RU2804591C1 - Method for predicting the risk of progression of primary open-angle glaucoma - Google Patents

Abstract

FIELD: medicine; ophthalmology.

SUBSTANCE: invention is intended to predict the risk of progression of primary open-angle glaucoma. Scoring is carried out for the worst value of pulse wave velocity indicators, cardio-ankle vascular index of the upper and lower extremities, flow dependent vasodilation indicators, biological age of vessels, ratio of low and high density lipoproteins, total cholesterol. One point for each indicator with PWV_worse >17 m/s, CAVI_worse <6.3, HPVD <7.5%, BV >71 years old, KA >3.5, OH >5.6 mmol/l. With a score of 5-6, a high risk of progression is predicted, 3-4 - medium risk, 0-2 - low risk.

EFFECT: method allows obtaining data with high sensitivity and specificity for subsequent monitoring of the patient's condition and determining the need to optimize the choice of adequate tactics for managing patients, depending on the risk of progression of primary open-angle glaucoma.

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Description

The invention relates to ophthalmology and is intended to predict the risk of progression of primary open-angle glaucoma.

Glaucoma is a continuous optic neuropathy usually caused by elevated intraocular pressure (IOP) due to resistance to aqueous humor drainage through the trabecular meshwork (TM) and Schlemm's canal (Tamm ER, Braunger BM, Fuchshofer R. Intraocular pressure and the mechanisms involved in resistance of the aqueous humor flow in the trabecular meshwork outflow pathways. Prog Mol Biol Transl Sci. 2015; 134:301-314. doi: 10.1016/bs.pmbts.2015.06.007). Most notably, the TM endothelium behaves like vascular endothelium. Recent studies have revealed increasing similarities between TM obstruction and endothelial dysfunction (eg, atherosclerosis) (Sacca SC, Pulliero A, Izzotti A. Trabecular meshwork dysfunction during glaucoma. J Cell Physiology 2015; 230(3): 510-25. doi : 10.1002/jcp.24826). It is believed that systemic factors such as dyslipidemia (Gubin D.; Neroev V.; Malishevskaya T.; Kolomeichuk S.; Weinert D.; Yuzhakova N.; Nelaeva A.; Filippova Y.; Cornelissen G. Daytime lipid metabolism modulated by CLOCK gene is linked to retinal ganglion cell damage in glaucoma. Int. J. Mol. Sci. 2022; 72(13). doi: 10.3390/app12136374), endothelial dysfunction (Malishevskaya T.N., Kiseleva T.N., Filippova Yu.E., Vlasova A.S., Nemtsova I.V., Vasilchenko V.V., Zaitsev M.S. Structural and functional features of peripheral vessels in glaucoma. Bulletin of Ophthalmology. 2020; 5(136):67-76 . https://doi.org/10.17116/oftalma202013605167) cause and increase the severity of the disease (Pinazo-Durán M.D., Gallego-Pinazo R., Garcia-Medina J.J., Zanón-Moreno V., Nucci C., Dolz-Marco R. et al. Oxidative stress and its downstream signaling in aging eyes. Clin Interv Aging. 2014;9:637-652. doi.org/10.2147/CIA.S52662.). Considering that the endothelium is involved in the control of vascular tone and blood flow (Resch, N., Karl, K., Weigert, G., Wolzt, M., Hommer, A., Schmetterer, L. et al. Effect of dual endothelin receptor blockade on ocular blood flow in patients with glaucoma and healthy subjects. Ophthalmol._Vis. Sci. 2009; 50:358-363. doi: 10.1167/iovs.08-2460), vascular dysregulation may be a consequence of endothelial dysfunction. Short-term control of arterial tone and coagulation status, as well as long-term control of smooth muscle cell proliferation and extracellular matrix formation are achieved using intact vascular endothelium. Damage to the vascular endothelium is a common precursor event in most, if not all, vascular diseases. Vascular dysfunction observed in patients with normal pressure glaucoma may be a consequence of vascular endotheliopathy (Henry E, Newby DE, Webb DJ, et al. Peripheral endothelial dysfunction in normal pressure glaucoma. Invest Ophthalmol Vis Sci 1999; 40: 1710-1714.) in the form of impaired functions of peripheral endothelial cells in these patients (Buckley C, Hadoke PW, Henry E, O'Brien C. Systemic vascular endothelial cell dysfunction in normal pressure glaucoma. Br J Ophthalmol. 2002; 86(2): 227-32. doi:10.1136/bjo.86.2.227).

