TEST
Vindico Medical Education
Go to the PCON SuperSite
Contact Us Compliance Office Services About Us
Optometry Learning Center
 EARN CE IN:

Ocular biomechanics, autoregulation potential factors in glaucoma pathogenesis

Research shows that altered biomechanics and vascular dysregulation in association with elevated IOP may contribute to POAG.

by José M. De Jesús, OD, MA

Download and mail the CE quiz

Privacy and Confidentiality Guidelines | Hardware and Software Requirements | Contact Us

Irrefutable evidence indicates that elevated intraocular pressure is a major risk factor in the development of primary open-angle glaucoma. Even so, only a minority of patients with elevated IOP generate the disease. This leads to the debate of other possible risk factors that may or may not work in concert with elevated IOP.

As studies in glaucoma evolve, the influence of ocular biomechanics and vascular autoregulation has been suggested. Shah and colleagues consider alterations in corneal integrity/ocular rigidity to pose as a risk factor associated with IOP. Proponents of the vascular theory, such as Pillunat and colleagues, suggest that the susceptibility of neural tissue to elevated IOP may be at the expense of autoregulatory mechanisms in the oculovascular system. Studies attempting to elucidate the pathogenesis of primary open-angle glaucoma (POAG) point towards discovering the possible role of these two factors and their relationship to IOP.

Difference in biomechanical behavior of the cornea upon applanation pressure
Left: Viscoelastic behavior of the cornea, whereupon applanation force returns to its normal contour through a different and delayed pathway. The area between the two curved arrows represents the energy dispersed during the process. This is defined as corneal hysteresis. Right: Elastic behavior of the cornea, whereupon applanation force returns to its normal contour through the same inward pathway once the applanation force ends. This is termed corneal resistance factor.
Source: De Jesús JM

Determining ocular biomechanics

Until a few years ago, it was thought that the most sensible way to extrapolate biomechanical properties of the cornea was through central corneal thickness (CCT) measurements. A tool that can be used in this assessment is the Ocular Response Analyzer (ORA) (Reichert Ophthalmic Instruments, Buffalo, N.Y.), an upgraded noncontact pneumotonometer that infers ocular rigidity based on viscoelastic and elastic properties of the cornea.

According to Luce and Kotecha, corneal hysteresis (CH) is the term used to define the viscoelasticity of the cornea as a result of an apparent combined effect of corneal thickness and rigidity. CH also appears to provide the basis for another parameter called corneal resistance factor (CRF). This parameter reflects elastic properties of the cornea and seems to relate more specifically to the overall ocular structural resistance, reported Luce.

Statistical analysis exposing the relationship between CCT and CH and CRF in eyes with ocular hypertension (OHT) or POAG revealed it to be proportional, according to Shah and colleagues. In other words, the higher the CCT, the higher the CH and CRF.

CH distribution of normal and glaucomatous subjects

Although the analysis proved to be statistically significant, the correlation coefficient was not very strong. This may imply that CH and CRF are related to CCT but are different biomechanical values for assessing ocular rigidity.

In addition to this relationship showing a positive effect, data also demonstrate that CH and CRF values tend to be greater in OHT patients. Shah and colleagues showed that in a group of 216 eyes with POAG and 199 eyes with OHT, the latter group had statistically significantly higher CH and CRF values. Sullivan-Mee and colleagues also revealed that OHT subjects had higher mean CH and CFR values than the POAG group.

In addition, a relationship of CH and CRF with the development and progression of glaucoma is seen. In the past, the Ocular Hypertension Treatment Study (OHTS) had emphasized the importance of CCT in diagnosing and managing the progression of glaucoma, according to Luce and Taylor. Data rightfully implied that thin corneas may be a risk factor for the development and progression of glaucoma.

