Special Report on Glaucoma by Media MICE

THE WORLD’S SECOND FUNKY OPHTHALMOLOGY MAGAZINE

Highlights

MEDICAL TREATMENT

Special Report

ALL ABOUT GLAUCOMA A CAKE magazine supplement

Say Hello to New Medical Therapies in Glaucoma Management

SURGICAL INTERVENTION

Get Off the Meds: Consider Earlier Surgical Intervention in Glaucoma

GENETICS, IMAGING AND OTHER RESEARCH AREAS

The Role of Corneal Biomechanics in Glaucoma Diagnosis and Progression

GLAUCOMA HOT TOPICS

Glaucoma Management in the Era of Artificial Intelligence

In this special issue... MEDICAL TREATMENT

04 06 08

Developments in Glaucoma Medical Treatments

Options for Angle-Closure Glaucoma: Arrows in the Quiver

Say Hello to New Medical Therapies in Glaucoma Management Let's get ready to rumble! Clearing up Controversies in Glaucoma Management

Brooke Herron

Get Off the Meds: Consider Earlier Surgical Intervention in Glaucoma

Editor

To MIGS or Not to MIGS: That is the Question

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Glaucoma – Now with Genetic Associations! Glaucoma Studies: Results Are In! New Developments in Ophthalmic Imaging Benefits Glaucoma The Role of Corneal Biomechanics in Glaucoma Diagnosis and Progression Biomechanics and Imaging in Glaucoma

Glaucoma Management in the Era of Artificial Intelligence New Insights into an Older Operation Trabeculectomy Complications Diagnosing Glaucoma with AI and Detecting Progression

Mark Hillen Editor-At-Large International Business Development

Ruchi Mahajan Ranga Brandon Winkeler Writers

Ankita Umapathy April Ingram Chris Higginson Sam McCommon Tan Sher Lynn Maricel Salvador Graphic Designer

Notable Gems of Glaucoma

GLAUCOMA HOT TOPICS Cataracts and Glaucoma and Surgeries, Oh My!

Robert Anderson

Chief Editor

GENETICS, IMAGING AND OTHER RESEARCH AREAS

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COO & CFO

Gloria D. Gamat

Dilemmas in Glaucoma Treatment

Hannah Nguyen

Media Director

SURGICAL INTERVENTION

12 14 16

Matt Young CEO & Publisher

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On Shunts and Gene Therapy: Finding the Right Therapy Matters

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ADVISORY BOARD MEMBERS SOCIETY FRIENDS

Arunodaya Charitable Trust (ACT) Prof. Jodhbir S. Mehta

Prof. Jodhbir S. Mehta, MBBS, FRCOphth, FRCS(Ed), FAMS, PhD(UK), is head of Cornea External Disease and senior consultant in the Refractive Service at Singapore National Eye Centre (SNEC), deputy executive director at Singapore Eye Research Institute (SERI), as well as a professor at Duke-National University of Singapore. With a main interest in corneal transplantation, he completed a corneal external disease and refractive fellowship at Moorfields Eye Hospital in London and at SNEC. He has co-authored nearly 20 textbooks and 333 citations, and holds 16 patents, six of which have been licensed. Prof. Mehta has won several awards from the AAO and ARVO, among others, the latest of which was from the ASCRS in 2018. Prof. Mehta is also a favorite keynote speaker and presenter in several international conferences. jodmehta@gmail.com

ASEAN Ophthalmology Society

Asia-Pacific Academy of Ophthalmology

Dr. William B. Trattler

He Eye Specialist Hospital

Dr. William B. Trattler, MD, is a refractive, corneal and cataract eye surgeon at the Center For Excellence In Eye Care in Miami, Florida, USA. He performs a wide variety of cataract and refractive surgeries, including PRK; all laser LASIK; no injection sutureless cataract surgery; as well as laser cataract surgery. He has been an investigator for next generation technologies (like the Tetraflex accommodating intraocular lens) and procedures like corneal collagen crosslinking (CXL). His involvement in the FDA-approval study for CXL led to its approval in 2016. In addition to his private practice, Dr. Trattler is on the Volunteer Faculty at the Florida International University Wertheim College of Medicine, as well as the University of Miami’s Bascom Palmer Eye Institute. He is board certified by the American Board of Ophthalmology and has been an author of several articles and abstracts. wtrattler@gmail.com

Ophthalmology Innovation Summit

Dr. Chelvin Sng

Orbis International

Dr. Chelvin Sng, BA, MBBChir, MA(Cambridge), MRCSEd, FRCSEd, MMed, FAMS, is a consultant at the National University Hospital (NUH) and assistant professor at National University of Singapore (NUS). She is also an honorary consultant at Moorfields Eye Hospital, London, and adjunct clinic investigator at SERI. A pioneer of minimally invasive glaucoma surgery (MIGS), Dr. Sng was the first surgeon in Asia to perform XEN, InnFocus Microshunt and iStent Inject implantation. A co-author of “The Ophthalmology Examinations Review”, Dr. Sng has also written several book chapters and publications in various international journals. Proficient in conventional glaucoma surgery and trained in complex cataract surgery, Dr. Sng co-invented a new glaucoma drainage device, which was patented in 2015. When not working, Dr. Sng can be found volunteering in medical missions in India and across Southeast Asia. chelvin@gmail.com

Dr. Harvey S. Uy, MD, is a clinical associate professor of ophthalmology at the University of the Philippines, and medical director at the Peregrine Eye and Laser Institute in Makati, Philippines. He completed his fellowships at St. Luke’s Medical Center (Philippines) and the Massachusetts Eye and Ear Infirmary (USA). Dr. Uy is a pioneer in femtosecond cataract surgery, accommodation restoration by lens softening, modular intraocular lenses and intravitreal drugs. He has published over 30 peer-reviewed articles and is on the editorial board of the American Journal of Ophthalmology Case Reports. He is a former president of the Philippine Academy of Ophthalmology (PAO) and current council member of the APVRS.

Russian Ophthalmology Society (ROS)

Young Ophthalmologists Society of India ( YOSI )

Dr. Harvey S. Uy

harveyuy@yahoo.com

September 2021

MEDICAL TREATMENT

Developments in Glaucoma Medical Treatments by Tan Sher Lynn

pdates on combination eye drops, ATX inhibitors and antifibrotic treatment were discussed during the 5th Asia-Pacific Glaucoma Congress on June 6, 2021.

Fixed combination therapy Fixed combination therapy is an attractive option for glaucoma treatment as it can improve compliance and reduce inconvenience and cost. Dr. Jelinar Mohamed Noor, senior consultant ophthalmologist at Hospital Kuala Lumpur, Malaysia, provided the latest developments of fixed combination eye drops. “In the last few years, one of the novel glaucoma medications that has appeared in the market are Rho

kinase (ROCK) inhibitors, which are a serine/threonine protein kinase that regulate cytoskeletal activities. The inhibition of ROCK causes the reduction of actin stress fibers and focal adhesions, which leads to the relaxation of trabecular meshwork (TM) cells, as well as an increase of outflow and ocular blood flow. It also reduces postoperative scarring and may possess neuroprotective properties,” she said. Two examples of ROCK inhibitors include ripasudil and netarsudil. “Another new glaucoma medication are adenosine receptor agonists, such as trabodenoson, a highly selective adenosine mimetic which targets the A1 receptor with the potential to lower IOP by increasing outflow facility at the trabecular meshwork,” said Dr. Noor.

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She added that other new combination eye drops are latanoprostene bunod and omidenepag. However, no studies on this combination of eye drops have been reported.