Low levels of high-density lipoprotein cholesterol (HDL-C) are a risk factor for cardiovascular disease (Review and Meta-Analysis. J Am Coll Cardiol. 2010; 55(13): 1318-1327; Nilsson PM, Lurbe E, Laurent S. The early life origins of vascular aging and cardiovascular risk: the EVA syndrome [review]. Journal of Hypertension. 2008; 26:1049-1057. doi.org/10.1097/HJH.0b013e3282f82c3e; European Guidelines on cardiovascular disease prevention in clinical practice. European Heart Journal. 2016; 7(29); 2-78). Pulse wave velocity of the brachial joint and ankle (PWV) is an indicator of arterial stiffness, which is recognized as a predictor of cardiovascular diseases (Zairova A.R., Rogoza A.N., Dobrovolsky A.B., Oshchepkova E.V., Titaeva E. V., Starostin I.V., Panchenko E.P., Trubacheva I.A., Serebryakova V.N., Kaveshnikov V.S., Chazova I.E., Karpov R.S. Arterial stiffness and “vascular aging” in the relationship with coagulological risk factors for the development of cardiovascular diseases, indicators of lipid and carbohydrate metabolism in the adult population of Tomsk according to the ESSE-RF study. Cardiological Bulletin 2018; 13(1): 5-15. doi: 10.17116/Cardiobulletin20181315-15; Vlachopoulos S, Aznaouridis K, Stefanadis S. Prediction of Cardiovascular Events and All-Cause Mortality With Arterial Stiffness. A Systematic Review and Meta-Analysis. J Am Coll Cardiol. 2010; 55(13):1318-1327. doi: 10.1016/j.jacc. 2009.10.061). HDL-C has an independent protective effect on arterial stiffness in middle-aged and elderly Chinese. Early detection of HDL cholesterol levels is important in high-risk groups with arterial stiffness (Zhao WW, Yang YH, Lu B et all. Serum high-density lipoprotein cholesterol and progression to arterial stiffness in middle-aged and elderly Chinese. Nutr Metab Cardiovasc Dis. 2013 ;23(10): 973-9.doi:10.1016/j.numecd.2012.08.001).

To date, the mechanisms explaining how hyperlipidemia may increase the risk of glaucoma progression are unclear. One possible explanation may be that excess blood lipid levels increase episcleral venous pressure and blood viscosity, leading to a subsequent decrease in outflow (Wang, S.; Bao, X. Hyperlipidemia, Blood Lipid Level, and the Risk of Glaucoma: A Meta-Analysis Invest Ophthalmol Vis Sci 2019, 60(4), 1028-1043. doi: 10.1167/iovs.18-25845). In addition, a meta-analysis identified a positive association between IOP levels and blood lipid levels. Therefore, possible reasons for the association between IOP and triglyceride levels may be the same as for the association between hyperlipidemia and glaucoma risk. Therefore, establishing a clearer understanding of the relationship between hyperlipidemia, endothelial dysfunction, and POAG may provide insight into the pathophysiology of this disease.

State of the art

There is a known method for predicting the risk of glaucoma progression based on assessing the degree of biomechanical stress of the fibrous membrane of the eye without contact with the cornea. Using bidirectional pneumoaplanation of the cornea, biomechanical parameters are determined: CH (corneal hysteresis) - corneal hysteresis, CRF (corneal resistance factor) - corneal resistance factor and intraocular pressure, according to Goldman (IOPg), the coefficient of biomechanical stress of the fibrous membrane of the eye is calculated using the formula: Kbs = IOPg/CH+CRF. With a Kbs value of 1.1 or more, the risk of development and progression of glaucoma is predicted; this method allows us to determine the need for additional optimization of the antihypertensive regimen [patent RU 2610565, 02/13/2017]. The disadvantage of this method is the unidirectional study of only local factors for the progression of GON without taking into account systemic risk factors. This disadvantage is due to the choice of only one mechanical pathogenetic factor for the progression of glaucoma - IOP, taking into account the biomechanical parameters of the cornea. As is known, glaucoma is a multifactorial disease and elimination of local risk factors for progression without correction of systemic factors will not stop the progression of GON.

