October 2018

GLAUCOMA

Glaucoma editor’s corner of the world
Aqueous humor outflow: Not quite as we thought it was


by Stefanie Petrou Binder, MD, EyeWorld Contributing Writer

With the arrival of a plethora of new and evolving MIGS procedures, surgeons today are fortunate to have a variety of surgical options that aid in aqueous outflow in different ways. All of the options beg for accurate diagnostics to allow us to determine the site of resistance within the outflow system so that we may optimally target our surgical approach to the appropriate region. Diagnosing problems with the outflow pathway, however, may be more difficult than providing treatments, given the complexity of the eye’s outflow system. In this “Glaucoma editor’s corner of the world,” we checked in with two experts in trabecular network imaging, Alex Huang, MD, and Murray Johnstone, MD, in order to learn where the state of the art finds us in 2018.
Dr. Huang’s research focuses on characterizing post-trabecular meshwork and scleral changes in glaucoma, optical coherence tomography visualization of aqueous humor outflow pathways in the eye, and angiographic visualization of aqueous humor outflow in the eye. Dr. Huang informs us that meshwork bypass surgery depends on two important factors: the presence of disease at the level of the meshwork (and the absence of disease of the distal pathway) and proper bypass placement to ensure adequate access to the canal. The canal is “segmentally heterogeneous.” This means that bypassing one area may not provide ideal access to the rest of the canal, and as such, bypassing several distinct areas or even opening up a larger area of the meshwork might help alleviate this problem.
Dr. Johnstone’s work is incredibly fascinating and raises many questions about the function of the outflow system as a whole and how surgeries may influence it. His research has used experimental models to investigate the canal of Schlemm, in particular its function as an aqueous pump and how it behaves as a pressure dependent system. He has also discovered fascinating aspects of canal microanatomy and biomechanics. Did you know that the meshwork is slightly stiffer in glaucoma patients? Less pulsatile? Did you know that it is possible for the canal to collapse and for the outer wall of the canal and meshwork to herniate into a collector channel? Such herniations can happen with high IOP, and these herniations would inactivate that collector channel and cause segmental canal disruption.
While our current outflow surgeries are “on target,” it may be awhile before we fully understand the outflow system well enough to know how to tailor MIGS therapies to the individual patient’s pathophysiology.

Nathan Radcliffe, MD,
Glaucoma editor



State-of-the-art imaging techniques aid physicians in visualizing outflow

New research on aqueous humor outflow (AHO) is helping physicians better understand the nature of the trabecular meshwork and guiding them in finding reliable ways to reestablish outflow. While once thought to be linear, physicians now know that aqueous outflow is segmented, pulsatile, and dynamic.

Bypassing the trabecular meshwork using MIGS

This can work, but it doesn’t always. Explaining this discrepancy, Alex Huang, MD, assistant professor, Doheny Eye Center of Pasadena, David Geffen School of Medicine, University of California, Los Angeles, proposed several hypotheses about what might be standing in the way of trabecular bypass surgery. One explanation is related to more practical issues, like the surgeon not executing the surgery correctly. One of the major lessons that surgeons have learned about MIGS is that while the surgery at first sounded straightforward, it is associated with a substantial learning curve. 
The idea behind bypass surgery is that the resistance to aqueous flow begins in the trabecular meshwork, and the logic behind surgery is therefore based on bypassing the trouble zone and reestablishing flow to an area somewhere behind the problem. What if, however, resistance was not proximal after all? “There are almost certainly biological reasons for inconsistent results of bypass surgery, too,” Dr. Huang said. “I roughly place these in two concepts. The first is the persistent presence of aqueous humor outflow resistance after the trabecular meshwork (TM). The idea of distal resistance is not new. Morton Grant’s seminal work in this space showed not only the presence of distal resistance but that this distal resistance was increased in glaucoma.1 While the TM is important, it isn’t the entire picture.”
Dr. Huang’s research with aqueous angiography holds the potential to personalize glaucoma surgery. He used aqueous angiography in living patients and discovered that outflow was segmentally heterogeneous and had a pulsatility, supporting the novel observation of the active nature of AHO. Based on these findings, Dr. Huang thinks that the second explanation for inconsistencies in trabecular bypass surgery is associated with MIGS placement. “The second concept is that surgical placement matters. Recent AHO research has proven the long-standing suspicion that AHO is segmental. We have performed aqueous angiography imaging (a method we developed with tracer introduction into the eye and subsequent real time visualization) in live humans and have published two manuscripts2,3 proving that AHO is segmental. This leads to the idea that it is important to place surgeries in the correct location,” Dr. Huang said.
These breakthroughs led to further questions: Should TM bypass be done where flow is good to ensure the surgeon accesses a stable pathway, or should TM bypass be placed in a region of initially poor flow to have more room for improvement? 
Dr. Huang explained, “While the answer isn’t clear, our published results in ex vivo eyes in the lab and preliminarily in glaucoma patients in the operating room have shown that regions of the eye without signal can be rescued after trabecular bypass.”4 The fundamental idea that this represents is that parts of the eye that are initially low flow are not necessarily permanently so.
His studies largely support the notion of dynamic AHO. In both live non-human primates5 and in live humans,3 Dr. Huang and his team have shown that regions with and without baseline angiographic signal can lose or gain it, respectively. The observation seemed to suggest that AHO can move from one part of the eye to another. 
“Therefore, the final picture is that AHO is more complex than our original linear description of aqueous moving from TM to Schlemm’s canal to collector channels and so forth. There are new and active AHO behaviors, and through study they represent opportunities to better understand AHO for current and future therapies,” he said.

More on the outflow pathway

According to Murray Johnstone, MD, Department of Ophthalmology, University of Washington, Seattle, evidence of pulsatile flow to the aqueous veins and from Schlemm’s canal (SC) pressure reversal in humans as well as in living primates has taught physicians that the outflow system tissues are in highly dynamic motion, actively responding to the ocular pulse. “SC pressure reversal is a physiologic phenomenon and can be mimicked in the laboratory with viscoelastics and by SC cannulas attached to reservoirs that allow transtrabecular pressure to be varied,” Dr. Johnstone said. “Scanning electron microscopy is a powerful additional tool that provides us with the ability to examine relationships among the TM, structures in SC, collector channel entrances, and intrascleral channels,” he said.
Dr. Johnstone explained that in addition to imaging structure, physicians can now look at function by changing pressure gradients in the AC and SC, providing a new picture of the aqueous outflow system. “In terms of structure, current evidence demonstrates that the TM structure varies dramatically in response to maintained steady state pressures, distending into and even occluding collector channel entrances as pressures rise,” he said. “We find flaps or leaflets at collector channel entrances that are attached at only one end providing them the ability to freely move. We also find many attachments between the TM and the hinged flaps at the SC external wall.”
Dr. Johnstone was part of a study group that used real-time high resolution OCT imaging to identify hinged flaps at collector channel (CC) entrances. They found that the motion of these flaps was synchronous with TM pressure-dependent motion and that TM motion could be imaged by phase OCT images and was synchronous with the cardiac pulse.6
Spectral domain OCT (SD OCT) has provided additional structural insights to the outflow pathway. “Recent innovations in platforms to study aqueous outflow dynamics with high resolution OCT teach us that the TM, the structures attaching the TM to the SC external wall and intrascleral channels all move in unison. The TM that senses IOP by changing shape is able to control CC lumen dimensions by means of the transcanalicular attachments, providing a dynamic means for the TM to sense pressure and to control flow through changes in dimensions of the CC lumen,” he said.
Phase sensitive OCT demonstrates that the outflow structures change shape in milliseconds and can thus easily track the ocular pulse. This recent innovation permits direct observation of pulse induced TM and collector channel motion that responds synchronous with the ocular pulse.7
“These recent discoveries together suggest that the aqueous outflow is controlled by an extremely sophisticated organ system entirely unlike the passive TM filter envisioned in the older textbooks,” Dr. Johnstone explained. “Although MIGS may not currently address the normal regulatory mechanisms of the organ system, they are of value in reducing IOP. While not perfect, they may well work by providing direct access to collector channels. In the course of scarring following the procedures, some CC entrances may scar in a relatively open position, while others may have ongoing remodeling that causes them to gradually close, a phenomenon all too familiar to those doing filtering surgery.”
Addressing the pathophysiology of TM damage, Dr. Johnstone explained, “In the vascular system, channels retain their normal structure by virtue of sensing flow that induces shear stress, particularly cyclic pulse-induced flow. Nitric oxide (NO) is a key player in modulating transient responses as well as optimizing long-term vascular wall dimensions. Recently NO has been found to have a profound effect on resistance in the distal pathways.8 In the absence of normal flow, cytokines are released that cause alterations in vascular walls leading to eventual closure of the vessel lumen. Due to variability in healing, some collector channels may be exposed to relatively normal flow patterns after MIGS procedures. In other cases, access to normally directed pulsatile flow may be absent or become abnormal as a result of remodeling leading to abnormal responses and increased resistance within the distal vessel walls.”
Dr. Johnstone thinks that a great deal of work still needs to be done to fully characterize the normal dynamic behavior of the outflow system. Such work can be pursued using PhS-OCT, which allows direct in-office observation of TM and CC motion in glaucoma patients before surgery.

References

1. Rosenquist R, et al. Outflow resistance of enucleated human eyes at two different perfusion pressures and different extents of trabeculotomy. Curr Eye Res. 1989;8:1233–40.
2. Huang AS, et al. Fluorescein aqueous angiography in live normal human eyes. J Glaucoma. 2018. Epub ahead of print.
3. Huang AS, et al. Aqueous angiography: aqueous humor outflow imaging in live human subjects. Ophthalmology. 2017;124:1249–1251.
4. Huang AS, et al. Aqueous angiography- mediated guidance of trabecular bypass improves angiographic outflow in human enucleated eyes. Invest Ophthalmol Vis Sci. 2016;57:4558–65.
5. Huang AS, et al. Aqueous angiography in living nonhuman primates shows segmental, pulsatile, and dynamic angiographic aqueous humor outflow. Ophthalmology. 2017;124:793– 803.
6. Xin C, et al. Aqueous outflow regulation: optical coherence tomography implicates pressure-dependent tissue motion. Exp Eye Res. 2017;158:171–186.
7. Xin C, et al. Quantification of pulse-dependent trabecular meshwork motion in normal humans using phase-sensitive OCT. Invest Ophthalmol Vis Sci. 2018;59:3675–3681. 
8. Aliancy J, et al. A review of nitric oxide for the treatment of glaucomatous disease. Ophthalmol Ther. 2017;6:221–232.

Editors’ note: Dr. Huang has financial interests with Aerie Pharmaceuticals (Durham, North Carolina), Heidelberg Engineering (Heidelberg, Germany), Glaukos (San Clemente, California), and Diagnosys (Lowell, Massachusetts). Dr. Johnstone has no financial interests related to his comments.

Contact information

Huang
: AAHuang@mednet.ucla.edu
Johnstone: johnstone.murray@gmail.com

Aqueous humor outflow: Not quite as we thought it was Aqueous humor outflow: Not quite as we thought it was
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