Potential of ATX inhibitors Associate Professor Megumi Honjo from the University of Tokyo, Japan, talked about the role of autotaxin (ATX) inhibitors in lowering intraocular pressure (IOP). According to Assoc. Prof. Honjo, increased outflow resistance in the conventional pathway results in IOP elevation. “Significant accumulation of extracellular matrix (ECM) at the conventional pathway is observed in the human glaucomatous eye. Rho-ROCK

signaling is crucial in the regulation of outflow resistance in the conventional pathway, through regulation of cellular response and ECM synthesis. Aqueous level of transforming growth factor beta (TGFß2), the strong agonists of RhoROCK signaling pathway, is upregulated in primary open-angle glaucoma (POAG), but low in other types of open angle glaucoma, secondary open-angle glaucoma (SOAG) and exfoliation glaucoma (XFG).

“ATX has a major impact in regulating IOP as a target molecule, and potent ATX inhibitors could be a promising therapeutic approach for lowering IOP.” — Assoc. Prof. Megumi Honjo “Lysophosphatidic acid (LPA) is generated from LPC by the enzyme ATX. It induces many types of cellular responses including Rho-regulated cell adhesion, contraction, cellular proliferation, cell migration, cytokine and chemokine secretion. It has been suggested to be involved in the pathogenesis of glaucoma by ex-vivo study,” she said. Through a study she performed, Assoc. Prof. Honjo found that aqueous levels of ATX and LPA were significantly high

in SOAG and XFG, which often show high IOP.

problematic, with a failure rate of 23% to 51% at five years,” she said.

Lipid mediator, ATX-LPA pathway, an agonist for Rho-ROCK signaling, was upregulated in glaucomatous aqueous humor, especially in SOAG and XFG subjects. Upregulation of ATX was significantly correlated with IOP elevation. In vitro, dexamethasone treatment upregulated ATX expression and secretion in cultured TM cells. Cytomegalovirus (CMV) infection also upregulated ATX in SOAG patients with Posner-Schlossman syndrome (PSS). The ATX-LPA pathway could be an attractive target for novel treatment of refractive IOP elevation in SOAG.

Inflammation is the killer of blebs. It equates to excessive scarring and trabeculectomy failure. As such, early recognition of persistent inflammation or impending bleb failure is of utmost importance, and one must intervene immediately. Multiple therapeutic approaches are the best way to tackle each stage of wound healing, including inflammation and fibrosis.

“ATX has a major impact in regulating IOP as a target molecule, and potent ATX inhibitors could be a promising therapeutic approach for lowering IOP,” she concluded.

Anti-fibrotic treatment in glaucoma surgery According to Prof. Tina Wong from the Singapore National Eye Centre, whenever eye surgeons perform trabeculectomy, they always strive for the perfect bleb — diffuse, elevated, with normal conjunctival vascularity and a low IOP, which can be maintained for the patient’s lifetime. “But this does not always happen, as the anti-metabolites that we use are

Conjunctival health is essential to maintain bleb function long-term. “To optimize your trabeculectomy outcomes, you must first prep your ocular surface or conjunctiva. Consider using non-steroidal anti-inflammatory drugs (NSAIDs) or steroid eye drops. At the time you use anti-metabolites, treat the inflammatory response with obsession and persistence. And consider using systemic oral steroids or NSAIDs to further reduce the fibrotic or inflammatory response,” Prof. Wong suggested. When it comes to rescuing failing blebs, the combination treatment of hyaluronic acid (HA) and fluorouracil (5FU) may provide a better outcome. “HA has an anti-fibrotic effect, it acts as a spacer to inflamed tissues post-needling, and allows for the retention of drugs at the injected site so that the drug can work a little longer,” she said. Prof. Wong and her team conducted a clinical trial to compare the outcome of bleb needling with HA-5FU versus 5F alone at 12 weeks. “Even though there’s no significant difference in IOP at the end, repeated needling was much higher in the 5FU group (50%) compared to the HA-5FU group (12%). This means that IOP was lowered at a faster rate with fewer interventions with the combination treatment,” she said.

Editor’s Note:

If only a simple pill could cure glaucoma…

The 5th Annual Asia-Pacific Glaucoma Congress (APGC 2021) was held virtually from June 4 to 8, 2021. Reporting for this story took place during the event.

September 2021

MEDICAL TREATMENT

Say Hello to New Medical Therapies in Glaucoma Management by Brooke Herron

laucoma, in its various forms, can be challenging to treat. While some cases call for surgical intervention, be it trabeculectomy or MIGS (minimally invasive glaucoma surgery), less severe cases can generally be managed medically. However, like surgery, medical management also has its obstacles — and patient compliance and adherence is among the top concerns. Thus, new drugs and treatment paradigms are emerging in the continued search for better outcomes for glaucoma patients, including advances in topical medications and drug delivery, as well as the potential for neuro-regeneration and non-IOP lowering therapies.

What’s new, doc? According to Prof. Makoto Aihara, from the University of Tokyo (Japan), unmet needs exist for glaucoma drugs that are safer, with more potent IOP-lowering effects, and/or a novel mechanism of action. He said current options, like FP receptor agonists (e.g., latanoprost, travoprost, bimatoprost and tafluprost) can cause local ocular adverse effects (i.e., prostaglandin associated periorbitopathy or PAP); while beta blockers can result in adverse systemic effects. However, there are new options that could circumvent these issues: EP2 agonists, ROCK inhibitors and new drug combinations. The new EP2 agonist, Omidenepag isopropyl (OMDI; EYEBELIS, Santen, Tokyo, Japan), is administered in a once daily drop and has a novel mechanism of action that differs from FP receptor agonists. “OMDI increases aqueous humor outflow via both uveoscleral and

trabecular pathways,” said Dr. Aihara, adding that it was first approved for use in Japan, Korea and Taiwan. Thus far, the RENGE study has shown that OMDI can achieve stable IOP over 52 weeks: In low IOP groups, baseline IOP was reduced by 19.5% (-3.66mmHg) and in high baseline groups, IOP was reduced by 23.4% (-5.64mmHg). The group with high baseline IOP who received combined therapy (OMDI and timolol) showed even better results, with an IOP reduction of 36.1% (-8.36mmHg). Importantly, OMDI has no cosmetic side effects like DUES — plus, patients with

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PAP have recovered after switching from FP agonists without changing IOP. Other new agents are also showing potential: ROCK inhibitors may be useful for the treatment of various ocular diseases and directly improve trabecular outflow, he said. These include ripasudil 0.4% (Glanatec, Kowa Pharmaceutical, Japan) and netarsudil 0.02% (Rhopressa, Santen, Japan).

Advances and challenges in drug delivery The issue of patient compliance was also addressed by Dr. Paul Singh, from

Studies have shown that vitamin B3 is well-tolerated and therefore, could be combined with other treatments as a supplement. “But to really firm up that recommendation, we need a much larger clinical trial,” said Prof. Martin. He shared that they’ve recently been funded by Glaucoma Australia to perform a clinical study in glaucoma patients using visual fields as the outcome measure in a longer-term study to see whether this effect is demonstrated.

Hopefully new glaucoma therapies will allow ophthalmologists to break through the brick wall of patient compliance.

the Eye Centers of Racine and Kenosha (Wisconsin, USA). In addition to SLT, laser trabeculotomy and MIGS, Dr. Singh discussed the potential for drug delivery (i.e., biodegradable and nonbiodegradable intracameral implants) to help improve compliance. He shared his experience with bimatoprost-SR (DURYSTA, Allergan, an AbbVie company, Dublin, Ireland) which is approved in the U.S. and is a sustained-released, biodegradable implant for the treatment of open-angle glaucoma or ocular hypertension. It’s designed to lower IOP for at least four months, and thus, free patients from their eyedrop regimens. The longevity effect can be even longer: “Phase 2 trials showed us that 25% of patients had two years of efficacy with just one implant,” he said, adding that the drug concentration is highest in target tissues, compared to topical drops. Any patients with compliance issues could be a good candidate for this type of device.