CH values after LASIK

Similarly, CH and CRF measurements obtained with the ORA imply this type of relationship. Luce and Taylor found that, compared to normals, patients with normal tension glaucoma (NTG) or POAG had lower-than-average CH and CRF values. CH distribution analysis of normal and glaucomatous subjects revealed a greater percentage of normal subjects with higher CH measurements.

However, it is worth noting that eyes with POAG showed a negative correlation between CH and CRF values related to elevated IOP in this study. The eyes with severely elevated pressures had much lower-than-average CH values and higher CRF values. Alternatively, this may imply that alteration in dynamic and static resistance of the cornea is a consequence of sustained elevated IOP in patients with POAG.

Patients diagnosed with keratoconus also have low CH and CRF values. The same proves true for patients who have both keratoconus and glaucoma.

Shah and colleagues measured CH values in normal eyes and those with keratoconus and found that CH in normal eyes was considerably higher in comparison to eyes with severe keratoconus.

Cohen and colleagues, comparing CH and CRF values in subjects with keratoconus (and others with pellucid degeneration) that have glaucoma or are glaucoma suspects (cases) with age-matched keratoconus (and pellucid patients) subjects without glaucoma (controls) revealed statistically similar low mean values in both groups. In addition, low values positively correlated with severity of keratoconus in both groups. However, this correlation was not observed in relation to the presence of glaucoma/glaucoma suspect in cases. In other words, no additional reduction in CH and CRF values was observed in the presence or suspicion of glaucoma. This is significant, as it indicates that factors other than alterations in corneal biomechanics influenced the development of glaucoma in these subjects.

CH values in normal keratoconic eyes

Corneal biomechanics may also be significant in LASIK refractive surgery. Studies by McGrath and Dupps and colleagues suggest that substandard biomechanical properties of the cornea challenge the consistency of visual results after LASIK and may have an adverse effect on the structural integrity of the cornea. Hence, taking CH and CRF measurements into consideration as part of the preoperative protocol in LASIK may help the clinician make better decisions about candidates’ suitability for surgery, particularly those at risk of developing postoperative keratectasia.

Moreover, data from diverse studies demonstrate a widespread reduction in CH and CRF values following LASIK. Luce and Taylor, in a study in pre- and post-LASIK eyes, revealed a decrease in CH values after LASIK in all eyes studied. The possible influence of corneal biomechanical properties on LASIK has led many researchers to believe that the inclusion of CH measurements in treatment algorithms may help improve predictability of visual outcomes after LASIK and minimize complications.

Like in glaucoma, a weak correlation exists between CH and CCT in corneal refractive surgery. Caitriona and colleagues concluded in their study that LASIK and laser-assisted subepithelial keratectomy (LASEK) surgery reduce CH almost to the same degree regardless of tissue ablation depth. In other words, with the cut of a thin flap, post-LASIK CCT causes an effect similar to surface ablation on the biomechanical integrity of the cornea.

Schematic representation of the contribution of autoregulation dysfunction to glaucomatous damage in association with elevated IOP

Interestingly, ORA signals obtained from eyes of NTG subjects look similar to the ORA signals obtained from eyes of post-LASIK patients, according to Luce and Taylor. This finding supports the hypothesis that the biomechanical integrity of the cornea is in some way involved in the glaucomatous disease process.

Autoregulation and perfusion pressure

Autoregulation can be described as a process in which normal blood flow is maintained in response to changes in perfusion pressure. In the eye, a decrease in perfusion pressure may be provoked by elevation in IOP.

For many years now, the concept of perfusion-pressure effect has been widely accepted in glaucoma. This means that any significant elevation in IOP will reduce perfusion pressure to the eye, which in turn may result in reduced blood flow to the optic nerve head (ONH). Nonetheless, only about 20% of patients with persistent elevated IOP develop glaucomatous damage.

ONH blood flow after NOS inhibition: POAG patients vs. healthy normals

Apparently, autoregulation impedes the process. As it occurs in other organs of the human body, ocular autoregulation maintains normal blood flow to the eye in response to changes in perfusion pressure by altering mechanical or chemical physiologic processes that influence the tone of blood vessel walls, thereby modifying vascular resistance.

