Article

The clues exist: aqueous outflow is segmental

If so, a team from Doheny thinks that finding normal aqueous flow can help with MIGS placement.

Many historical and laboratory clues have suggested that aqueous humor outflow is segmental. Different parts of the eye have more or less so-called outflow. For Minimally Invasive Glaucoma Surgeries (MIGS), early investigators spoke to this issue when they noted in the literature more outflow pathways on the nasal side of the eye; here, they argued for nasal placement of these surgeries.1 In the laboratory, animal work with fluorescent microbeads2,3 has identified segmental uptake in the trabecular meshwork that was then associated with biological differences in higher-flow and lower-flow segments.3,4

Given the true segmental nature to aqueous outflow, how can we make these observations compatible and synergistic with patient care and these minimally invasive glaucoma surgeries?

The answer is aqueous angiography.

But first, a conversation about MIGS.

TIME TRAVEL

In the last decade, we’ve witnessed the tremendous expansion of pharmaceutical and surgical options for lowering intraocular pressure (IOP) in glaucoma. A sizable portion of that expansion is due to MIGS. Directed in part toward anterior segment surgeons and comprehensive ophthalmologists who are deft at phacoemulsification, these minimally invasive glaucoma surgeries, when compared to conventional trabeculectomies and glaucoma drainage devices,1 are faster and safer, and have the potential to be as effective at lowering IOP in the proper patient.

WHAT’S IN A NAME?

While the meanings of the letters “I,” “G,” and “S” in the acronym MIGS are clear, the definition of minimal (M) is more obscured. Analogous to the maturation of cataract surgery’s steps from extracapsular to phacoemulsification, minimal simply implies smaller or fewer elements than similar factors in other types of glaucoma surgeries, be it wound size, the time required for surgery or other factors, such as overall length of time and number of visits for recovery.

For “G” and “S” (glaucoma surgeries), there are also potentially new meanings, because traditional glaucoma surgeries, such as trabeculectomies and glaucoma drainage devices, rely on the creation of a pathway leading from inside of the eye to an extraocular reservoir or bleb outside of the eye. Minimal glaucoma surgeries can be different.

WHAT’S IN A DEFINITION?

Conventionally, “minimal” refers to accessing and enhancing native outflow pathways, either trabecular as with the iStent (Glaukos), Trabectome (NeoMedix), or Kahook Dual Blade (New World Medical) or uveoscleral as with the CyPass Micro-Stent (Alcon) and the investigational iStent Supra (Glaukos).

Today, minimal could also mean finding innovative new ways to create the same blebs as trabeculectomies with smaller wounds or alternative approaches, such as the recently FDA-approved Xen Gel Stent (Allergan). Moving forward, with so many options, a surgeon likely will make her surgical choice based on her experience of the impact of IOP-lowering over time and the chosen surgery’s ability to evolve into future iterations.

Now, I look at the next step toward progression.

SAFE BUT NOT ALWAYS EFFECTIVE

First, we must recognize the limitations of MIGS. Our most extensive experience is still in trabecular-targeted MIGS.

Because the conventional outflow pathway runs past the trabecular meshwork, through Schlemm’s canal and eventually into the episcleral veins, an episcleral venous pressure floor can limit the potency of IOP-lowering in trabecular-targeted MIGS. While safe, this floor could disqualify trabecular MIGS in advanced glaucoma patients because they require the very lowest of acceptable IOP.

Often, episcleral venous pressure is considered to reside between 14 to 16 mm Hg, but this number is susceptible to technical artifacts inherent in noninvasive episcleral venous pressure measurements. Invasive catheterization of episcleral veins and more recent improvement of noninvasive episcleral venous pressure measurement tools by Arthur Sit, MD,5 at the Mayo Clinic indicate that episcleral venous pressure (and the theoretical floor of trabecular-targeted MIGS) likely reside in the 8- to 10-mm Hg range. This IOP would be desirable for most patients, even those with advanced glaucoma.

Therefore, imagine if a modification of current methods is all that it took to get surgeons and patients to that point.

LOCATION, LOCATION, LOCATION

Many hypotheses exist as to why trabecular-targeted MIGS, while successful, are not more consistent in creating a very low IOP. Surgeon experience and proper placement are obvious factors, but location may be another.

Almost all MIGS instruction starts with creation of temporal wounds leading to placement of the device on the nasal side of the eye. While driven in part by the notion that the nasal part of the eye has more natural outflow pathways,1 another motivation for this surgical route is surgeon familiarity with the temporal clear-cornea approach, such as that taken in phacoemulsification. In support of using the road most traveled, a third reason is traditional resident education about aqueous humor outflow. We normally teach aqueous humor outflow using a two-dimensional picture with aqueous moving from the anterior chamber past the trabecular meshwork into Schlemm’s canal. However, this depiction insinuates that the outflow pathways are the same no matter where you are on the eye: nasal, inferior, temporal or superior; so therefore MIGS could go anywhere. But, the trabecular meshwork and aqueous humor outflow pathways are three-dimensional, and segmental outflow exists.

THE ANSWER: AQUEOUS ANGIOGRAPHY

So, to restate the question: Given the true segmental nature to aqueous outflow, how can we target the best placement of MIGS for optimal patient care?

Aqueous angiography is one potential way.6 Aqueous angiography is a new, real-time outflow imaging technique that borrows from techniques of retina physicians. If retina clinics can put fluorescent tracers (fluorescein and indocyanine green) into a patient’s vein to image retinal and choroid blood flow, why can’t anterior segment surgeons place the same tracers into the anterior chamber and use the same cameras to image aqueous humor outflow?

Originally intended for patient care, aqueous angiography was developed by re-engineering clinical equipment that is FDA approved for retinal blood flow angiography (Spectralis, Heidelberg Engineering) for anterior segment and aqueous outflow imaging. First tested in postmortem eyes (pigs, cows and humans), aqueous angiography was validated to image aqueous humor outflow and showed segmental patterns with multiple tracers.7,8 Combining aqueous angiography guidance and MIGS, trabecular bypass iStent inject (Glaukos) improved the outflow in regions initially without signal.9

The Spectralis FLEX module (Heidelberg Engineering: the FLEX is under development and not available for sale) has allowed reorganization of the Spectralis for supine imaging necessary in the operating room (Figure 1, page 35). With this setup, aqueous angiography in intact eyes of living nonhuman primates confirmed segmental aqueous humor outflow that then demonstrated a pulsatile (almost cardiac) nature with a newly observed dynamic phenomenon.10 This meant that aqueous humor outflow had the capacity to turn on, turn off and move from one part of the eye to the next.

Figure 1. Heidelberg’s Spectralis FLEX module arranges the Spectralis so that imaging (optical coherence tomography or angiography) can be performed in a supine position in the operating room. The FLEX is still under development.

Always intended for potential clinical benefit, aqueous angiography has been “translated” from the basic research arena into the operating room in a collaborative venture between investigators at UCLA’s Doheny Eye Institute and UC San Diego’s Shiley Eye Institute. Opportunistically, aqueous angiography fluorescent dyes (fluorescein and indocyanine green) has doubled as outflow tracers and capsular stains. Already used by retina surgeons as stains for membranes peels, these dyes also are used in phacoemulsification to stain the capsule to assist in the capsulorhexis.11

Currently, aqueous angiography has been performed in the intact eye of human subjects undergoing cataract surgery with similar findings: segmental outflow patterns (Figure 2), pulsatile outflow and the potential for dynamic movement across the eye.12

Figure 2. Aqueous angiography was performed in the left eye of a 60-year-old Asian female during cataract surgery. 0.4% indocyanine green (ICG) was introduced into the anterior chamber. Angiographic images were taken using a Spectralis OCT+HRA (Heidelberg Engineering). Centrally, the anterior chamber is filled with ICG. Posterior to the limbus, the green arrows show areas of distal angiographic outflow. The red arrow shows a region without.

WHAT DOES THE FUTURE HOLD?

Making surgery more predictable is a key future innovation for MIGS. Advances may happen in design, delivery or both, and adjunctive imaging such as aqueous angiography may help in guidance. In this way, one could imagine customized and personally targeted MIGS for each individual eye based on outflow patterns.

Noninvasive imaging such as anterior-segment OCT also shows promise, but it remains unclear how structural outflow data parameters like lumen size and shape relate to flow characteristics, such as flow rate. Combining structural (anterior segment OCT) and functional data (flow studies such as aqueous angiography) may offer the synergy needed similar to what is seen by combining structural (OCT optic nerve) and functional (visual field) data in the posterior pole of the eye for glaucoma diagnosis.

The reality is that MIGS are here now. Their future will depend on the next critical steps and innovative advances. OM

REFERENCES

  1. Johnstone M, Jamil A, Martin E. Aqueous veins and open angle glaucoma. In: Schacknow PN, Samples JR, eds. The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care. New York: Springer, 2010.
  2. Battista SA, Lu Z, Hofmann S, et al. Reduction of the available area for aqueous humor outflow and increase in meshwork herniations into collector channels following acute IOP elevation in bovine eyes. Invest Ophthalmol Vis Sci. 2008;49:5346-5352.
  3. Keller KE, Bradley JM, Vranka JA, Acott TS. Segmental versican expression in the trabecular meshwork and involvement in outflow facility. Invest Ophthalmol Vis Sci. 2011;52:5049-5057.
  4. Vranka JA, Bradley JM, Yang YF, et al. Mapping molecular differences and extracellular matrix gene expression in segmental outflow pathways of the human ocular trabecular meshwork. PLoS One. 2015;10(3):e0122483.
  5. Sit AJ, Ekdawi NS, Malihi M, McLaren JW. A novel method for computerized measurement of episcleral venous pressure in humans. Exp Eye Res. 2011;92:537-544.
  6. Huang AS, Mohindroo C, Weinreb RN. Aqueous humor outflow structure and function imaging at the bench and bedside: a review. J Clin Exp Ophthalmol. 2016;7(4).
  7. Saraswathy S, Tan JC, Yu F, et al. Aqueous angiography: real-time and physiologic aqueous humor outflow imaging. PLoS One. 2016;11(1):e0147176.
  8. Huang AS, Saraswathy S, Dastiridou A, et al. Aqueous angiography with fluorescein and indocyanine green in bovine eyes. Transl Vis Sci Technol. 2016;5(6):5.
  9. Huang AS, Saraswathy S, Dastiridou A, et al. Aqueous angiography-mediated guidance of trabecular bypass improves angiographic outflow in human enucleated eyes. Invest Ophthalmol Vis Sci. 2016;57:4558-4565.
  10. Huang AS, Li M, Yang D, Wang H, Wang N, Weinreb RN. Aqueous angiography in living nonhuman primates shows segmental, pulsatile, and dynamic angiographic aqueous humor outflow. Ophthalmology. 2017. [Epub ahead of print]
  11. Jacobs DS, Cox TA, Wagoner MD, et al. Capsule staining as an adjunct to cataract surgery: a report from the American Academy of Ophthalmology. Ophthalmology. 2006;113(4):707-713.
  12. Huang AS, Camp A, Xu BY, Penteado RC, Weinreb RN. Aqueous angiography: aqueous humor outflow imaging in live human subjects. Ophthalmology. 2017. doi: 10.1016/j.ophtha.2017.03.058. [Epub ahead of print]

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