Is neuro-regeneration possible? During his presentation, Dr. Jeffrey Goldberg (USA) from the Byers Eye Institute at Stanford University (California, USA) steered the conversation away from IOP and toward retinal ganglion cell (RCG) degeneration and the role it plays in glaucoma. He

said this is an unmet need in glaucoma and better treatments are needed “beyond IOP.” According to Dr. Goldberg, the fundamental problem is the irreversibility of vision loss because there’s no RGC regeneration after optic nerve injury. However, there is a critical and short time period where intervention can help: “There is a window before RGCs die — and it’s that interval between injury and death where we really want to intervene and promote survival, neuroprotection and axon regeneration.” Further, “neurotrophic factors, rhokinase inhibition and other strong candidates are ready for neuroprotection testing in glaucoma,” he concluded.

Non-IOP lowering treatments for glaucoma While intraocular pressure (IOP) is an important risk factor for glaucoma, it’s become apparent that there are numerous other factors involved, began Prof. Keith Martin, from the University of Melbourne (Australia). This begs the question: What do we do when IOP reduction is insignificant? One potential solution could be vitamin B3 (nicotinamide), which has been shown to modulate mitochondrial vulnerability and prevent glaucoma in mice, where higher doses almost abolished glaucoma in these animals, he pointed out.

Another strategy involves exercise to improve RCG function. This was demonstrated in a study that showed when aging mice were exposed to a period of exercise they became more resistant to IOP-induced injury. These data led him to ask two main questions: How do we know if a nonIOP lowering therapy works in human patients — and — do drugs that lower IOP by a similar amount always reduce VF progression to the same degree? “We tend to make that assumption, but is it actually true?” he continued. To do this, Prof. Martin said more clinical trials are needed with manageable numbers of patients, and shorter-term to make them affordable. With all of the potential treatments — both current and upcoming — for glaucoma, it appears that ophthalmologists will have a wide range of options available to treat patients based on individual need. Indeed, we look toward a brighter future that prevents and limits glaucoma progression and saves sight, in the safest and most effective way possible.

Editor’s Note: The World Glaucoma E-Congress 2021 was held from June 30 to July 3. Reporting for this story took place during the event. These presentations, and much more, are now available on-demand on the WGC 2021 platform — so check them out!

September 2021

MEDICAL TREATMENT

Let’s get ready to rumble! Clearing up Controversies in Glaucoma Management by Ankita Umapathy

hile there was no fist-fighting in the Controversies Symposium at the 5th Annual Asia-Pacific Glaucoma Congress, the session speakers did use strong (medical) language to provide evidence-based opinions on current hot topics in clinical glaucoma practice. Their key message? New toys are fun, but there’s a time and place for everything. Oh, and, eyedrops rule!

LPI in PACG Dr. Poeman Chan, from the Chinese University of Hong Kong, began by questioning the prophylactic benefit of laser peripheral iridotomy (LPI) against primary angle-closure glaucoma (PACG), despite being commonly prescribed in both Hong Kong and the United Kingdom. The 2019 Zhongshan angle-

closure (ZAP) trial, which assessed the safety and efficacy of LPI prophylaxis against PACG in a Chinese population with bilateral primary angle-closure suspect (PACS; control vs LPI eye), provided food for thought. Although LPI reduced the risk of PAC by 47%, the annual risk reduction was only 0.38%. Dr. Chan explained, “It worked out that the number neededto-treat, to prevent mostly non-sight threatening incidences, was 44 PACS patients over six years.” This makes LPI cost-prohibitive — even in populations with high prevalence of PAC. Instead, he suggests restricting LPI to higher risk patients, such as those who have fellow eye with acute PAC, live in remote areas with limited access to care, use antidepressants, have a family history of glaucoma, or require regular mydriasis (e.g., diabetics).

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MIGS in mainstream Dr. Arthur Sit from the Mayo Clinic, USA, then demonstrated how minimally invasive glaucoma surgery (MIGS) has joined mainstream glaucoma surgeries, through a review of excisional and bypass devices. Given its favorable safety profile, ease of use, significant reductions in medication use, and minor or short-lived complications, MIGS has been rapidly adopted in the United States, surpassing trabeculectomies and drainage surgeries. It also provides additional intraocular pressure (IOP) reduction over cataract surgery alone. However, postoperative IOP remains in the teens, likely due to episcleral vasculature distal to Schlemm’s canal, which is not affected by MIGS. Specifically, flow in Schlemm’s canal

is not circumferential, making device placement and size key to accessing collector channels. Additionally, distal flow is dynamic and flow patterns can change. Therefore, patient selection is key, particularly considering these limitations. “Filtering surgery is not going away for patients who need large IOP reduction or target IOP is in the low teens or less,” concluded Dr. Sit.

Cognitive function tests for early glaucoma detection? Next, in considering both the optical and cerebral aspects of glaucoma, Dr. Fei Li from the Zhongshan Ophthalmic Center in China, hypothesized that cognitive function tests could detect glaucoma earlier than optical tests. Since visual field (VF) defects begin at the periphery of the central VF, which also detects topological information, he investigated whether glaucoma was associated with impairments in topological perception. Behavioral testing revealed that mild-stage glaucomatous eyes had significant topological perception impairment in the periphery of the central VF compared to ocular hypertensive or normal eyes. Dr. Li also noted that only glaucomatous eyes demonstrated perifoveal deficit (i.e., topological discriminative ability was worse in the periphery than the center). Pearson’s correlation also showed an association between disease severity and impairment in topological

discrimination. As myopia can often accompany glaucoma, a separate study demonstrated that refractive error does not affect topological perception. In future studies, Dr. Li hopes to perform neuroimaging to understand the dynamic function of nuclei in the brain associated with topological perception in glaucoma patients.

AI reality check in glaucoma diagnosis Dr. Xiulan Zhang, also from the Zhongshan Ophthalmic Center in China, then provided a reality check on the utility and power of artificial intelligence (AI) — specifically, deep learning algorithms in glaucoma diagnosis. “Imaging data such as VF and optical coherence tomography (OCT) scans are provided as input. The deep learning algorithm then directly outputs a diagnosis; however, the process behind this is actually very complex,” said Dr. Zhang. Building a diagnostic model with supervised deep learning includes data preparation, data labeling, model training and model validation. Despite the mammoth effort, Dr. Zhang showed that deep learning algorithms grading VF, OCT images, volume scans and fundus photos misclassified just as many cases as ophthalmologists — some cases are just clinically difficult. Moreover, unlike humans who learn via sensorimotor experiences, algorithms cannot similarly understand input.

While they can summarize the clues that humans use in medical diagnosis, they cannot generate new knowledge. She was, however, optimistic about the use of deep learning to uncover and investigate associations, likely to be a lot easier and more feasible with current technology.

The eye drop’s staying power For the final talk of the session, Prof. Tina Wong from the Singapore National Eye Centre, harkened back to the humble eyedrop, arguing for its continued presence on the mantle. Although the modality has bioavailability, drug release profile and significant compliance issues, she noted that simplified treatment regimens and better formulations (e.g., ocular surface-sparing) would add to its staying power. In addition to providing good IOP control,Prof. Wong astutely observed that eyedrops would remain on the shelf because new drug treatments often enter the clinic as eyedrops. In attempting to reduce the patient’s burden of disease management, other treatments have emerged, including sustained drug delivery, laser therapy and MIGS. While advantageous in their own ways, these options may not be suitable for or accessible to all patients, and could be cost-prohibitive, particularly in countries with overstretched government funding. In such instances, eye drops will necessarily provide adjunct therapy. “Eye drops will remain the cornerstone of glaucoma management, but will be joined by other methods of treatment and thereby, expand our armamentarium and choices on offer to truly provide a more personalized treatment to our patients,” Prof. Wong concluded.

