Glaucoma: The second most common cause of blindness AND the most common cause of preventable visual disability worldwide. To date, reducing intraocular pressure (IOP) remains the mainstay for treating this progressive, neurodegenerative disease – however, this treatment is often only partly effective.
This could be because some patients – like those with normal-tension glaucoma (NTG) – never experience elevated IOP. In fact, research shows that 20 to 30 percent of patients never have IOP of more than 20mmHg, but still show glaucomatous damage.1
Norman M. Aquino, M. D., clinical associate professor and chief of the Glaucoma Service of the University of the Philippines-Philippine General Hospital, Manila, Philippines, says that glaucomatous optic neuropathy is brought about by a variety of complex and interrelated biomechanical and biochemical factors. “These initiate a cascade of events that will eventually lead to retinal ganglion cell death,” he added.
Studies have found that some glaucoma patients may present with signs of ocular and vascular abnormalities. Moreover, patients with glaucoma have a higher incidence of vascular-related clinical symptoms such as low systolic blood pressure, migraines, peripheral vasospasm and obstructive sleep apnea syndrome.2 These suggest that factors other than IOP may be involved in the disease pathogenesis.
“The effects of IOP and vascular dysregulation are recognized as major risk factors in the pathogenesis of glaucoma,” said A/Prof. Aquino. “Their effects on ocular structures like the lamina cribrosa, ocular microcirculation and perfusion, and apoptosis are known and well documented.”
So, is IOP – while agreeably the most important risk factor for glaucoma – just one culprit of this progressive pathology?
The current understanding of OBF in glaucoma
In 2010, Martinez and Sanchez hypothesized that changes in ocular blood flow (OBF) are associated with the progression of glaucomatous damage.3 The authors believed it was conceivable that an increase in OBF may protect against glaucomatous visual field (VF) deterioration, and in the almost decade since, additional research has corroborated this theory. Assessing VF progression remains one of the most important but challenging aspects of glaucoma management – therefore, a better understanding of pathology’s clinical risk factors may encourage the development of new strategies to improve care.
A review article published in the Asia-Pacific Journal of Ophthalmology (2016) stated that many studies have found that glaucoma is associated with decreased OBF. Research also shows that OBF reduction in the optic nerve head (ONH) is associated with glaucoma progression, and glaucoma patients with asymmetric visual field loss have lower blood velocity in the central retinal artery of the more affected eye.4
There is also a correlation between mean flow velocity and mean arterial blood pressure in the central retinal artery, and it’s stronger in subjects with primary open-angle glaucoma (POAG) than in healthy control subjects. Eyes with advanced NTG also have significantly lower blood flow velocity and a higher resistive index in the central retinal artery and the short posterior ciliary arteries than eyes with milder visual field defects, even when IOP is similar. These findings led the authors to conclude that vascular factors may play an important role in patients with POAG and NTG.4
In addition, the Leuven Eye Study – which is noted to be the largest clinical trial on OBF in glaucoma – found that glaucoma groups had lower retrobulbar velocities, higher retinal venous saturation and choroidal thickness asymmetries when compared to healthy groups.2 This is supported by color doppler imaging, which has shown that retrobulbar blood velocity is significantly reduced in eyes with high IOP.4 Population-based epidemiological and clinical studies have found that low ocular perfusion pressure (OPP) is closely related to the prevalence and progression of POAG.4
Therefore, determining the causative role of low OBF in the pathophysiology of glaucoma is an important goal of current research because it may lead to the discovery of new glaucoma treatments based on OBF.
Neuroprotection: Improving blood flow and preserving the visual field with medication
Different drugs have been used for the treatment of glaucoma and have been effective in lowering IOP. Among these, topical carbonic anhydrase inhibitors (CAIs) have been routinely used as concomitant medications. Dorzolamide was the first topical CAI with a significant IOP-lowering activity to become available on the market.3
Medications from Santen Pharmaceutical Co. Ltd. (Tokyo, Japan) including dorzolamide and tafluprost (a prostaglandin analog) have been noted to aid in visual field preservation and have been studied for their neuroprotective benefits for patients with glaucoma. Now, they’re also being studied for their effects on OBF.
According to a paper published in the Journal of Ophthalmic Visual Research (2016), “neuroprotection in the field of glaucoma is defined as any treatment, independent of IOP reduction, which prevents retinal ganglion cell (RGC) death.” Neuroprotection aims to protect undamaged, and to rescue already damaged neurons, from the glaucoma insult(s) to retinal ganglion cells. It has the potential to prevent retinal ganglion cell death independently of the factors that damage the optic nerve. The authors list glaucoma medications with blood regulatory effects and nitric oxide synthase inhibitors among compounds with possible neuroprotective activity in preclinical studies.5
In 2010, Martinez and Sanchez studied rates of VF progression in eyes treated with dorzolamide–timolol compared with eyes treated with brinzolamide–timolol. They concluded that “the fact that both combinations (dorzolamide–timolol and brinzolamide–timolol) had a similar IOP-lowering effect, although different vascular effects, provides further evidence to support a local vasoactive effect as opposed to an ocular tension mechanism.” Treatment also had a strong influence on progression: The dorzolamide–timolol combination reduced the relative risk for progression by 48 percent compared with brinzolamide–timolol.3 This led the authors to suggest that that dorzolamide significantly increases hemodynamic parameters in retrobulbar vessels – and thus, is perhaps evidence that reduced OBF is associated with VF loss.