There is a known method for predicting the risk of glaucoma progression by assessing the elastic properties of the cornea and sclera of the eye. The elasto-lift coefficients are determined with differential tonometry according to Schiotz (γS) and with elastotonometry according to Maklakov (γM). Their ratio is calculated using the formula K=γS/γM-. When the ratio is more than 2.4, the risk of glaucoma progression is determined. The method provides the possibility of eliminating the high risk of error in determining intraocular pressure, determining the possibility of developing excavation of the optic nerve head with a more accurate assessment of the risk of developing glaucomatous damage associated with the biomechanical characteristics of the corneoscleral membrane of the eye, and determining the tactics of further treatment [patent RU 2599208: 10.10.2016] . The disadvantage of this method is the prolonged exposure to the cornea when performing elastotonometry using two methods without interruption on the same eye, which can lead to damage to the cornea and ocular surface, which in the case of glaucoma is extremely undesirable, since due to the constant instillation of antihypertensive drops in 89 % of patients with POAG initially have ocular surface disease. This disadvantage is due to the contact method of performing the techniques: differential tonometry according to Schiotz and elastotonometry according to Maklakov with loads of different weights under local anesthesia, the absence in many institutions of a GlauTest 60 tonograph. In addition, the contribution to the progression of glaucoma is taken into account only by the biomechanical component - the elastic-elastic properties of the cornea and sclera .

There is a known method for predicting the course of glaucomatous optic neuropathy, which is based on determining the total albumin concentration (TCA) and effective albumin concentration (ECA) in a tear of a POAG patient and calculating the TAC/TCA ratio. If its value is 0.3 or less, the risk of GON progression over the next year is predicted [patent RU 2235503:2003]. The disadvantage of this method is the need to use expensive equipment - a fluorimeter, which is available only in a few specialized centers. There is a known method for predicting the risk of progression of glaucoma described which suggests the use of tear crystallography to assess progression [patent RU 2281023:2006]. The disadvantage of this method is the method of collecting tears to study protein levels. This method is lengthy and associated with discomfort for patients.

The closest analogue is a method for the same purpose, in which the level of lactate in the blood of patients with glaucoma is determined and the relationship between the level of lactate and the progression of GON is proven. If the lactate level is above 4.33 mmol/l, the risk of progression of GON is predicted within 1 year after the examination [patent RU 2530588:2014]. The disadvantage of this method is that it only takes into account the severity of oxidative stress, namely lactate, to identify the risk of glaucoma progression. Oxidative stress is a universal mechanism of damage characteristic of many age-associated diseases: hypertension, coronary artery disease, diabetes mellitus, etc., but cannot act in isolation as a predictor of progression of GON without taking into account other pathogenetic mechanisms, especially in conditions of concomitant comorbid pathology in patients with POAG.

The objective of the present invention is to develop a comprehensive general somatic approach to predicting the risk of progression of primary open-angle glaucoma.

The technical result of the proposed method is the ability to select adequate patient management tactics depending on the degree of risk of POAG progression.

The technical result is achieved through a scoring of pulse wave velocity, cardio-ankle vascular index of the upper and lower extremities, flow-dependent vasodilation, biological age of the vessels, the ratio of low- and high-density lipoproteins, and total cholesterol.

