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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 58  |  Issue : 3  |  Page : 180-185

Review article: Ocular blood flow in glaucoma


1 Indira Gandhi Eye Hospital and Research Centre, Lucknow, Uttar Pradesh, India
2 Senior Consultant and Glaucoma Specialist, MN Eye Hospitals, Chennai, Tamil Nadu, India
3 Ex Professor, Institute of Opthalmology, Madurai, Tamil Nadu, India

Date of Submission29-Jun-2020
Date of Acceptance30-Jun-2020
Date of Web Publication14-Sep-2020

Correspondence Address:
Dr. Shweta Tripathi
No 8, Blunt Square, Durgapuri, Lucknow - 226 004, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tjosr.tjosr_81_20

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  Abstract 


Primary open-angle glaucoma is a condition with multiple risk factors. Although intraocular pressure is the most established among them, vascular factors and ocular blood flow (OBF) also play a significant role, especially in patients of normal tension glaucoma. This review article discusses the various vascular factors and the various methods of measurement of OBF with their clinical importance.

Keywords: Glaucoma, IOP, ocular blood flow


How to cite this article:
Tripathi S, Ariga M, Srinivasan M M. Review article: Ocular blood flow in glaucoma. TNOA J Ophthalmic Sci Res 2020;58:180-5

How to cite this URL:
Tripathi S, Ariga M, Srinivasan M M. Review article: Ocular blood flow in glaucoma. TNOA J Ophthalmic Sci Res [serial online] 2020 [cited 2020 Oct 25];58:180-5. Available from: https://www.tnoajosr.com/text.asp?2020/58/3/180/295004




  Introduction Top


Glaucoma is the leading cause of irreversible blindness affecting more than 60 million people.[1]

Although intraocular pressure (IOP) is the most important risk factor in the development and progression of glaucoma, reducing the IOP does not always slow the cessation of the disease progression.

Glaucoma is a multifactorial disease with IOP-dependent and IOP-independent risk factors, including decreased ocular blood flow (OBF), oxidative stress, decreased axoplasmic flow, and genetic background.[2]

A number of epidemiological studies have generated strong evidence that OBF may be an especially important risk factor for the progression of glaucoma as some patients show glaucoma progression maintaining a low IOP.

Primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) share similar risk factors for the pathogenesis.[3] Vascular factors may play an important role in a subgroup of patients with POAG and NTG.

The prognostic vascular factors include disc hemorrhage, per papillary atrophy, stroke, aging, systemic hypertension, and migraine [Table 1].[4]
Table 1: Vascular risk factors

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Table 2: Calculation of perfusion pressure

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In this review, we will discuss the various prognostic vascular factors, methods to measure OBF and its significance in the diagnostic armamentarium of glaucoma.


  Vascular Risk Factors Top


It is generally accepted that NTG is classified as a subtype of POAG;[9] however, evidences have been found recently which suggest the difference between NTG and POAG. In NTG patients, the shape of defect of visual field is different, the decrease of retinal nerve fiber layer is earlier, and the incidence of optic disk hemorrhage is significantly higher than those in POAG patients.[10]

Increase of IOP has limited contribution to glaucomatous change, according to the vascular theory of glaucoma; other potential causative factors which are related to vascular abnormality may have influence.[2],[11] Thus, the relationship between retro bulbar hemodynamic and NTG becomes an important subject in the field of glaucomatous researches. It has been hypothesized that vascular spasticity and dysregulation of retro bulbar hemodynamic [Figure 1] are connected with NTG, in other words, some cases with normal IOP in POAG.[12]
Figure 1: Blood supply of the eye

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A recent study presented a possible theory, which was more related to vascular factors, describing pathways depending on low ocular perfusion pressure (OPP).[13] OBF is dependent on perfusion pressure. OBF is equal to OPP divided by the vascular resistance; hence, OPP is directly proportional to the OBF. OPP is defined as the difference between the arterial and venous pressure. In the eye, venous pressure is equal to or slightly greater than IOP. Hence, BP may not be the most important factor rather the difference between arterial pressure and IOP is more significant [Table 1]. By vascular autoregulation, stable blood flow is maintained despite changes in OPP. Autoregulation can be impaired by vascular factors and increasing age. Low OPP might decrease mitochondria energy state in the retinal ganglion cells (RGCs) or reduce nutrient flow of the RGC axons. Thus, the oxidative stress due to reactive oxygen species causes RGC apoptosis.[13] In future, neuroprotective strategies such as blocking apoptosis of RGCs could be used with conventional therapies.

