafovea, characterized in that it additionally determines indicators of vascular density in the Fovea region, in the lower hemisphere and the nasal sector of the macula of the superficial vascular plexus, retinal thickness in the Fovea, inferior hemisphere and inferior sector of the macula, optical coherence tomography indicators: average thickness of the retinal ganglion cell complex in the inferior sector, level of focal losses, and the risk of developing the disease is calculated by the formula: RFNTG=(-0.552)*GCCINF+6.376*FLV-0.258*SFOVEA-0.121*SPARAFOVEA-0.502*TINFHEMI-0.213*TINF-1.236*SINFHEMI-0.223*SNASAL-0.229*TFOVEA+255.36, where RFNTG is the risk coefficient for developing GND; GCCINF – OCT indicator of the GCL complex Inferior GCC – average thickness of the GCL complex in the lower sector, µm; FLV – OCT indicator of the GCS complex – level of focal losses of the GCS, %; SFOVEA – OCTA indicator of vascular density in the Fovea region of the superficial choroid plexus, %; SPARAFOVEA – OCTA indicator of vascular density in the Parafovea region of the superficial choroid plexus, %; TINFHEMI – OCTA indicator of retinal thickness in the inferior hemisphere of the macula, µm; TINF – OCTA index of retinal thickness in the lower sector of the macula, µm; SINFHEMI – OCTA indicator of vascular density in the inferior hemisphere of the macula of the superficial choroid plexus, %; SNASAL – OCTA indicator of vascular density in the nasal sector of the macula of the superficial choroid plexus, %; TFOVEA – OCTA index of Fovea thickness, µm; 255.36 – mathematical constant, and with an RFNTG value of -158.0 or more, the development of low-tension glaucoma is predicted.