Increased stiffness of the arteries of the extremities provides direct information about damage to the vessels of target organs and has prognostic value for assessing the progression of the disease. To assess the stiffness of the vascular wall, the velocity of propagation of the pulse wave was determined - Pulse Wave Velocity (PWV) - the greater the rigidity, the higher the speed. As a value used to identify earlier atherosclerosis, PWV makes it possible to predict the progression of the atherosclerotic process and evaluate the effectiveness of therapy. The study was carried out using a VaSera VS-1000 Fukuda Denshi sphygmomanometer. (Trifonova S., et all. Application of methods of assessment of vascular stiffness in clinical practice, the possibility of cardio-ankle vascular index (CAVI), Cardiologic, 2015; Milyagin B.A., Milyagina I.V. et al. Non-invasive research methods great vessels, Smolensk, 2012], Balakhonova T.V., Soboleva G.N., Atkov O.Yu., Karpov Yu.A. Determination of the sensitivity of the brachial artery to shear stress on the endothelium as a method for assessing the state of endothelium-dependent vasodilation using high-resolution ultrasound in patients with arterial hypertension // Cardiology. - 1998. - T.38. - No. 3. - P. 37. 4; Malishevskaya T.N., Astakhov S.Yu. Reactivity of the vascular endothelium in elderly patients with primary open-angle glaucoma and physiologically aging people, depending on the severity of endothelial dysfunction // Regional blood circulation and microcirculation - No. 4 - volume 15 (60)-2016. - P. 59-68).

The CAVI index (Cardio-Ankle Vascular Index) was determined by recording plethysmograms on 4 limbs (using cuffs), an electrocardiogram (ECG), and a phonocardiogram (PCG). Measurements were performed sequentially, first on the right shoulder and lower leg, then on the left shoulder and lower leg. The worst value of indicators was chosen for the model to demonstrate the general manifestations of the systemic pathological process. The biological age of the vessels was calculated automatically by the device when entering parameters - the patient’s age and body weight.

To study the degree of endothelial dysfunction (ED), a test with reactive hyperemia was performed using an En Visor ultrasound device from Philips. Vasodilation was assessed using an ultrasonic vascular sensor (7 MHz) based on changes in the diameter of the brachial artery. Calculation of flow-dependent vasodilation (FVD) was carried out according to the formula:

PVD(%) = (DRG-ID)/ID⋅100,

where DRG is the maximum diameter value against the background of reactive hyperemia. The degree of dilatation of the brachial artery against the background of reactive hyperemia by more than 10% of the initial diameter was considered normal. A lower value or detection of vasoconstriction was regarded as a pathological reaction (Ivanova, O.V. Determination of the sensitivity of the brachial artery to shear stress on the endothelium as a method for assessing the state of endothelium-dependent vasodilation using high-resolution ultrasound in patients with hypertension / O.V. Ivanova, G.N. Soboleva et al. // Cardiology. - 1998. - Z. - P. 37-41).

The blood serum lipid profile (total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)) in patients was assessed using reagents from Lachema (Hungary). The content of low-density lipoprotein cholesterol was calculated using the Friedwald formula: LDL-C=TC-HDL-TG/2.2. Based on the data obtained, the atherogenic coefficient (AC) = LDL cholesterol/HDL cholesterol was calculated. (Friedewald, W.T. Estimation of the Concentration of Low-Density Lipoprotein Colesterol in Plasma, Without Use of the Preparative Ultracentrifuge // Clinical Chemistry. Clin Chem. 1972 Jun; 18(6): 499-502.).

We conducted studies to establish the relationship between vascular endothelial function, atherosclerotic changes in the vessels of the upper and lower extremities, dyslipidemia and the risk of POAG progression.

We observed 200 patients with primary open-angle glaucoma (POAG). It is well known that the nature of the course of glaucoma: progressive course or stabilization of visual functions is determined on the basis of dynamic changes in the index of mean deviation of retinal photosensitivity (MD) according to static automated perimetry (SAP) and the index of global ganglion cell volume loss (GLV) according to optical coherence tomography. (OCT). As a result of dynamic observation, the group of patients with progressive glaucoma (P-POAG) included 50 people (men - 31 (62%), women - 19 (38%), average age 69.9±8.2 years) with a decrease in the index MD by more than 2.0 decibels (dB) per year and a decrease in GLV by more than 2% per year at follow-up.

The group of patients with a stable course (S-POAG) included 65 people (men - 19 (29%), women - 46 (71%), average age -67.6±7.6 years), in whom the mD value did not change or changes were no more than 0.5 decibels (dB) per year, and GLV decreased no more than 2% per year during follow-up.