Editor’s Note: The 5th Annual Asia-Pacific Glaucoma Congress (APGC 2021) was held virtually from June 4 to 8, 2021. Reporting for this story took place during the event.

September 2021

MEDICAL TREATMENT

Options for Angle-Closure Glaucoma

Arrows In the Quiver by Sam McCommon

with a shallow anterior chamber, he indicated. Additionally, while angles opened after LPI, around 25% of patients had irido-trabecular contact after LPI. He concluded that, while LPI protected against AAC, it mostly protected against interim outcomes — mostly peripheral anterior synechiae (PAS). In short, he suggested we may be doing too many LPIs.

Phaco for glaucoma: A solid all-rounder Phacoemulsification of a clear lens can lead to a significant improvement in IOP in glaucoma, as well as better visual quality in general. This conclusion was shared by Dr. Mingguang He, of the Centre for Eye Research Australia at the University of Melbourne. The repurposing of an already-common treatment is common in medicine in general, and ophthalmology is no different. In this case, phaco of a clear lens was valuable for both primary angle closure (PAC) and acute primary-angle closure (APAC).

he World Glaucoma E-Congress (WGC 2021) naturally covered primary angle-closure glaucoma (PACG) in a session on angle-closure disease. In this session, some of the best and brightest glaucoma specialists out there shared some invaluable takeaways.

Why Not Just LPI?

As he noted, LPI can have adverse outcomes. These can include a bloodaqueous-barrier disruption, acute IOP rise, burns on the cornea, lens and retina, glare and diplopia, and may even lead to cataracts and endothelial cell loss.

Now, while LPI certainly has its place — it’s a valuable treatment, and will likely remain so — its success relies on many conditions, including the stage of the disease. For example, Dr. He pointed out that satisfactory IOP control can be achieved in 42 to 72% of cases with LPI for symptomatic ACG before glaucomatous optic neuropathy (GON) has developed. After that, however, LPI doesn’t cut it — essentially all patients will need additional treatment to control their IOP.

There are plenty of other arrows in a glaucoma specialists’ quiver, and one of the most common ones is laser primary iridotomy. We’ll start there — and we’ll end with one that may well get the axe.

In one study he shared, following LPI, 10% of patients had IOP elevation of ≥8mmHg at one hour, while 0.5% had an IOP spike of ≥30mmHg. Now, that’s certainly not everybody, but it is certainly enough to raise eyebrows. Spikes were most common in patients

A 2012 study really turned heads when it showed that IOP dropped significantly and remained lower after cataract surgery. Dr. He now concludes that phacoemulsification of a clear lens can lead to even better long-term results than LPI.

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Phacoemulsification (phaco) has proved itself to be one of the most useful treatments for closed-angle glaucoma — even beating out more traditional treatments. Indeed, it may be the way forward for a number of patients, and it gives doctors more tools to manage glaucoma.

Dr. David S. Friedman, director of glaucoma service at Massachusetts Eye and Ear, a teaching hospital of Harvard Medical School, shared his thoughts on laser primary iridotomy (LPI).

Like Dr. Friedman, Dr. He has reservations about LPI. A study published in Ophthalmology by Dr. He back in 2007 showed that 20% of patients still had closed angles immediately following LPI, with a pupillary block rate of 80% and a nonpupillary block or mixed rate of 20%.¹

One significant argument in support of this conclusion is that additional glaucoma surgery following phaco essentially doesn’t happen. It’s simply not necessary. In one study, 1 in 208 patients needed additional glaucoma surgery following phaco as opposed to 24 of 211 following LPI. If we’re keeping track, that’s 0.004% versus north of 11%. If you’re like many readers, you’d agree that 0.004 is a very small number. Additionally — and just to add insult to injury for LPI — 16 of those 24, or twothirds, needed lens extraction. So, the case is pretty clear that clear lens extraction can be a valuable tool in fighting glaucoma. It’s not necessarily for everyone, of course — plenty of patients would balk at the idea of having their lens removed. Dr. He recommended that clear lens extraction should be considered for PACG or PAC patients with high IOP, (i.e. greater than 30mmHg). As he noted, clear lens extraction later led to better visual acuity and contrast sensitivity, better visual function and quality of life, and fewer complications than LPI.

Mix ‘n’ match IOP treatments: Dr. Clement Tham’s sliding scale Dr. Clement Tham is a member of the WGA’s board of governors and professor of ophthalmology at the Chinese University of Hong Kong. He further confirmed the concept that phacoemulsification can be a valuable treatment for PACG, and even combines it with additional treatments — most notably trabeculectomy. Trabeculectomy on its own is generally of limited use for phakic PACG patients. For one thing, it can lead to an even shallower anterior chamber than before and malignant glaucoma. It can also lead to a 33% chance of cataract progression within two years, followed by cataract surgery. Furthermore, subsequent cataract surgery may compromise filtration. So, trabeculectomy comes with some risks. Over time, phaco patients and trabeculectomy patients experience an evening-out of IOP. While trabeculectomy patients experience a more significant drop in IOP within the first year, after two years the results are essentially the same. For Dr. Tham, however, lens extraction is a first intervention of choice for PACG when a visually significant cataract is present, or when the lens is considered a major contributing factor to angle closure and IOP reduction is required.

However, sometimes lens extraction isn’t enough. Dr. Tham suggested it may not be sufficient if there's very advanced GON (glaucomatous optic neuropathy), necessitating very low target IOP, or grossly uncontrolled IOP, including very high IOP or a very high dependence on drugs.

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In such cases, phaco plus trabeculectomy may be the way to go. Patients who had both trabeculectomy and phaco procedures required even fewer medications than trabeculectomy patients, which indicates that the surgeries complemented each other. In a study Dr. Tham referenced, around 20% of phaco patients required trabeculectomy at

a six year follow-up, with a mean time 2.53 ± 1.38 years post-op. So, phaco doesn’t always do the trick entirely. Not everyone needs both phaco and trabeculectomy either, however. There’s a range between phaco and phaco-trabeculectomy: For Dr. Tham, it requires a combination of phaco and endoscopic cyclophotocoagulation (ECP). So, Dr. Tham’s sliding scale of PACG treatment looks like this: phaco, then phaco-ECP, then phaco-trabeculectomy. That’s from least severe to most. It’s good to have options, isn’t it?

A brief bit on goniosynechialysis Dr. Winnie Nolan, a consultant ophthalmologist at Moorfields Eye Hospital in the U.K., shared an interesting conclusion with us. Simply put, goniosynechialysis (GSL) simply isn’t worth it in most cases. When comparing a phaco group to a phaco plus GSL group, for example, there were no significant differences in results between the two. As she put it, there’s little evidence to support the additional benefit of GSL to phaco alone, which is quite effective. GSL may be more effective in recent onset PAS, however. But large studies of GSL showed little effect of long-term IOP control. Additionally, GSL can be a difficult technique, though as Dr. Nolan noted, it’s gotten easier with MIGS surgery. She suggests learning viscogoniosynechialysis (say that three times fast), which is both easier to learn and may be less traumatic to a patient.

Editor’s Note: The World Glaucoma E-Congress 2021 was held from June 30 to July 3. Reporting for this story took place during the event.

September 2021

SURGICAL INTERVENTION

Dilemmas in Glaucoma Treatment by Tan Sher Lynn

uring the 5th Annual Asia-Pacific Glaucoma Congress (APGC 2021), ophthalmologists from the Philippines discussed interesting cases that warrant a more innovative approach.