The equation blood flow (BF) equals perfusion pressure (PP, Pa – Pv), over vascular resistance (R) can be used to illustrate this.

PP is equal to the difference between the perfusion pressure in arteries and perfusion pressure in veins. The pressure in the venous system exiting the eye needs to be slightly higher than or equal to the IOP; otherwise a venous collapse may occur, according to Anderson. Thus, an increment in venous perfusion pressure provoked by elevated IOP may result in a decrease in ocular PP.

Elevated IOP and a resultant decrease in ocular perfusion pressure challenge vascular regulatory function in the eye, according to Moore and colleagues. Furthermore, instability in ocular blood flow (OBF) may ensue when autoregulation dysfunction is present. This may lead to ischemic glaucomatous damage to the ONH and retinal ganglion cell (RGC) death, which, in turn, may partially lead to further regulatory dysfunction.

Fluorescein angiography flow characteristics following infusion of serotonin in atherosclerotic monkeys

Evidence shows that autoregulation response to elevated IOP varies among individuals. Pillunat and colleagues measured autoregulation response in 10 healthy subjects exposed to varying degrees of IOP. Autoregulation response in eight of the subjects was sufficient to maintain normal circulation up to IOPs of approximately 40 mm Hg. In the other two subjects, ocular blood flow began to compromise at about 20 mm Hg.

The precise blood flow regulatory system at the ONH still remains somewhat obscured. Nonetheless, some data suggest that abnormalities in lipid metabolism, primary vasospastic syndrome and vascular endothelial dysfunction may be implicated in ocular circulatory differences and ONH susceptibility in response to elevation and fluctuations in IOP, according to Moore and colleagues.

Atherothrombosis is a consequence of lipid deposition at the vascular tunica with subsequent intimal thickening and rupture forming an atheroma, complemented by aggregation of inflammatory cells and platelets. Ultimately, this impedes flow, interferes with perfusion and leads to ischemic insult to tissue, reported Rother and colleagues.

According to Badimon, extracellular transduction signaling leading to abnormalities in endothelial cell function appears to be the triggering mechanism for thrombus formation. These abnormalities have been thought to initiate abnormal vasoreactivity leading to autoregulatory dysfunction in compromised vessels. Moreover, it is known that during thrombus formation in an atheromatous plaque, serotonin is one of the substances released by endothelial cells.

A study by Hayreh and colleagues on atherosclerotic monkeys suggests that the presence of serotonin in atherothrombotic pathogenesis triggers vasospasm of the central retinal artery (CRA) and posterior ciliary artery, consequently impairing blood flow.

In this study, the infusion of serotonin in atherosclerotic monkeys produced either a complete occlusion or delayed circulation in the central retinal artery (CRA) or posterior ciliary artery (PCA) in nine of 18 eyes evaluated. In addition, three of the nine eyes with impaired circulation had complete occlusion of both CRA and lateral PCA.

Despite the correlation found in these studies, further investigation would be necessary to comprehend how atherothrombotic endothelial pathophysiology may relate to ocular autoregulatory dysfunction in POAG.

Most vasospastic episodes arise secondary to underlying diseases such as Prinzmetal’s angina and multiple sclerosis, according to Joing and colleagues. However, a primary vasospastic syndrome has also been identified as a response to cold stimulus and emotional stress, which may have direct involvement in ocular autoregulatory dysfunction. These patients often suffer from episodes of cold extremities, low blood pressure, migraines, silent myocardial ischemia and ocular vasospasm. Haufroid and Collignon-Robe suggest that patients with ocular vasospasm tend to be more susceptible to ONH damage as a result of elevated IOP.