And according to A/Prof. Aquino, dorzolamide has been shown to influence ocular hemodynamics by dilating ocular blood vessels and thereby improving blood flow. “This will be beneficial in addressing the vascular aspect of the pathogenesis of glaucoma,” he said.
A study published in the British Journal of Ophthalmology by Stewart et al., suggests that dorzolamide, as a single agent and in fixed combination with timolol, has been shown to increase red blood cell velocity with pulsatile OBF, color Doppler and laser Doppler techniques in normal individuals as well as NTG and POAG patients. This positive effect on ocular hemodynamics has been greater than observed with other drugs – even with similar or lesser intraocular pressure lowering.6 Topical CAIs increase the velocity of OBF in the retinal circulation, central retinal, and short posterior ciliary arteries, but not in the ophthalmic artery.4
Tafluprost has also shown to have the effect of increasing OBF. This was shown in a 2017 study by Iida, et al., which evaluated retinal blood flow velocity change in the parafoveal capillary after topical tafluprost treatment in eyes with POAG. The authors found that mean IOP was significantly decreased (1 week, −19.1%; 4 weeks, −17.7%; and 12 weeks, −23.5%; all P<0.001) and mean pBFV was significantly increased from the baseline at all follow-up periods after initiating treatment (1 week, 14.9%, P=0.007; 4 weeks, 21.3%, P<0.001; and 12 weeks, 14.3%, P=0.002). These results reveal that tafluprost may not only lower IOP but may also improve retinal circulation in POAG eyes.7
The experts chime in
Dr. Poemen Chan, Assistant Professor from the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong (CUHK), Hong Kong, notes that some people continue to experience [glaucoma] disease progression despite meeting an acceptable intraocular pressure target: “We usually talk about reduction of IOP by 20 to 30 percent, but even with that, some people’s progression is out of control.” He says this has led experts to consider vascular components.
“We know that compromising vascular health is an issue [a risk factor] in the progression,” he explained. “When the blood supply to the optic nerve is compromised, we have degeneration.” “If we have a situation where glaucoma continues to progress despite adequate pressure control, then we need to think about neuroprotection – and blood supply is part of neuroprotection,” said Dr. Chan. “The aim is to slow down the progression of glaucoma. Either it’s a ‘push factor’ – the IOP – or it’s the “supply factor” – the OBF.”
“First of all, we know OBF plays a role. However, we don’t have a definite guideline of how much we should improve and when we should do it,” continued Dr. Chan. “There are several large population-based studies that specifically identify a decrease in ocular perfusion pressure, similar to ocular blood flow, as a risk factor for glaucoma. They manage to find ways to reduce retinal or choroidal or retrobulbar blood flow – but how should we quantify it? That’s the problem.”
Although ocular circulation at the retina and optic disc is known to be associated with the pathology of glaucoma, direct measurement of blood flow velocity has been difficult to obtain.4 This is because blood flow in glaucoma however does not depend upon one type of circulation but rather involves multiple circulations including retina, choroid and optic nerve head. So far there is not a single device or a technique, which can measure all three circulations. Therefore, multiple techniques have to be employed to study these circulations.7
“Medical treatment that will be able to adequately address both IOP and vascular dysregulation would be ideal,” said A/Prof. Aquino. “By controlling these two risk factors, the cascade of events leading to retinal ganglion cell death can be modified and will result in better control of the glaucomatous disease process. This will be translated to improved treatment outcomes.”
“The role of OBF is certainly worth looking into, especially in a significant portion of patients whom we have lowered the pressure enough, but glaucoma is still progressing,” said Dr. Chan. “All these need further investigation. And I suppose that’s the major challenge.”
References:
1 Mahar PS. Ocular Blood Flow and its Determination and Relevance in Glaucoma. Pak J Ophthalmol. 2006, Vol. 22 No. 3.
2 Abegao, L, et al. Ocular blood flow in glaucoma – the Leuven Eye Study. Acta Ophthalmol. 2016: 94: 592–598
3 Martinez A, Sanchez-Salorio M. Predictors for visual field progression and the effects of treatment with dorzolamide 2% or brinzolamide 1% each added to timolol 0.5% in primary open-angle glaucoma. Acta Ophthalmol. 2010: 88: 541–552.
4 Nakazawa, T. Ocular Blood Flow and Influencing Factors for Glaucoma. Asia Pac J Ophthalmol. 2016;5: 38–44.
5 Doozandeh A, Yazdani S. Neuroprotection in Glaucoma. J Ophthalmic Vis Res. 2016 Apr-Jun; 11(2): 209–220.
6 Stewart W, Feldman R, Mychaskiw MA. Ocular blood flow in glaucoma: the need for further clinical evidence and patient outcomes research. Br J Ophthalmol 2007;91:1263–1264. 7 Iida Y, et al. Retinal Blood Flow Velocity Change in Parafoveal Capillary after Topical Tafluprost Treatment in Eyes with Primary Open-angle Glaucoma. Scientific Reports. 2017. 7: 5019.