When aqueous meets oil Dr. Jose Martinez from the East Avenue Medical Center shared how he treated a case of silicone oil induced glaucoma with an anterior chamber tube shunt to encircling band (ACTSEB) procedure. A 24-year-old woman came to the clinic with floaters and blurred vision. Her visual acuity was 20/100 and she is a myope with no history of trauma, nor family history of glaucoma. She was diagnosed with retinal detachment on the right eye. The correction included retinal surgery (pars plana vitrectomy with encircling band (#240), endodiathermy, drainage of subretinal fluid, fluid air exchange, endolaser, and silicone oil injection (5000cs). On the first day, her IOP was 52mmHg, indicating possible inflammation. Both topical and oral medications were prescribed to control it. Intraocular pressure (IOP) was controlled for two months postsurgery with three topical glaucoma medications (including alpha agonist, beta blockers and prostaglandin analogues).

Near term, she developed a redetachment and more emulsified

oil was found at the anterior chamber (AC). After she gave birth, phacoemulsification with a change of oil, as well as endodiathermy was performed. The retina was successfully attached, however, pressure control was still marginal. Two months post-op, her IOP was 22mmHg. The patient had a scarred cornea, borderline IOP control with full glaucoma medication, open

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Then eight months post-op, the patient came in with an IOP of 40mHg; she was pregnant and had stopped all her glaucoma medications. As she was in her second trimester, Dr. Martinez could only prescribe her brimonidine.

angles with emulsified oil superiorly and micelles in all quadrants. Surgical options considered were trabeculectomy, glaucoma drainage device and cyclodestruction. The patient had silicone oil induced glaucoma (open-angle) with borderline IOP control and advanced glaucomatous damage, as well as the need for

prolonged retinal tamponade, a scarred conjunctiva with implants, and was financially challenged. Thus, Dr. Martinez opted to perform the ACTSEB procedure on her eye. “The procedure involves a lacrimal stent and silicone tube for the aqueous to flow through. The space between the silicone band and surrounding capsule acts as a potential aqueous reservoir. It was a simple procedure and significantly cheaper. The patient did very well after the procedure. IOP was controlled up to 4-6 months after the surgery with no medications required. But the IOP started going up again when some droplets of emulsified oil reappeared on the anterior chamber. However, it tended to stick onto the tube and didn’t affect the pressure much or go inside the ostium,” he said.

A perplexing case of recurrent anterior chamber shallowing Meanwhile, Dr. Norman Aquino, associate professor of the University of the Philippines, shared a case involving a 71-year-old man who had myopic LASIK and phacoemulsification with the implantation of a single piece acrylic lens and capsular tension ring in both eyes. The patient was doing quite well until early last year when he began noticing transient episodes of blurring of vision in the eight eye. “He went to see his surgeon who did a comprehensive check which included a dilated retinal exam that revealed no significant findings. But as he prepared to leave the clinic, he complained of pain in the right eye and the IOP of the eye was found to be 40mmHg. He was given topical medication and went home when the IOP dropped to 25mmHg,” Dr. Aquino said. Nine hours later, the patient called the clinic complaining of severe pain and blurring in his right eye. So around midnight, Dr. Aquino was called to attend to the patient. He found that the pupil of the right eye was mid-dilated and immobile. The AC was shallow and IOP was 56mmHg even after receiving two anti-glaucoma drops. The vision was down to 20/200. He prescribed the patient with a stacked dose of

acetazolamide and the IOP dropped to 10mmHg after 12 hours. Ultrasound revealed normal studies for both eyes. OCT of the optic disc and perimetry findings was found to be consistent with the patient having openangle glaucoma affecting both eyes. On regular follow-up, the patients’ eyes had equally deep anterior chambers, clear corneas, good IOP control and a BCVA of 20/20. But the story didn’t end there. On three separate occasions within the same year, Dr. Aquino was called to attend to the patient and who presented with very much the same picture as the first occasion: shallowing of the AC, elevation of IOP, a drop in visual acuity, a hazy cornea and discomfort. Each time, Dr. Aquino prescribed oral acetazolamide and told him to continue with his drops. “One of the puzzlements associated with this case is that there seems to be evidence of glaucoma progression in the span of 13 months despite seemingly adequate IOP control in both eyes, and the progression was more in the left eye, which was the non-problematic one,” he said. Since shallowing was universal across the entire anterior chamber, pupillary block was ruled out. Co-chairperson Dr. Maria Imelda YapVeloso from the Asian Eye Institute, the Philippines, suggested doing provocative tests with the patient in different head positions. And Dr.

Martinez suggested doing an anterior segment OCT with the patient sitting upright and his head tilted a bit. “I’m thinking that this particular case may be caused by zonular laxity that creates movements in the capsular tension ring (CTR)-IOL complex,” he said. As the patient would not accept major surgery, Dr. Martinez suggested that perhaps the surgeon could access the eye and fixate the haptic capsule complex into the scleral. “Taking out the whole IOL complex would be rather invasive, maybe going with an iris fixated lens would be safer,” he said. Dr. Yap-Veloso also suggested localized and low dose transscleral cyclophotocoagulation to necrose the ciliary process and shrink it. “By retracting the ciliary process you can create a space between the CTR-IOL complex and the ciliary body, as well as disrupt the ciliary hyaloid phase. That might be more acceptable to the patient,” she said.

Editor’s Note: The 5th Annual Asia-Pacific Glaucoma Congress (APGC 2021) was held virtually from June 4 to 8, 2021. Reporting for this story took place during the event.

September 2021

SURGICAL INTERVENTION

Get Off the Meds Consider Earlier Surgical Intervention in Glaucoma by Brooke Herron

lthough patients and physicians often take the less invasive route of topical medications to control glaucoma, this treatment is not always effective. One major reason? Patient adherence is universally poor. From simple forgetfulness to the desire to avoid side effects, there are varying reasons why compliance fails when it comes to topical medications — and this can result in uncontrolled intraocular pressure (IOP) and the threat of vision loss. In fact, a 2019 study1 of 201 glaucoma patients reported that nonadherence was reported by 30.3% of participants – and this is a significant barrier to success. However today, glaucoma specialists have an “arsenal” of therapies at their fingertips to battle glaucomatous progression and compliance alike. These, of course, include minimally invasive glaucoma surgeries (MIGS) which decrease IOP by increasing aqueous outflow — safely and effectively — in a less invasive

procedure than traditional surgery, like trabeculectomy. The option for a safer (yet efficacious) procedure combined with poor patient compliance are central to the argument for earlier surgical intervention in glaucoma. Two recent conferences — the 9th World Glaucoma E-Congress (WGC 2021) and the 5th Asia-Pacific Glaucoma Congress (APGC 2021) — highlighted some of these devices and the data behind them. Below, we explore one of these innovative MIGS devices — which is helping to change the treatment approach and paradigm in treating glaucoma: the PRESERFLO™ microshunt from Santen (Osaka, Japan).

Operate early and avoid collateral damage At APGC 2021, Dr. Paul Palmberg, MD, PhD, professor of ophthalmology at the Bascom Palmer Eye Institute and University of Miami School of Medicine

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(Florida, USA) shared that current glaucoma surgeries like trabeculectomy can cause adverse events and require considerable training, equipment and material costs. “What’s not to like about trabs [trabeculectomy] and tubes? Our top weapons cause collateral damage,” said Dr. Palmberg. To mitigate these effects, he recommends using PRESERFLO™. He continued that microshunts like PRESERFLO™ are also a more ideal treatment choice for patients with a higher risk of hypotony, leaks or cataract progression, and for those who are losing ganglion cells more rapidly than as anticipated with normal aging. Certainly, this procedure is appealing for patients (and physicians) who are looking for a meaningful reduction of both IOP and medications — without an invasive surgery like trabeculectomy. And only does this device pose less risk than other procedures, it’s backed by clinical and real-world data. Some of this evidence was shared during WGC 2021 — we’ll cover those highlights now…

Why the microshunt? Detailing results from the longest published follow-up of patients implanted with the microshunt, was Dr.