Endothelial vascular dysfunction is also implicated in autoregulatory dysfunction associated with the disease process of POAG, reported Resch and colleagues. Endothelial biochemical alterations initiated by oxidative stress alter the vascular tone and destabilize vascular regulation function.

Nitric oxide (NO) and endothelin-1 (ET-1) are the endothelial vasoactive mediators that sustain the physiological balance between vasodilator and vasoconstrictor pathways, respectively, according to Parris and Webb and Verhaar and colleagues. NO is made available via endothelial cell synthesis and endothelin-B receptor (ETB) stimulation. ETB receptor activity is triggered through interaction with ET-1 that is synthesized and released by endothelial cells. ET-1 interacts primarily with endothelin-A receptor to mediate physiological vasoconstriction. A decrease in the biosynthesis or bioavailability of NO and an excess of ET-1 causes altered vasoreactivity (increased vasoconstriction), which leads to an imbalance in basal vascular tone, according to Resch and colleagues and Henry and colleagues.

A variety of diseases such as systemic hypertension, atherosclerosis and diabetes are associated with endothelium-dependent altered vasoreactivity. Aberrant lipid metabolism and systemic hypertension have been associated with inhibition of endothelial NO signaling in many organs, including the eye.

ORA signal from a normal subject's eye prior to LASIK
ORA signal from a normal subject's eye after LASIK
ORA signal from the eye of a NTG subject

Kawakami and colleagues demonstrated in a study performed in mice that apolipoprotein CIII in hyperlipidemia impairs insulin uptake by endothelial cells necessary for the production of NO. A similar study by Duplain and colleagues demonstrated that mice lacking nitric oxide synthase (NOS), the enzyme present in endothelial cells that mediates the conversion of the amino acid L-argenine to NO, had hyperlipidemia and hypertension. Likewise, faulty ET-1 activity provoking pathological vasoconstriction has been identified in conditions such as hypertension, heart failure, renal failure and secondary vasospastic diseases, according to Verhaar and colleagues and Haynes and Webb.

There is convincing evidence that POAG is associated with endothelial dysfunction in the ocular vasculature. Polak and colleagues demonstrated in their study that NOS inhibition in ocular vasculature reduced ONH blood flow in patients with POAG significantly less than in healthy controls at 30 minutes. Moreover, studies on the NOS-mediated L-arginine-NO pathway in eyes of patients with POAG suggest that the pathway is genetically defective, according to Delaney and colleagues and Tunny and colleagues.

Another study by Emre and colleagues evaluating glaucomatous field progression in 31 patients with POAG with specific radioimmunoassay revealed that 16 of these patients had increased ET-1 plasma levels. Furthermore, all 16 patients exhibited progressive visual field damage possibly linked to primary or secondary ocular vascular regulatory dysfunction.

IOP, biomechanics, dysregulation and POAG

Clearly, POAG is a progressive optic neuropathy that has a multifactorial etiology, in which elevated IOP is the most important risk factor. Nonetheless, research observations indicate that altered ocular biomechanics and vascular dysregulation in association with elevated IOP may also contribute to the disease process.

Comparing the two factors, however, it appears that altered autoregulation function has a more positive correlation with POAG. According to Moore and colleagues, a strong association exists between decreased ocular perfusion pressure precipitated by elevated IOP and decreased OBF in patients with vascular regulatory dysfunction.

Ocular biomechanics data, on the other hand, appears to be a bit more contending. Similarities in signals obtained with the ORA in patients with NTG and post-LASIK patients support the theory that the biomechanical integrity of the cornea is in some way involved in the glaucomatous disease process, reported Luce and Taylor.

It is without question, however, that further longitudinal studies are needed to determine if indeed in vivo CH and CRF values are independent predictors of glaucoma susceptibility. In addition, the possibility remains that alterations in corneal biomechanics may result from POAG rather than be a risk factor. It is hoped that future glaucoma research will focus on more specific variables that may further elucidate the association of alterations in ocular biomechanics and autoregulation with POAG.

References: