Glaucoma is the leading cause of irreversible blindness worldwide with over 120 million people affected [Citation1]. It is a progressive optic neuropathy, characterized by the loss of retinal ganglions cells and their axons and tissue remodeling involving both the optic nerve head (ONH) and the retina. It leads to visible cupping of the ONH and as a result patients experience progressive visual field loss [Citation2]. Increased intraocular pressure (IOP) is a major risk factor and, at present, the only modifiable one.
Despite its public health importance, the pathophysiology of glaucoma is not well understood. The ‘mechanical’ glaucoma theory stipulates axonal injury based solely on increased IOP. Yet half of patients with confirmed glaucoma have daytime IOP levels that are considered normal, whereas half of individuals with ‘high’ IOP never develop glaucomatous damage. Worse, some patients have progressive disease despite low, almost non-physiological, IOP levels.
The ‘vascular’ theory explains these inconsistencies by implicating other factors besides IOP such as compromised blood flow for glaucoma [Citation3]. On average, blood flow is reduced in glaucoma patients in various tissues of the eye, including the iris, retina, optic nerve, and choroids. Blood flow reduction is even more pronounced in normal tension glaucoma (NTG) than primary open angle glaucoma (POAG) with high tension. These changes in blood flow suggest that impaired regulation of ocular blood flow results in periods of relative ischemia and repeated reperfusion damage to the optic nerve.
In the past, researchers have used various technologies to assess ocular blood flow, such as angiography with injectable dyes, lasers, and ultrasonography. Among these, color Doppler ultrasonography imaging (CDI) was deemed the promising imaging technology. CDI can measure blood velocity but not actual blood flow. Using this device, velocity measurements have been reported for the ophthalmic, central retinal, and posterior ciliary arteries in different cohorts of glaucoma patients and healthy subjects [Citation4]. Most studies show impaired orbital blood flow in POAG. There are, however, important disparities including contradictory findings in between studies. Part of these may have been due to inter-study methodological differences, such as the inclusion criteria. The main reason, however, is the operator-dependent nature of CDI, leading to low reproducibility of measurements. An important source of error is incorrect angle of incidence. Another potential source of error is increased IOP caused by the degree of pressure applied on the eyelid. Moreover, CDI measurements are subjective. Plange et al. [Citation5] concluded that Doppler imaging had a mere sensitivity of 48% and a specificity of 90% for the identification of NTG. Finally, CDI is an expensive device (>$100.000) and not readily available in glaucoma centers.
Despite inconsistencies, data from these imaging technologies seem to support the hypothesis whereby glaucoma is related to compromised ocular blood flow. However, their numerous shortcomings have discouraged a generation of researchers from entering the field of ocular blood flow and prompted them to seek safer and less uncontroversial research activities.
1. Enter optical coherence tomography angiography (OCT)
Optical coherence tomography angiography (OCT-A) may be one of the greatest breakthroughs in ophthalmology in a decade. It has the potential to shed light into the pathophysiology of glaucoma and may very soon change clinical practices in ophthalmology. It was first described in 2006 but its application to ocular diseases only started to be explored in 2013. The technology first became commercially available only in 2014 with the introduction of the Avanti OCT-A (Optovue Inc., USA) [Citation6].
Contrary to traditional angiography with fluorescein, this technology does not require the injection of extrinsic contrast dye. Instead, OCT angiography detects blood flow through the motion contrast generated by red blood cells and therefore is sensitive to both transverse and axial flow in time. This was made possible by the high speed of Fourier-domain OCT (>50 kHz), which allows multiple cross-sectional images to be obtained at the same location to detect relative motion in vessels. OCT angiograms combine color-coded blood flow information with gray-scale structural information. Therefore, both blood flow and retinal structural information are presented together. Three-dimensional volumetric OCT-A can be obtained in seconds. OCT-A generates a data cube, segmentation, and en face presentation of vessels at various layers of the retina and the ONH that can summarize the flow information at relevant anatomic layers or ‘slabs.’ Of practical importance, existing OCT hardware can be upgraded to perform angiography and use either the Doppler shift or variations in speckle pattern. Both varieties of Fourier-domain OCT, spectral or swept source, are used. Split-spectrum amplitude-decorrelation angiography is an algorithm that is capable of flow detection both at the ONH and at the macula and quantifies the data as both flow index and vessel density.
Recently, Liu et al. [Citation7] evaluated peripapillary retinal perfusion in 12 glaucoma eyes and compared it with 12 age-matched healthy eyes. They showed a dense microvascular capillary network around the ONH in healthy eyes, which was significantly attenuated in the glaucoma eyes. Using the OCT-A’s vessel density parameter, the discriminating ability between glaucoma versus normal eyes (area under receiver operating characteristic curve) was a strong 0.938. Interestingly, the authors found a strong correspondence (Pearson r = −0.835) between functional loss in glaucoma eyes (assessed by perimetry) and structural damage to the optic nerve. These results are very encouraging but are derived from a small sample of subjects.
For management of patients with retinal pathologies, the introduction of OCT-A has been a huge advancement as it provides both functional and morphological assessment of retinal from a single dye-less examination. Its role in the management of glaucoma is yet to be shown. In the case of ONH microcirculation, the network is so fine and tightly packed that it could not been visualized with traditional fluorescein angiography. With OCT-A the status of the retinal capillary perfusion can be assessed with more confidence than traditional methods.
2. Future directions
While there is a general agreement that hemodynamic alterations are one of the key factors in the pathophysiology of glaucoma, it remains unclear whether it is causative or secondary to retinal injury. This ‘chicken or egg first’ quandary has persisted for decades without evidence to support one or the other conclusion. Clinical studies generally address this question by evaluating the correlation between ocular hemodynamics and structural or functional damage in glaucoma. The results from such studies, however, are constrained by cross-sectional design. Thus, the importance of compromised blood flow as a potential pathogenic factor in glaucoma remains unsettled. An interesting question is also whether patients with signs of vascular dysregulation (such as migraine, Raynaud’s phenomenon) have a higher risk of developing progressive glaucoma. Before any new diagnostic instrument can be used to assess longitudinal changes, its repeatability and reproducibility has to be evaluated. Our group recently conducted a study in healthy and glaucoma eyes to study this question. Results showed good repeatability and reproducibility of OCT-A, similar to values with standard OCT measurements of retinal layers (Mansouri K., unpublished results).
In conclusion, OCT-A holds the promise to shed light into the as-yet unknown causative mechanisms of glaucoma as well as improve and complement current management of glaucoma.
Declaration of interest
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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References
- Resnikoff S, Pascolini D, Etya’ale D, et al. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004;82(11):844–851.
- Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014;311(18):1901–1911.
- Flammer J, Orgul S, Costa VP, et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res. 2002;21(4):359–393.
- Stalmans I, Vandewalle E, Anderson DR, et al. Use of colour Doppler imaging in ocular blood flow research. Acta Ophthalmol. 2011;89(8):e609–e630.
- Plange N, Kaup M, Weber A, et al.. Performance of colour Doppler imaging discriminating normal tension glaucoma from healthy eyes. Eye. 2009;23(1):164–170.
- Jia Y, Wei E, Wang X, et al. Optical coherence tomography angiography of optic disc perfusion in glaucoma. Ophthalmology. 2014;121(7):1322–1332.
- Liu L, Jia Y, Takusagawa HL, et al. Optical coherence tomography angiography of the peripapillary retina in glaucoma. JAMA Ophthalmol. 2015;133(9):1045–1052.