Perspective

Aqueous angiography: A new frontier in glaucoma surgery and pharmacology

A close view into aqueous outflow could enhance the results and improve the consistency of MIGS procedures.

A new frontier in glaucoma surgery and pharmacological research is taking form in aqueous angiography.

“We borrowed the technology that is used to visualize retinal blood flow, took it back to the lab and adapted it to a different location, in this case the front of the eye, to visualize aqueous humor outflow,” Alex S. Huang, MD, PhD, of Doheny Eye Centers and University of California, Los Angeles, told Ocular Surgery News.

The technology uses the Spectralis HRA+OCT (Heidelberg Engineering), modified to be used with patients lying on the operating table in the supine position. Heidelberg collaborated on this project to create a flexible arm, called the Flex module, on which the angiographer was mounted.

“It is exactly the same Spectralis that we use in the clinic but installed on an arm, so that you can do imaging in different body positions,” Huang said.

After successful laboratory studies, the novel Spectralis Flex module was used for aqueous angiography in eight patients during cataract surgery. Through a side-port paracentesis, after inserting a 20-gauge Lewicky anterior chamber maintainer (Katena), aqueous humor was evacuated with a syringe, and indocyanine green (ICG) was injected as a tracer for aqueous angiography images. Placing the Spectralis Flex camera head above the eye, aqueous angiography was performed at various time points in different cardinal positions of gaze or face-on. Videos were alternatively taken.

Alex S. Huang

“Segmental outflow patterns were clearly visible, with stronger signal in the nasal sector. Dynamic and pulsatile flow were captured by videos,” Huang said.

To confirm that the angiographic signal represented aqueous humor outflow, confocal scanning laser ophthalmoscopic infrared images and anterior segment OCT images were taken concurrently with aqueous angiography.

The study demonstrated the ability to safely perform the procedure and provided the elements needed to develop a protocol for further trials, according to Huang.

Potential applications

In this first pilot study in humans, it was considered opportune to perform the procedure concurrently with cataract surgery.

“Aqueous angiography requires the injection of a tracer in the eye and is therefore an invasive procedure. Having patients who were scheduled for cataract surgery gave us a reason to be in the eye anyway and to use a tracer. It is not uncommon, particularly with dense cataracts, to use a stain to facilitate the capsulorrhexis, and ICG is also a capsular stain,” Huang said.

However, once the rationale for the procedure is validated, there is no reason why it could not be performed as a stand-alone procedure, he said.

“We are still in the preliminary stages, but our aim is to make this technology available for mainly two purposes, on the surgical side and on the pharmacological side. We started on the surgery side, which was the lower hanging fruit, and want to ultimately apply it to trabecular MIGS,” Huang said.

Inconsistencies in how some people do or do not respond well to trabecular microincision glaucoma surgery, such as Trabectome (NeoMedix) and iStent (Glaukos), may be explained by interindividual variations in anatomy and outflow pathways, according to Huang.

“MIGS procedures were designed in part to be comfortable for cataract surgeons, meaning that by using your temporal cataract wound, you’re sitting temporal. If you are sitting temporal, you will always place the MIGS device nasal, but maybe everyone’s outflow pattern is different,” he said. “With aqueous angiography, we may be able to get to that step where we can actually visualize the outflow pattern, see if it is uniform or segmental, if it is the same for everyone or different. What I envision is that we do this type of imaging right before surgery in the OR and choose where to place the surgery for the best effect.”

Visualization of the outflow will also offer opportunities for developing better targeted drugs, based on fluid dynamics.

“We have seen that the outflow is segmental, dynamic and pulsatile, and a better understanding of these patterns might give us new insights to discriminate between healthy and unhealthy outflow behaviors and to look at ways to improve outflow efficiency through screening for new drugs. That is a much longer-term view on the research side, but it is worth exploring,” Huang said.

A technology in evolution

The downside of the procedure is that it is invasive and requires an OR setting. However, future advances might lead to a less invasive approach that is easier to integrate into routine clinical practice. Huang imagines an evolution like that of intravenous angiography of the retina.

“Early on, when that modality was developed, some people thought, ‘I will never do it; it is too cumbersome,’ and it took more than 10 years to streamline. Now doctors are not even in the room while technicians and nurses handle it together. Aqueous angiography may very well evolve in the same way,” he said. “It is hard to imagine this right now, but the technology may not even look the same as it looks today.”

The question that arises is, why not use a noninvasive technology, such as OCT angiography, rather than a tracer-based method?

“OCTA requires changing reflectivity. Currently, it’s about identifying the movement of the red blood cells, but in the normal aqueous there is nothing that moves. Thus, OCTA would give an empty signal in the anterior chamber or rather pick up the blood flow instead of the aqueous flow in the sclera,” Huang said.

Potentially, OCT technology could be adapted to imaging the aqueous outflow if something in the aqueous could be specifically detected. For instance, vitamin C is present at about 100 times higher concentration in the aqueous than in the blood.

“Theoretically, if we created vitamin C imaging, we could titrate the technique to pick up aqueous movement over blood movement, noninvasively. Of course, it does not have to be vitamin C; it can be anything in the aqueous that is high level compared to the blood that you can devise a modality around,” Huang said.

The Spectralis Flex module is currently available to be purchased outside the U.S. but is not yet FDA approved.

“By using it, people will start building the body of evidence and evolution necessary to streamline aqueous angiography. Meanwhile, we will continue our research to determine outflow differences between glaucomatous eyes and those without glaucoma and to find out whether aqueous angiography-guided MIGS placement is feasible and holds the potential to enhance the efficacy of MIGS,” Huang said. – by Michela Cimberle

Disclosure: Huang reports he receives research support from Heidelberg Engineering, Glaukos and Diagnosys and consults for Aerie.

A new frontier in glaucoma surgery and pharmacological research is taking form in aqueous angiography.

“We borrowed the technology that is used to visualize retinal blood flow, took it back to the lab and adapted it to a different location, in this case the front of the eye, to visualize aqueous humor outflow,” Alex S. Huang, MD, PhD, of Doheny Eye Centers and University of California, Los Angeles, told Ocular Surgery News.

The technology uses the Spectralis HRA+OCT (Heidelberg Engineering), modified to be used with patients lying on the operating table in the supine position. Heidelberg collaborated on this project to create a flexible arm, called the Flex module, on which the angiographer was mounted.

“It is exactly the same Spectralis that we use in the clinic but installed on an arm, so that you can do imaging in different body positions,” Huang said.

After successful laboratory studies, the novel Spectralis Flex module was used for aqueous angiography in eight patients during cataract surgery. Through a side-port paracentesis, after inserting a 20-gauge Lewicky anterior chamber maintainer (Katena), aqueous humor was evacuated with a syringe, and indocyanine green (ICG) was injected as a tracer for aqueous angiography images. Placing the Spectralis Flex camera head above the eye, aqueous angiography was performed at various time points in different cardinal positions of gaze or face-on. Videos were alternatively taken.

Alex S. Huang

“Segmental outflow patterns were clearly visible, with stronger signal in the nasal sector. Dynamic and pulsatile flow were captured by videos,” Huang said.

To confirm that the angiographic signal represented aqueous humor outflow, confocal scanning laser ophthalmoscopic infrared images and anterior segment OCT images were taken concurrently with aqueous angiography.

The study demonstrated the ability to safely perform the procedure and provided the elements needed to develop a protocol for further trials, according to Huang.

Potential applications

In this first pilot study in humans, it was considered opportune to perform the procedure concurrently with cataract surgery.

“Aqueous angiography requires the injection of a tracer in the eye and is therefore an invasive procedure. Having patients who were scheduled for cataract surgery gave us a reason to be in the eye anyway and to use a tracer. It is not uncommon, particularly with dense cataracts, to use a stain to facilitate the capsulorrhexis, and ICG is also a capsular stain,” Huang said.

However, once the rationale for the procedure is validated, there is no reason why it could not be performed as a stand-alone procedure, he said.

PAGE BREAK

“We are still in the preliminary stages, but our aim is to make this technology available for mainly two purposes, on the surgical side and on the pharmacological side. We started on the surgery side, which was the lower hanging fruit, and want to ultimately apply it to trabecular MIGS,” Huang said.