Diagnostic Modalities for Ocular Blood Flow[14]

Other newer modalities are Doppler Fourier domain optical coherence tomography (Doppler Fourier–domain OCT) and OCT angiography (OCT-A).[14]


  Color Doppler Imaging Top


Color Doppler Imaging (CDI) is a technique which evaluates erythrocyte velocity in the large ophthalmic vessels, such as ophthalmic artery, central retinal artery, and nasal and temporal short posterior ciliary arteries.[12]

Two blood velocity values are measured by CDI: peak systolic value (PSV) and the end diastolic value (EDV), The CDI unit calculates a resistive index which is expressed as RI = (PSV − EDV)/PSV.
Table 3: Diagnostic modalities for ocular blood flow[15]

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This ultrasonic technique combines synchronous B-ultrasonic wave imaging with color which represents the movement of blood flow based on Doppler frequency shifts [Figure 2] and [Figure 3]. The advantages of CDI are, it is non-invasive, it does not require contrast medium, it is not influenced by poor ocular media and it has no radiation.[15] Limitation are its inability to measure vessel diameter and thus volumetric blood flow calculations are not possible. Furthermore, the equipment is expensive.
Figure 2: Colour Doppler imaging machine (courtesy Bharat scans, Chennai)

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Figure 3: Colour Doppler Image showing normal biphasic pattern (courtesy Bharat scans, Chennai)

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  Laser Doppler Velocimetry Top


Bidirectional LDV allows for the assessment of absolute (blood flow) BF velocities in retinal arteries and veins. This noninvasive technique measures centerline blood velocity (mm/s), vessel diameter (m), and cross-sectional area, and thus total BF (L/min) can be assessed.[16]

This technique has been used to study the effect of various antiglaucoma medications and other experimental drugs on ocular BF.[17],[18] The main drawback of this method is that it may be confounded by eye motion and centerline displacement along with tear film break up, upper lid obstruction, inadequate dilation, blurred images due to media opacities; and it cannot be used to measure circulation in optic nerve head (ONH).[12],[14]


  Laser Speckle Technique Top


Laser speckle flowgraphy (LSFG) is a noninvasive, real-time technique that uses laser scattering to determine blood flow in the ONH, retina, and choroid.

The basic operating principle underlying LSFG is the laser speckle phenomenon, which occurs when surfaces are illuminated by coherent laser light. When such light is used to illuminate the ocular fundus, the resulting light scattering in the tissue gives rise to as speckle pattern on the image plane. Changes in the velocity of blood flow then cause blurring of this speckle pattern. Finally, the blurring is quantified by specialized software, producing the main measurement parameter of LSFG, the mean blur rate (MBR). This is an arbitrary unit calculated from the light intensity of the speckle pattern on a point-by-point basis. Thus, MBR is a parameter that quantifies the contrast of the speckle pattern and reveals ocular blood velocity.

In addition, the mean MBR in the vessel area and tissue area can be evaluated separately, through software processing of the LSFG data.[19],[20]

Superior frontal gyrus is a noninvasive, easy-to-use method that enables researchers to assess ocular autoregulation by measuring MBR alterations. It has the limitation that it measures only the velocity and not the diameter of the vessel; hence, it cannot be used to study volumetric blood flow.

Other techniques are Laser Doppler flowmetry which is characterized by quantitative measurement of blood flow in retinal and choroid capillaries limited by no absolute blood flow measurement, retinal vessel analyzer which helps in measuring the diameter of large retinal vessels limited by no information of flow or velocity, and retinal oxymetry which measures relative oxygen saturation in retina vessels and limited by not being fully validated.

Scanning laser ophthalmoscopic angiography with fluorescein and/or indocyanine green (ICG) dye.

Digital scanning laser ophthalmoscope angiography is a set of techniques that quantify the various aspects of blood filling the retinal and choroidal vasculature. Fluorescein dye is used to examine retinal hemodynamics, and ICG allows visualization of the filling of both retinal and choroidal vessels.

Utilizing SLO video technology, evidence of reduced retinal hemodynamics has been observed in patients with glaucoma.[21]

The disadvantages are it is invasive; the equipment is expensive and requires experienced operators.


  Doppler Fourier Domain Optical Coherence Tomography Top


Doppler OCT is based on the principle that moving particles, such as red blood cells inside blood vessels cause a Doppler frequency shift to the back scattered light.

Doppler OCT can be used to measure blood velocity and volumetric flow rate in retinal branch vessels. Since the cross-sectional velocity profile of the blood vessel is captured, both peak and average velocity could be analyzed as a function of time along the cardiac cycle.

Eyes with glaucoma, diabetic retinopathy, retinal vein occlusion, and anterior ischemic optic neuropathy have been found to have reduced total and hemispheric retinal blood flow. Wang et al. have indicated that the reduction of total retinal blood flow was also correlated with glaucoma severity.[22]

The drawbacks include it being only sensitive to blood low parallel to the OCT beam though it has an advantage of being quantifiable and repeatable.


  Optical Coherence Tomography Angiography Top


OCTA is a technique for noninvasively imaging the blood vessels of the ONH and retina in vivo. Further, it offers the potential for enhancing our understanding of the role of OBF and the retinal microvasculature in glaucoma.

Compared with flowmetry, which can only provide insight into blood flow velocity and the amount of avascular zone, OCTA provides a quantitative assessment of “vessel density” (VD). “VD is defined as the percentage area occupied by the large vessels and microvasculature in a particular region.” Contrary to traditional angiography with fluorescein, OCTA does not require the injection of extrinsic contrast dye. Fluorescein angiography and ICG angiography only provide two-dimensional images, lacking depth information, whereas OCTA allows for three-dimensional imaging [Figure 4], [Figure 5], [Figure 6].
Figure 4: Normal angio disc right eye (courtesy Uma eye clinic, Chennai)

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Figure 5: Angio disc left eye showing decreased vessel density in the area of retinal nerve fiber layer thinning. eye (courtesy Uma eye clinic, Chennai)

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Figure 6: Optic nerve head/ganglion cell complex report of the same example as shown in Figures 4 and 5 above

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VD measurement can be affected by various subject-related, eye-related, and disease-related factors. Overall, OCTA has a good repeatability and reproducibility, and can differentiate glaucoma eyes from normal eyes. It can also help detect early glaucoma, reach a floor effect at a more advanced disease stage than OCT, and adds information about glaucoma patients at risk of progression. Although it has higher variability than OCT, it also promises to be useful for monitoring glaucoma by detecting progression throughout the glaucoma continuum.[23]

OCTA VD has had similar diagnostic accuracy to retinal nerve fiber layer thickness measurements for differentiating between healthy and glaucoma eyes. The results suggested that OCT-A measurements reflect damage to tissues relevant to the pathophysiology of OAG.[24]


  Conclusion Top


In cases of open angle glaucoma and inpatients of NTG where the progression is not only explained by the raised IOP consideration of vascular factors gains utmost importance.

There are numerous vascular factors related to the pathogenesis which can be elicited during history taking and examination. The OBF could be needed to be evaluated in this subset of patients.

Not all the methods mentioned are available commercially. Of them the OCT –angiography is mostly available in the clinical settings.

Amongst the topical antiglaucoma drugs carbonic anhydrase inhibitors have been shown to improve ocular circulation and enhance the blood flow regulation beyond their hypotensive effect.[25]

We emphasize to consider vascular risk factors as important component of the glaucoma work up so patients of glaucoma could also be approached with medications which improve OBF and this would ensure a holistic treatment approach.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Flammer J, Orgül S, Costa VP, Orzalesi N, Krieglstein GK, Serra LM, et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res 2002;21:359-93.  Back to cited text no. 2
    
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Sugiyama K, Tomita G, Kitazawa Y, Onda E, Shinohara H, Park KH. The associations of optic disc hemorrhage with retinal nerve fiber layer defect and peripapillary atrophy in normal-tension glaucoma. Ophthalmology 1997;104:1926-33.  Back to cited text no. 5
    
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Kim SH, Park KH. The relationship between recurrent optic disc hemorrhage and glaucoma progression. Ophthalmology 2006;113:598-602.  Back to cited text no. 6
    
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Wang YX, Hu LN, Yang H, Jonas JB, Xu L. Frequency and associated factors of structural progression of open-angle glaucoma in the Beijing Eye Study. Br J Ophthalmol 2012;96:811-5.  Back to cited text no. 7
    
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Lin HC, Chien CW, Hu CC, Ho JD. Comparison of comorbid conditions between open-angle glaucoma patients and a controlcohort: Acase –control study. Ophthalmology 2010;117:2088-95.  Back to cited text no. 8
    
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Yamamoto T, Kitazawa Y. Vascular pathogenesis of normal-tension glaucoma: A possible pathogenetic factor, other than intraocular pressure, of glaucomatous optic neuropathy. Prog Retin Eye Res 1998;17:127-43.  Back to cited text no. 11
    
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13.
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Maram J, Srinivas S, Sadda SR. Evaluating ocular blood flow. Indian J Ophthalmol 2017;65:337-46.  Back to cited text no. 14
[PUBMED]  [Full text]  
15.
Xu S, Huang S, Lin Z, Liu W, Zhong Y. Color Doppler imaging analysis of ocular blood flow velocities in normal tension glaucoma patients: A meta-analysis. J Ophthalmol 2015;2015:919610.  Back to cited text no. 15
    
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Mohindroo C, Ichhpujani P, Kumar S. Current imaging modalities for assessing ocular blood flow in glaucoma. J Curr Glaucoma Pract 2016;10:104-12.  Back to cited text no. 16
    
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Pemp B, Garhofer G, Lasta M, Schmidl D, Wolzt M, Schmetterer L. The effects of moxaverine on ocular blood flow in patients with age-related macular degeneration or primary open angle glaucoma and in healthy control subjects. Acta Ophthalmol 2012;90:139-45.  Back to cited text no. 18
    
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Aizawa N, Yokoyama Y, Chiba N, Omodaka K, Yasuda M, Otomo T, et al. Reproducibility of retinal circulation measurements obtained using laser speckle flowgraphy-NAVI in patients with glaucoma. Clin Ophthalmol 2011;5:1171-6.  Back to cited text no. 19
    
20.
Shiga Y, Asano T, Kunikata H, Nitta F, Sato H, Nakazawa T, et al. Relative flow volume, a novel blood flow index in the human retina derived from laser speckle flowgraphy. Invest Ophthalmol Vis Sci 2014;55:3899-904.  Back to cited text no. 20
    
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22.
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23.
Moghimi S, Hou H, Rao H, Weinreb RN. Optical Coherence Tomography Angiography and Glaucoma: A Brief Review. Asia Pac J Ophthalmol (Phila) 2019. doi: 10.22608/APO.201914. Epub ahead of print.  Back to cited text no. 23
    
24.
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25.
Weinreb RN, Harris A, editors. Ocular blood flow in glaucoma. In: The 6th Consensus Report of the World Glaucoma Association. Amsterdam/The Hague, The Netherlands: Kugler Publications; 2009. p. 157-8.  Back to cited text no. 25
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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Abstract
Introduction
Vascular Risk Fa...
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Color Doppler Im...
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Doppler Fourier ...
Optical Coherenc...
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