Juan Batlle from the Bascom Palmer Eye Institute in Miami. Not only did these patients show sustained IOP reduction at 5 years, the mean IOP at follow-up was 12.4 mmHg. Plus, the glaucoma medications used was dramatically decreased to 0.8 drops — which directly addresses the issues with adherence.2 “We have a wonderful microshunt that I think is going to change the future of how we do glaucoma filtering procedures,” said Dr. Batlle. This was echoed by data from a twoyear multicenter European study, presented by Dr. Henny Beckers, a glaucoma specialist at University Eye Clinic, Maastricht Medical Center, The Netherlands. Like Dr. Batlle, her data showed a significant IOP reduction from baseline, as well as a significant drop in medications: At 24 months, 79% of patients were classified as having qualified success – meaning an IOP value of ≤18 mmHg without additional glaucoma intervention.3 It’s clear that clinical data shows the efficacy of the microshunt — especially its ability to lower topical medications. It’s also pretty effective at lowering IOP as well, another aspect pleasing to patients — and their expectations. “The average patient from the FDA study was 14 mmHg, and that was a randomized clinical trial — so at one year you can expect to get that, and that’s a reasonable expectation to tell patients because it’s pretty hard evidence,” said Dr. Keith Barton, glaucoma service at Moorfields Eye Hospital London (United Kingdom).

Match the patient and the microshunt According to New York-based ophthalmologist Dr. Joseph Panarelli, the device’s success all begins with Th e b en e fi t s o

the dimensions of the microshunt, as well as its biocompatibility. Essentially, the PRESERFLO™ is a micro-tube without an end-plate: “It’s 8.5 mm in length and has a 70 micron lumen. The length and lumen diameter help to restrict flow to help minimize hypotony related complications.” The 70 micron lumen was designed to allow sloughed corneal epithelial cells to pass through the lumen without causing blockages. He added that it’s made from a highly compatible bio-inert material called styrene-block-isobutylene-block-styrene (SIBS), which is well-tolerated by the human body. “That’s key for any new device that we’re going to implant into the body.” However, not only does the device need to be compatible with the body — the patient needs to be a good fit for the particular surgery. And when it comes to glaucoma surgery, matching the patient and procedure can be critical to obtain the best outcomes. This was one of the messages from Dr. Chelvin Sng, associate professor at the National University Hospital of Singapore. She shared her real-world experience using the microshunts in more than 50 patients, most of whom had advanced glaucoma. Results from her pilot Singaporean study showed that 84.8% of patients were medication-free at 12 months, and 77.4% were medication-free at 24 months.4 “When it worked — just like trabeculectomy — it worked very well, with IOP in the single digits,” she explained, adding that bleb complications like scarring can occasionally occur with this procedure. “In comparison to the iStent and the XEN, the microshunt is able to achieve target IOP in appropriate patients,” she explained. “Importantly, patient selection is crucial to the success of MIGS and depends on target IOP,

f early surgic a l i n t e r ve nt ion in g t he risk s- - an laucoma ca d lead to i n o u t we i g h m p r ove d o utcomes .

glaucoma severity and whether the glaucoma is controlled or uncontrolled.” Dr. Sng shared that the microshunt has had an impact on her practice: “Prior to the microshunt, I selected patients with mild to moderate glaucoma for MIGS. But now with the microshunt, I offer this as an option for my patients on the more advanced spectrum, so my number of trabs has decreased.” Indeed, these results support the indication for earlier surgical intervention in patients with poor adherence — not only will their needed medications be eliminated (or greatly decreased), their IOP will also be lowered and maintained … and aren’t those the results we’re all looking for?

REFERENCES: 1.

Wolfram C, Stahlberg E, Pfeiffer N. PatientReported Nonadherence with Glaucoma Therapy. J Ocul Pharmacol Ther. 2019; 35(4): 223–228.

Batlle J, Corona A, Albuquerque R. Long-term Results of the PRESERFLO MicroShunt in Patients With Primary Open-angle Glaucoma From a Single-center Nonrandomized Study. J Glaucoma. 2021;30(3):281-286.

Scheres LMJ, Kujovic-Aleksov S, Ramdas WD, et al. XEN ® Gel Stent compared to PRESERFLO™ MicroShunt implantation for primary open-angle glaucoma: two-year results. Acta Ophthalmol. 2021;99(3):e433-e440.

Sng, C. 9th World Glaucoma E-Congress (WGC 2021). 2021 June 30. [Real World Experience with the PRESERFLO Microshunt in Singapore.]

Editor’s Note: The 5th Annual Asia-Pacific Glaucoma Congress (APGC 2021) was held virtually from June 4 to 8, 2021, while the 9th World Glaucoma E-Congress (WGC 2021) was held from June 30 to July 3, 2021. Reporting for this story took place during the events. The Santen styrene-blockisobutylene-block-styrene (SIBS) microshunt is CE-marked in The European Union and currently marketed under the brand name of PRESERFLO™. It is not yet approved for use in other countries except Canada, Australia, Malaysia and Singapore. This article is based on the speakers’ actual presentations at the above-mentioned congresses and there are no financial interests to disclose.

September 2021

SURGICAL INTERVENTION

Cost is a big consideration when it comes to performing MIGS procedures.

To MIGS or Not to MIGS That is the Question

inimally invasive glaucoma surgery (or MIGS) represents an exciting development for physicians and patients looking for a safer, less invasive procedure to manage the disease, while still being effective at lowering IOP. However, MIGS procedures can be expensive and difficult to perform. For many surgeons, this begs the question: To MIGS or not to MIGS?

Filtering versus MIGS The first debate asked: Which is better, filtering or MIGS? On the pro-filtering side was Dr. Antonio Fea from the Ophthalmic Hospital of Turin (Italy).

by Chris Higginson

Dr. Fea began by explaining that the problems solved by MIGS — such as the controlled release of aqueous and flattening of the AC (anterior chamber) — can be solved in other ways. However, the issues MIGS brings along with it, such a higher requirement of mitomycin-C (MMC), as well as the fact that posterior filtration determines less fibrotic reaction, cannot be avoided. In addition, MIGS is an expensive procedure that the majority of people cannot afford. But, he said that the primary issue is that MIGS is “an unknown and unproven pathway, whereas in filtration we have a procedure that is endorsed by years of clinical experience.”

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On the pro-MIGS side was Dr. Mitchell Lawlor from the University of Sydney (Australia). He said that MIGS has been proven, again and again, to be effective. “Although there are patients who are not best served by MIGS, such as those who need a big pressure reduction, there are many, such as those trying to reduce their use of topical medication and those who need only slight IOP reductions, for whom MIGS is the best available treatment.”

Trabecular bypass: KDB versus trabectome Dr. Ricardo Guedes, from the Paletta Guedes Eye Institute (Brazil), spoke on two tools for trabeculectomy. The trabecular meshwork (TM) is believed to be the greatest source of outflow resistance and performing a trabeculectomy allows the aqueous direct access to the Schlemm’s canal. One possible tool for this is the Kahook Dual Blade (KDB; New World Medical, California, USA), which is a single-use ophthalmological knife that removes the TM. The other potential tool is the

Trabectome (NeoMedix, California, USA), which uses plasma to cauterize and ablate the nasal arc TM. Both tools work well, extending to the full thickness of the TM and cause few or no injuries to the sclera. There are only a few studies that compare the two techniques and the data suggests that they offer very similar results for IOP lowering. There is possibly a slightly better removal of the TM with Trabectome, whereas the KDB can provide a slight medication reduction. He concluded that, “more research, especially randomized control trials, need to be done to compare the two techniques in the future.”

