Episcleral Venous Pressure

Arthur Sit
Rochester, MN, USA

Episcleral venous pressure (EVP) is an important determinant of intraocular pressure (IOP), but has previously been difficult to measure, resulting in a lack of understanding about its role in modulating IOP. Also, knowledge of its role in the mechanisms of action of glaucoma therapies has been incomplete, resulting in a lack of interest in its potential as a therapeutic target. However, recent advances in our ability to measure EVP may potentially transform our understanding of this parameter.

EVP in aqueous humor dynamics

In addition to its intrinsic role in determining IOP, EVP is also a critical determinant in the calculation of uveoscleral outflow. The modified Goldmann equation describes IOP as being determined by several factors:

IOP=EVP+(Q−U)/c

where Q is the aqueous humor flow rate, c is the conventional outflow facility, and U is the pressure-insensitive uveoscleral outflow rate. While IOP, EVP, Q and c can be measured non-invasively, U is typically calculated from the modified Goldmann equation. Small errors in EVP can cause much larger errors in the estimate of uveoscleral flow. For example, if IOP = 17 mmHg, Q = 2.3 μL/min, c = 0.22 μL/min/mmHg, and EVP is 8 mmHg, then U would be 0.32 μl/min, or 14% of total aqueous humor outflow. If EVP were erroneously estimated to be 9 mmHg (a 12% error), the estimate of U would be 0.54 μL/min, or 23% of total aqueous humor outflow, an over-estimate of 69%. Despite its significance, difficulty in EVP measurement has resulted in uncertainty about its characteristics, and often an assumption that it has a largely static value.

The anatomy of the outflow system distal to Schlemm’s canal is consistent with a vascular system capable of pressure regulation

Regulation of EVP

Although it is uncertain if EVP is actively regulated, the anatomy of the outflow system distal to Schlemm’s canal is consistent with a vascular system capable of pressure regulation, with the episcleral vasculature consisting of arteries, veins, and arteriovenous anastomoses.^1-3 One possible mechanism for the regulation of EVP is the direct modulation of vascular resistance in the episcleral venous system. Episcleral vessels, including the veins, stain intensely for smooth-muscle α-actin,⁴ which suggests the presence of muscular walls. Since outflow resistance varies with vessel diameter to the fourth power, relatively small changes in vascular tone may result in venous constriction that increases fluid resistance and EVP.

Dynamic modulation of the episcleral arteriovenous connections, possibly through nitric oxide signaling, could also alter EVP by controlling the degree to which the episcleral venous system is exposed to the higher pressure arterial system. Funk et al.⁵ reported that topical administration of a vasodilator and nitric oxide donor (nitroprusside) increased EVP in rabbits, and Zamora and Kiel⁶ demonstrated that a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester) reduced EVP. These results suggest that vasodilation of the episcleral arteriovenous anastomoses, mediated by nitric oxide, can increase EVP and subsequently IOP.

Measurement of EVP

Measurement of EVP is difficult due to the small caliber of the vessels. Human episcleral veins typically range from 50 to 100 mm in diameter, and less in small animal models. EVP has been measured both invasively and non-invasively. Invasive measurement can be performed by direct cannulation of episcleral veins and indirectly by controlling the pressure in the anterior chamber. With direct cannulation, the small diameter and the low volume of fluid in the vessel preclude direct measurement by a pressure transducer through the cannula. Instead, a ‘zero-flow’ or ‘servo-null’ technique is utilized in which the pressure in the cannula is adjusted by using a manometer until fluid stops moving through the cannula in either direction. At that point, the boundary between the blood in the vein and the perfusion fluid oscillates with the cardiac pulse, indicating that the pressure set by the manometer was equal to average venous pressure.^7-9 With smaller animals, such as mice, an alternate, indirect measurement technique is used due to the small size of the episcleral veins.^10,11 Pressure in the anterior chamber is controlled through a glass intracameral needle connected to a water-filled reservoir and pressure transducer, and the intracameral pressure is reduced until blood refluxes into the collector channels and Schlemm’s canal. The pressure that allowed blood to reflux is assumed to be equal to the EVP. While these measurements can be very precise, it is not clear how animal EVP compares with human EVP due to differences in body position and possible effects of cannulation on the vascular tone.

Non-invasive measurement of EVP is based on the principle of venous compression. An episcleral vein is identified, a force is applied to the vein with a clear flexible membrane until it collapses, and venous pressure is determined from the pressure in the membrane required to collapse the vessel to a predetermined endpoint. However, vessels do not collapse instantaneously, but collapse gradually over a range of several mmHg of applied pressure. Based on ideal tube laws,¹² and confirmed with animal experiments,¹³ EVP is best represented by the pressure that is required to just start the collapse of the episcleral vein. This is a very difficult point to detect manually, and most investigators have assumed an endpoint where visible collapse has occurred. Unfortunately, this can be subjective and likely results in a pressure reading higher than the true EVP, and a wide array of values for mean normal EVP reported in the literature, ranging from 7.6 mmHg to 11.4 mmHg.¹⁴ A recently developed objective technique for EVP measurement utilizes the pressure chamber technique, but combines video imaging synchronized with readings from a pressure transducer.¹⁵ By using image processing techniques, the initial point of episcleral vein collapse can be easily identified. With this technique, mean EVP in normal subjects is typically around 7 mmHg.

Modulation of EVP

Due to the previous lack of objective techniques for measurement, many studies evaluating mechanisms of action for glaucoma therapies assumed a static EVP. Most human studies that have evaluated existing pharmacologic agents have not found an effect on EVP, but may have been limited by the precision of the measurements. This includes studies of beta-blockers,^16-18 prostaglandin analogs,¹⁹ carbonic anhydrase inhibitors,²⁰ and alpha-agonists,²¹ which have all reported no change in EVP with medication administration. However, one study of calcium channel blockers indicated that topical verapamil 0.25% reduced EVP by 12% after two weeks of administration three times a day.²² In that study, EVP also decreased in the control eye, suggesting a systemic effect. In contrast, animal studies have suggested that EVP can be modified by a variety of pharmacologic agents. Zamora and Kiel²³ reported that topical proparacaine decreased EVP in rabbits when conjunctiva was removed, possibly by blocking efferent neural inputs in the episcleral vasculature. Similarly, Reitsamer et al.²⁴ found that EVP decreased 42% within five to ten minutes after topical application of brimonidine in rabbits. In a study in mice, Millar et al. reported that latanoprost reduced EVP by 50%, while betaxolol and brimonidine had no effect on EVP.²⁵ The reasons for the discrepant results between human and animal studies, as well as different animal models, in unclear and further measurements of EVP using objective measurement methods are needed.

The physiology of the episcleral vascular plexus suggests that EVP can be modulated, and reduction of EVP may be a viable target for glaucoma therapy

Summary

EVP is an important contributor to IOP and assessment of aqueous humor dynamics requires accurate measurements of this parameter. Although past attempts to measure this parameter were limited by the technology available, current techniques appear able to measure EVP reliable. The physiology of the episcleral vascular plexus suggests that EVP can be modulated, and reduction of EVP may be a viable target for glaucoma therapy. Animal studies suggest that even some existing therapies may modulate this parameter. While modification of EVP is unlikely to be a primary target for initial therapy of primary open-angle glaucoma, due to the limited amount of IOP reduction possible, it may be a reasonable target for adjuvant therapy or treatment of normal-tension glaucoma patients.