Although results of multiple studies demonstrate the importance of ocular perfusion pressure and ocular blood flow as risk factors for glaucoma and its progression, there is insufficient evidence to conclude that vascular insults are a primary instigator to the disease process, said Alon Harris, PhD.
“More longitudinal studies are needed to gain insight in this area; OCT angiography is emerging as a tool that will allow dual-purpose assessment of structure and function. Clinical research, however, has limitations, including limitations of measurements that can be obtained in patients and the complexity of the anatomy and vascular supply of the optic nerve head. These limitations make specific determination of its relevance to glaucoma challenging,” said Dr. Harris, Letzer Endowed Professor of Ophthalmology, professor of cellular and integrative physiology, and director of clinical research, Glick Eye Center, Indiana University School of Medicine, Indianapolis.
“The use of physically-based mathematical models, however, might provide a virtual laboratory that would allow for better understanding of the importance of risk factors in isolation and their synergistic actions.”
Discussing research that is relevant to understanding how ocular blood flow might affect the course of glaucoma, Dr. Harris noted that studies clearly show ocular blood flow is altered in multiple ocular structures in patients with glaucoma, including in the optic nerve head, retina, choroid, and retrobulbar vessels.
In addition, there is an understanding that there are multiple underlying causes for the changes, including autoregulation mechanisms, vasospasm, aging, genetics, and racial influences.
Further support for the idea that vascular abnormalities are important in glaucoma pathophysiology comes from evidence of extraocular vascular abnormalities/disease in patients with glaucoma.
Vascular abnormalities have been described in the nailfold capillary bed and cerebral vasculature of patients with glaucoma, reduced renal function was found to correlate with glaucoma prevalence in one study, and patients with open angle glaucoma have also been shown to have increased risks of cardiovascular disease and stroke.
Patients with African descent
“Glaucoma patients of African descent represent an interesting subgroup in relation to the topic of vascular abnormalities in glaucoma considering they are at increased risk for ischemic heart disease, diabetes, hypertension, cardiovascular disease, and stroke along with earlier onset of glaucoma, faster progression, and more severe visual field loss,” Dr. Harris said.
“The idea that altered blood flow may be a contributing factor for the racial disparity in glaucoma is supported by findings of a longitudinal study we recently reported. It showed that among glaucoma patients, reductions in retinal capillary and retrobulbar blood flow much more strongly correlated with changes over time in the optic nerve head and macular thickness in people of African descent compared with patients having European ancestry.”
Filling the gaps
Among the obstacles limiting clinical research has been the absence of any imaging modality that is capable of simultaneously quantifying all of the vascular beds that are relevant in glaucoma. In addition, until recently, there have not been devices able to measure structure and blood flow simultaneously.
OCT-based blood vessel imaging, including split spectrum amplitude decorrelation angiography, Doppler OCT, and optical microangiography OCT, shows promise for addressing the existing gaps in imaging. It has attributes that make it useful for studying blood flow in glaucoma considering that it allows detailed visualization of the vasculature, calculation of vessel density and flow index, and visualization of the full optic disc vascular tissue layer networks in the peripapillary and prelaminar regions, optic nerve head, and lamina cribrosa.
In addition, OCT angiography allows for simultaneous evaluation of structure and function, and when used in studies of patients with glaucoma, it has generated some interesting findings.
For example, one recent study reported that OCT angiography-measured vessel density had similar diagnostic accuracy compared with retinal nerve fiber layer measurements for differentiating between glaucoma patients and healthy controls.
However, OCT angiography still has limitations, Dr. Harris said.
“There are still a lot of artifacts in the images that are related to the superficial vessels, especially when imaging the deeper layers. In addition, flow index may include retinal microvasculature when measuring the optic disc vasculature, and most importantly, we do not have any longitudinal data related to glaucoma patients and do not know the prognostic ability of this technology,” he explained.
Many other factors, including demographic influences and individual susceptibilities, also make it challenging to study relationships between ocular blood flow and glaucoma.
To overcome the multiple confounders, Dr. Harris and colleagues have proposed using a mathematical model to leverage the analogy between blood flow in a network of vessels and current flow in a circuit.
The model calculates ocular blood flow taking into account vascular regulation, cerebrospinal fluid pressure, blood pressure, venous blood pressure, and IOP.
He illustrated its performance by describing its application for determining how changes in IOP and blood pressure affect retinal blood flow. Inputs for the model included three theoretical patients with different blood pressures (low, normal, and high) and IOP values ranging from 15 to 45 mm Hg.
According to the model, retinal blood flow was unchanged for IOP values < 26 mm Hg in the theoretical patients with high or normal blood pressure.
The plateau was explained by autoregulation. However, retinal blood flow continued to increase with decreasing IOP in the patient with low blood pressure.
The calculations also showed that when IOP was > 36 mm Hg, the predicted decrease in retinal blood flow decreased at a steeper slope compared with lower IOP levels as a result of partial venous collapse.
The venous collapse started earlier (at a lower IOP) in the theoretical patient with low blood pressure compared with the normal and high blood pressure patients.
“These data explain the findings of population-based studies showing that decreased blood pressure and decreased perfusion pressure are independent risk factors for glaucoma,” Dr. Harris said.