In addition to the well-known structural and functional differences in the state of the retina and optic nerve in the progressive and stabilized course of glaucoma, we found that the progression of POAG is accompanied by metabolic disorders, which manifest themselves in changes in the ratio of LDL\HDL (CA), total cholesterol (TC), early atherosclerotic changes in peripheral vessels of the upper and lower extremities, endothelial dysfunction. We identified a relationship between the risk of POAG progression and hemodynamic indices that characterize the elasticity of the vascular wall of the peripheral vessels of the extremities, namely: pulse wave velocity (PWV_worse), cardio-ankle vascular index (CAVI_worse), biological age of blood vessels (BV). In addition, in a test with reactive hyperemia, we found that a decrease in flow-dependent vasodilation (FSVD) inversely correlated with the rate of glaucoma progression.

Scoring based on the totality of non-ophthalmological manifestations of the progression of the glaucomatous process made it possible to further predict the course of the disease.

The method is carried out as follows

A point assessment is made of the worst value of pulse wave velocity (PWV_worse), cardio-ankle vascular index (CAVI_worse) of the upper and lower extremities, flow-dependent vasodilation (FVD), biological age of blood vessels (BV), ratio of low- and high-density lipoproteins (KA) , total cholesterol (TC). One point is assigned for each indicator for PWV_worse >17 m/s, CAVI_worse <6.3, PVD <7.5%, BV >71 years, CA >3.5, TC >5.6 mmol/l. With a score of 5-6, a high risk of progression is predicted, 3-4 - average, 0-2 - low.

Clinical examples

Example 1. Patient A., a 63-year-old man diagnosed with Primary open-angle glaucoma Ia hyp of both eyes. IOP is compensated. Hypotonic regimen - Tafluprost 0.0015%. IOP (T10.0) OD\OS 14\13 mm. Hg Visual acuity of the right eye is 0.3+1.5 D sph=1.0, visual acuity of the left eye is 0.6+1.0 D sph=1.0. On ophthalmoscopy, the optic disc is pale pink in color, the boundaries are clear, the excavation/disc ratio is 0.5 on the right, 0.4 on the left. Optical coherence tomography (OCT) of both eyes revealed thinning of the peripapillary retinal nerve fiber layer in the superotemporal quadrants. GLV of the right eye is 7.1%, the left eye is 6.2%. On computer perimetry (30-2) MD of the right eye = -5.21 dB, scotoma in the Bjerrum zone in the lower nasal sector, MD of the left eye = -4.26 dB.

The concentration of total blood cholesterol was 4.6 mmol/l, the calculated atherogenic coefficient (AC) was 3.7. Sphygmamonography revealed the worst indicator of pulse wave velocity on the right and left side (PWV_worse) - 15 m/s, the worst indicator of the cardio-ankle vascular index on the right and left side (CAVI_worse) - 7.1 and BV of the vessels - 66 years. In the sample with reactive hyperemia, the PVD indicator was 7.9%.

Progression assessment: score -1 - the risk of POAG progression is low.

During dynamic observation of this patient for 2 years, no progression of POAG was detected: the MD index decreased by no more than 0.5 dB per year according to SAP protocols, there was no decrease in GLV according to OCT protocols.

Recommendations: Considering the stabilized course of glaucoma on the given regimen of hypotensive drugs, a follow-up examination by an ophthalmologist after six months is recommended. A consultation with a therapist is necessary to correct lipid metabolism.

Example 2. Patient S., a 61-year-old woman diagnosed with Primary open-angle glaucoma Ia hyp of both eyes. Moderate myopia in both eyes. IOP was compensated with medication. Hypotonic regimen - Dorzolamide 2%. IOP (T10.0) OD\OS 15\17 mm. Hg Visual acuity of the right eye is 0.2-3.5 D sph=1.0, visual acuity of the left eye is 0.1-4.0 D sph=0.9. On ophthalmoscopy, the optic disc is pale pink in color, the boundaries are clear, the excavation/disc ratio is 0.6 on the right, 0.5 on the left. Optical coherence tomography (OCT) of both eyes revealed thinning of the peripapillary layer of retinal nerve fibers in all sectors. GLV of the right eye is 6.4%, the left eye is 7.5%. On computer perimetry (30-2) MD of the right eye = -6.22 dB, MD of the left eye = -5.26 dB.