For those who are not so concerned with having a larger outflow — and in his experience of using both tools — he said that “there is no question that the iStent Inject is significantly simpler and easier to use.” Although, Dr. Au noted that it needs to be done carefully, as it can be over-implanted due to the firing mechanism. In order to deal with this issue, Glaukos has released the iStent Inject W, which has a wider flange, thus avoiding the problem of overimplantation. The Hydrus Microstent is “simply a harder device to use” and it takes a lot of practice and getting used to. However, in FDA clinical studies the Hydrus does seem to give slightly better results.

GATT versus viscodilation

XEN versus Preserflo

Next, Dr. Paul Harasymowycz from the University of Montreal (Canada) compared gonioscopy-assisted transluminal trabeculotomy (GATT) with viscodilation for trabeculotomy procedures.

Dr. Kaweh Mansouri from the University of Colorado (USA) discussed the benefits of the Xen Gel Stent (Allergan, an AbbVie company, Dublin, Ireland) in comparison to the PreserFlo (Santen, Tokyo, Japan).

He said that GATT can be used to remove 180 or 360 degrees of the TM and is usually reserved for young patients — especially those who are myopic or phakic. It generally achieves good results with a significant reduction in IOP, although it can result in hyphema.

The Xen is a 6mm, cross-linked gelatine stent with an inner lumen of 45 microns, and the PreserFlo as an 8.5mm microshunt made from a material called “SIBS” with a slightly larger luminal flow of 70 microns.

“On the other hand, viscodilation, using stents similar to the Hydrus (Ivantis, California, USA), has been shown, at 12 and 24 months, to lower IOP, with most patients having IOP of ≤18mmHg,” shared Dr. Harasymowycz, adding that it also offers freedom from secondary surgery and less medication.

iStent versus Hydrus Dr. Leon Au from the Manchester Royal Eye Hospital (UK) discussed another popular MIGS debate: iStent versus Hydrus. Clinical trials show that Hydrus (Ivantis) is a little more efficacious. For those who believe that bigger lumens are always better, the Hydrus offers almost five times the lumen outflow compared to the original iStent (Glaukos, California, USA), which itself provides more than twice the flow of the iStent Inject (Glaukos).

Dr. Mansouri went through the published literature regarding both devices, and compared their effectiveness. Because it has been on the market longer, there is more data on XEN, with longer follow-ups — however, these are usually investigatordriven studies. There is less data for the PreserFlo, but there is a higher proportion of randomized control trials. After comparing the best evidence available, he concluded that they had comparable results in POAG eyes in terms of IOP lowering and surgical success, with a similar safety profile. Dr. Mansouri concluded that a proper head-to-head comparison is necessary to determine which procedure is superior.

The economics and ethics of MIGS

Toronto (Canada) said that the first thing considered are conflicts of interest — and authors are generally very good at announcing these. However, it is well known that there are often further conflicts that go unreported, such as an author being a shareholder of the device they report on, or the author being an industry employee. In a study comparing the abstract conclusions in industry versus nonindustry studies, 62% of conclusions were not supported by the results of the study; 24% of industry-funded studies had a statistically significant main outcomes measure; and 90% of industry-funded studies had a proindustry abstract conclusion. “We may be crossing the line into papers becoming product promotions rather than scientific studies,” she cautioned. Regarding MIGS in particular, uptake has been slow in some places due to the uncertainty of evidence about its efficacy. “Evidence is lacking both for the relative benefits of any MIGS device or procedure over any other, either overall or for a subset of patients,” she said. “There is a disparity between the existing quality of evidence on the clinical effectiveness of MIGS and the belief in its value.” In some cases, MIGS has been found to not be cost-effective in comparison to filtration surgery or laser therapy. Dr. Buys’ final question was: As we develop new and more expensive devices, what is the point of having devices or medicines that are not affordable to the majority of the public?

Regarding ethics for researchers, Dr. Yvonne Buys from the University of

September 2021

GENETICS, IMAGING AND OTHER RESEARCH AREAS

Glaucoma – Now with Genetic Associations! by Ankita Umapathy

e are living in the age of personalized medicine. In glaucoma alone, genetic studies have identified several risk factors and functional gene pathways as potential treatment targets. The glaucoma genetic heavyweights in the Genetics Symposium at the 5th Annual Asia-Pacific Glaucoma Congress highlighted how the field has discovered — and leveraged — genetic clues and associations in managing glaucoma. “We want to be ambitious in our studies on glaucoma genetics,” stated Dr. Calvin C.P. Pang, from the Chinese University of Hong Kong, who summarized the genome-wide association studies (GWAS) which identified several key primary openangle glaucoma (POAG) associated genetic risk factors. Ethnic and sexspecific differences have also been observed at loci associated with different types of glaucoma. More

recently, a global POAG GWAS identified 127 risk loci, of which 44 were novel, with consistent effect across European, Asian and African ancestries. Despite overlaps between the top signals of different POAG GWAS, validation and functional characterization of genes/ gene pathways remain top priorities due to the methodological differences between GWAS. Dr. Pang then shared unpublished data from the Hong Kong Children Eye Study revealing significant association of two SIX1-SIX6 singlenucleotide polymorphisms with retinal nerve fiber layer (RNFL) thickness.

Studying understudied populations Dr. Edward Ryan Collantes from Massachusetts Eye and Ear, USA, then shared three advantages of studying genetically diverse, understudied populations. Genetic testing of 25

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Filipino families revealed 14 with juvenile open-angle glaucoma, but only 4 with known disease-causing mutations. Consequently, first, he could identify and functionally characterize a novel mutation in the well-known glaucoma gene, MYOC, which caused glaucoma in 17 affected members of a 56-member family. Second, he discovered novel POAG genes and strengthened their diseasecausing association through in vitro characterization. “Upon review of the unsolved cases, three unrelated families had novel rare EFEMP1 variants. Each of these three variants were predicted to be pathogenic and segregated with disease in each family.” Third, such studies allowed robust documentation of the natural history of the disease which, Dr. Collantes believes, will be critical in determining the timing of future gene-based therapies.

Current concepts in POAG genetics Providing an overview of current concepts in POAG genetics, Dr. Periasamy Sundaresan from Aravind Eye Hospital, India, explained: “No single molecular pathway can encompass the pathophysiology of POAG. Analyses suggest that inflammation and senescence may play pivotal roles in both development and perpetuation of retinal ganglion cell (RGC) degeneration seen in POAG.” By mapping the spectrum of MYOC variants in a southern Indian population, and performing functional characterization, Dr. Sundaresan postulates that intracellular retention of MYOC mutants may increase cell-to-cell interaction and extracellular matrix deposition, resulting in elevated IOP. Similar workflows with a 4bp deletion variant of the SIX6 gene determined its association with reduced RNFL thickness and POAG. Pointing to preclinical studies showing RGC preservation by neurotrophic factors, he concluded:“There seems to be ample opportunity to develop novel and effective therapeutic interventions to tackle the neuroinflammation, tissue remodeling, and cell death that ultimately result in blindness.” Next, Dr. David Mackey with the University of Western Australia, urged genetic testing of glaucoma patients’ families, given that glaucoma is known to be a highly heritable disease. The life-time risk of glaucoma is 10fold greater in relatives of patients than controls. A 2011 Tasmanian cascade screening study saw high

rates of participation and found that although 6% of first-degree relatives had diagnosed glaucoma, 5% were undiagnosed, 15% were glaucoma suspects, and 6% had ocular hypertension. Dr. Mackey noted: “The number needed to screen to find a new case of glaucoma was 19 in this cascade screening compared to 68 in the larger population-based Blue Mountain Eye Study.” The screening produced continued impact in the next decade, with Tasmania boasting greater rates of glaucoma screening than other Australian states. Based on the polygenic nature of glaucoma, he concluded a polygenic risk score could “facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment for lower-risk groups.”