Inconsistencies in how some people do or do not respond well to trabecular microincision glaucoma surgery, such as Trabectome (NeoMedix) and iStent (Glaukos), may be explained by interindividual variations in anatomy and outflow pathways, according to Huang.

“MIGS procedures were designed in part to be comfortable for cataract surgeons, meaning that by using your temporal cataract wound, you’re sitting temporal. If you are sitting temporal, you will always place the MIGS device nasal, but maybe everyone’s outflow pattern is different,” he said. “With aqueous angiography, we may be able to get to that step where we can actually visualize the outflow pattern, see if it is uniform or segmental, if it is the same for everyone or different. What I envision is that we do this type of imaging right before surgery in the OR and choose where to place the surgery for the best effect.”

Visualization of the outflow will also offer opportunities for developing better targeted drugs, based on fluid dynamics.

“We have seen that the outflow is segmental, dynamic and pulsatile, and a better understanding of these patterns might give us new insights to discriminate between healthy and unhealthy outflow behaviors and to look at ways to improve outflow efficiency through screening for new drugs. That is a much longer-term view on the research side, but it is worth exploring,” Huang said.

A technology in evolution

The downside of the procedure is that it is invasive and requires an OR setting. However, future advances might lead to a less invasive approach that is easier to integrate into routine clinical practice. Huang imagines an evolution like that of intravenous angiography of the retina.

“Early on, when that modality was developed, some people thought, ‘I will never do it; it is too cumbersome,’ and it took more than 10 years to streamline. Now doctors are not even in the room while technicians and nurses handle it together. Aqueous angiography may very well evolve in the same way,” he said. “It is hard to imagine this right now, but the technology may not even look the same as it looks today.”

The question that arises is, why not use a noninvasive technology, such as OCT angiography, rather than a tracer-based method?

PAGE BREAK

“OCTA requires changing reflectivity. Currently, it’s about identifying the movement of the red blood cells, but in the normal aqueous there is nothing that moves. Thus, OCTA would give an empty signal in the anterior chamber or rather pick up the blood flow instead of the aqueous flow in the sclera,” Huang said.

Potentially, OCT technology could be adapted to imaging the aqueous outflow if something in the aqueous could be specifically detected. For instance, vitamin C is present at about 100 times higher concentration in the aqueous than in the blood.

“Theoretically, if we created vitamin C imaging, we could titrate the technique to pick up aqueous movement over blood movement, noninvasively. Of course, it does not have to be vitamin C; it can be anything in the aqueous that is high level compared to the blood that you can devise a modality around,” Huang said.

The Spectralis Flex module is currently available to be purchased outside the U.S. but is not yet FDA approved.

“By using it, people will start building the body of evidence and evolution necessary to streamline aqueous angiography. Meanwhile, we will continue our research to determine outflow differences between glaucomatous eyes and those without glaucoma and to find out whether aqueous angiography-guided MIGS placement is feasible and holds the potential to enhance the efficacy of MIGS,” Huang said. – by Michela Cimberle

Disclosure: Huang reports he receives research support from Heidelberg Engineering, Glaukos and Diagnosys and consults for Aerie.

    Perspective
    Thomas W. Samuelson

    Thomas W. Samuelson

    This is exciting and important work in the current MIGS environment for two reasons: to help facilitate intelligent placement of MIGS devices for interventions within the canal as well as to help identify those patients with distal outflow disease who may not be candidates for canal-based surgery. That said, the intelligent placement discussion will soon lessen a bit as newer indwelling canal devices are approved. The next-generation canal devices will be either multicentric, for example, iStent inject (Glaukos), or will extend several clock hours around the canal, for example, Hydrus (Ivantis). Each of these newer strategies will reduce the need for intelligent placement. This has been one of the advantages of incisional approaches, such as ab interno trabeculotomy and gonioscopy-assisted transluminal trabeculotomy. However, it will still be important to identify proximal vs. distal disease within the outflow system to best select the most appropriate outflow pathway for individual patients. For example, if the distal collector system is diseased, surgeons will be more likely to move on to supraciliary or the more traditional transscleral approach.

    • Thomas W. Samuelson, MD
    • OSN Glaucoma Section Editor

    Disclosures: Samuelson reports he is a consultant for Ivantis, Glaukos, Alcon, Sight Sciences and New World Medical.