The concentration of total blood cholesterol was 5.1 mmol/l, the calculated atherogenic coefficient (AC) was 3.3. Sphygmamonography revealed the worst indicator of pulse wave velocity on the right and left side (PWV_worse) - 20 m/s, the worst indicator of the cardio-ankle vascular index on the right and left side (CAVI_worse) - 6.0 and BV of the vessels - 69 years. In the sample with reactive hyperemia, the PVD indicator was 5.5%.

Progression assessment: number of points - 3 - the risk of progression of POAG is average.

During dynamic observation of this patient for 2 years, thinning of the layer of retinal ganglion cells was observed according to OCT data, while the visual field and ophthalmoscopic picture of the fundus remained at stage I of POAG.

Recommendations: Considering the risk of glaucoma progression, active follow-up of the patient, daily measurement of IOP and blood pressure are necessary to identify IOP fluctuations during the day and possible periods of nighttime decrease in perfusion pressure. If the target pressure is not achieved, a review of antihypertensive treatment is necessary. A consultation with a therapist is necessary to correct lipid metabolism and determine a program for the prevention of cardiovascular risks.

Example 3. Patient G., a 60-year-old man diagnosed with Primary open-angle glaucoma IIa hyp of both eyes. Initial age-related cataracts of both eyes. IOP was compensated with medication. Hypotonic regimen - Tafluprost 0.0015%. IOP (T10.0) OD\OS 17\18 mmHg. Visual acuity of the right eye is 0.4 s/k - 1.0 D sph=0.9, visual acuity of the left eye is 0.5 s/k - 0.5.0 D sph=1.0. On ophthalmoscopy, the optic disc is pale pink in color, the boundaries are clear, the excavation/disc ratio is 0.6 on the right, 0.6 on the left. Optical coherence tomography (OCT) of both eyes revealed thinning of the peripapillary layer of retinal nerve fibers in all sectors. GLV of the right eye is 7.8%, the left eye is 8.7%. On computer perimetry (30-2) MD of the right eye = -8.312 dB, MD of the left eye = -7.43 dB.

The concentration of total blood cholesterol was 5.2 mmol/l, the calculated atherogenic coefficient (AC) was 4.2. Sphygmamonography revealed the worst indicator of pulse wave velocity on the right and left side (PWV_worse) - 25 m/s, the worst indicator of the cardio-ankle vascular index on the right and left side (CAVI_worse) - 4.3 and BV of the vessels - 75 years. In the sample with reactive hyperemia, the PVD indicator was 3.1%.

Progression assessment: number of points - 5 - the risk of progression of POAG is high.

During the dynamic observation of this patient for 2 years, even with normalized IOP, a progressive deterioration in the photosensitivity of the retina was observed (decrease in MD by 2 dB per year), a pronounced thinning of the retinal ganglion cell layer according to OCT data (increase in the global loss index GLV by more than by 2% per year).

Recommendations: Considering the risk of progression of glaucoma, active follow-up of the patient, strengthening of the antihypertensive regimen and, possibly, transition to surgical treatment are necessary. A consultation with a therapist is necessary to correct lipid metabolism and determine a program for the prevention of cardiovascular risks.

Thus, the method allows one to obtain data with high sensitivity and specificity for subsequent monitoring of the patient’s condition and determining the need to optimize treatment tactics.

Claims (1)

A method for predicting the risk of progression of open-angle glaucoma, characterized in that a score is made for the worst value of the indicators: pulse wave velocity (PWV_worse) and cardio-ankle vascular index (CAVI_worse) of the upper and lower extremities, indicators of flow-dependent vasodilation (FVD), biological age of the vessels (WD), the ratio of low and high density lipoproteins (KA), total cholesterol (TC), assign one point for each indicator with PWV_worse >17 m/s, CAVI_worse <6.3, PVVD <7.5%, BV > 71 years old, KA >3.5, TC >5.6 mmol/l and with a score of 5-6, a high risk of progression is predicted, 3-4 - average, 0-2 - low.