In other genetic news Shifting to exfoliation syndrome (XFS), Dr. Mineo Ozaki from Ozaki Eye Hospital, Japan, presented his recent study correlating rare CYP39A1 gene variants with altered protein function and potentially XFS pathogenesis. He explained: “Of the 42 variants predicted to be damaging by Polyphen-2, 34 were classified as functionally-deficient by CYP39A1 functional enzymatic assay.” CYP39A1 protein expression was significantly reduced in XFS ciliary epithelium compared to controls. Conversely, exfoliation material in the ciliary body contained significantly greater extracellular deposits of esterified cholesterol, colocalizing with

apolipoprotein E and LOXL1, in XFS patients compared to controls. Dr. Ozaki postulated that deficient CYP39A1 may dysregulate cholesterol homeostasis and transport, leading to excess cholesterol accumulation in extracellular exfoliation material, a hallmark of XFS. He suggested: “Future research efforts aimed at restoring deficient CYP39A1 function and inhibiting the formation of exfoliation material in the eye could be an approach to assess new strategies to treat XFS.” Rounding out all the talks, Dr. Shahin Yazdani from Shahid Beheshti University of Medical Sciences, Iran, emphasized how clinical and genetic studies could complement each other. “We found that 70% of an Iranian cohort with primary congenital glaucoma (PCG) carried CYP1B1 mutations, with several genotypephenotype correlations. Patients with CYP1B1 mutations had earlier onset disease, higher baseline IOP, significantly higher IOP throughout the follow-up, more operations were required, and the disease severity score was overall much higher.” They also found that CYP1B1 was responsible for a range of OAGs from birth to approximately 60-years-ofage, prompting a recommendation for seemingly unaffected relatives of PCG patients to undergo regular ophthalmologic examination to allow early OAG diagnosis. Finally, having noted the paucity of literature on primary angle-closure glaucoma (PACG) genetics, Dr. Yazdani developed a better understanding of familial inheritance in PACG, which eventually led to the discovery of the first PACG-associated genetic risk factor.

Editor’s Note: The 5th Annual Asia-Pacific Glaucoma Congress (APGC 2021) was held virtually from June 4 to 8, 2021. Reporting for this story took place during the event.

Does grandpa have glaucoma? Odds are higher his relatives will too…

September 2021

GENETICS, IMAGING AND OTHER RESEARCH AREAS

Glaucoma Studies Results Are In!

ho doesn’t love digging through clinical results to find the most compelling new evidence for treatments? Well, maybe some people, but not ophthalmologists, darn it. If basing your medical decisions on evidence were a crime, doctors would be unrepentant felons on the lam. That’s a fun scenario to consider, but fortunately the scientific method is legal and more than just accepted. Consequently, the 9th World Glaucoma E-Congress (WGC 2021) hosted a discussion of some of the most groundbreaking clinical trials — and there’s some fun info in here, if you’re into that kind of thing.

by Sam McCommon

Selective laser trabeculoplasty in the limelight One of the most compelling studies discussed in the session was the “Laser in Ocular Glaucoma and Hypertension (LiGHT)” study. There are significant takeaways from it, as the treatment involved may indeed become a frontline option for primary open-angle glaucoma (POAG). What’s that treatment, you ask? Why, look at the section title above. It’s selective laser trabeculoplasty (SLT), and it looks like it’s here to stay. It may be time for eyedrops to scooch over and leave some room for SLT as it

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offers some significant advantages over eyedrops. In this discussion, it got the thumbs up from all who discussed it. Dr. Kuldev Singh, of Stanford University, first brought the study to our attention. The primary outcome studied was health-related quality of life (HRQoL) at 3 years. Secondary outcomes included disease-specific HRQoL, clinical effectiveness and safety. The two approaches weighed by the study were a medication-first approach and a laser-first approach. Both groups did well in HRQoL outcomes. That’s some good news. The first crack in the medication edifice started to show when Dr. Singh reported that SLT performed slightly better than medication in helping patients reach IOP goals. One significant feather in SLT’s cap is its cost: SLT is more cost-effective than medicine, especially in the long-term. This makes perfect sense, after all — a one-time treatment would ideally be cheaper than a lifetime of medicine.

There’s another immediately practical benefit of SLT: There are no concerns about patient adherence. We were treated to a visit by Dr. Gus Gazzard, author of the LiGHT study and ophthalmologist at University College London. He pointed out that one of the most significant barriers to improvement in patients is compliance, persistence, and adherence. As he noted, around one-third of patients stop using or change their medicine within the first year of prescription. You don’t have to be an expert to see how that could throw a monkey wrench in an ophthalmologist’s treatment strategy. While not all noncompliance is bad — indeed, Dr. Singh suggested that glaucoma is often overmedicated, and medications can lead to multiple side effects — noncompliance with SLT is simply not a problem. Doctors will know just who has been treated and how with laser therapy.

Tell me more about this SLT One important note is that SLT’s safety has improved significantly over prior iterations. For example, the argon lasers used in previous laser trabeculoplasty used to burn the trabecular meshwork (TM). SLT, however, leaves the TM much more intact — so intact, in fact, that any damage can barely be noticed even when observed under a microscope at 1230x. Another benefit of SLT is that it frees many patients from dependence on medications. As the LiGHT study showed, 78% of patients who underwent the laser-first strategy were medication-free and at their target IOP at 36 months. What’s more, 77% of those who went the SLT route only needed one SLT treatment. It’s a repeatable process, so if another procedure needs to be done it’s not a problem. And hey, just to boot, there was only 1 patient out of 776 that experienced an IOP spike. Do you like math? If so, consider this: That’s 0.001% of the study population. That’s, like … nobody, man. The one non-positive note Dr. Gazzard

shared was that SLT is probably less successful for those with their IOP uncontrolled on 3+ medications. In that case, other options need to be considered. In general, however, both Dr. Singh and Dr. Gazzard are gung ho for SLT. Not only should it be considered as a primary treatment for POAG or ocular hypertension, it should also be considered if there are patients who are unhappy with their medication or forgetful about taking it.

ZAP! Iridotomies for prevention? ZAP isn’t just a noise you make when you shoot someone with an imaginary laser gun — it’s the acronym for the Zhongshan Angle Closure Prevention trial. Yes, they left out the C in the acronym, but they get the benefit of the doubt on that. The goal of the study was to see whether or not laser peripheral iridotomy could prevent angle closure. It was a single-center study in Zhongshan, a city of some three million in the Pearl River Delta in China. For the geographically challenged, that’s the same area in China’s southern Guangdong province that contains Guangzhou, Shenzhen, Hong Kong and Macau.

“Efforts to identify and treat PACS with iridotomy on a population are probably not the best use of resources.”

disease was lower in eyes that had undergone LPI. However, there were low rates of angle-closure disease in both groups, to the tune of 4.19 per 1,000 eye-years in treated eyes and 7.97 per 1,000 eye-years in untreated eyes. Dr. Singh suggested that, essentially, there are far too many iridotomies being conducted and many patients would be better off without iridotomies. What the ZAP trial did, perhaps above all, is give us data on the actual incidence of PACD. Many patients will still opt for iridotomies because they’re a generally safe treatment, and because of the potential catastrophic dangers of acute angle-closure (AAC). Dr. Benjamin Xu, ophthalmologist at the University of Southern California’s Roski Eye Institute, summed it up well. “Efforts to identify and treat PACS with iridotomy on a population are probably not the best use of resources.” He pointed to the cost effectiveness of the potential treatment, which looks, well … unreasonable. Essentially, 44 primary angle-closure suspects (PACS) would need to be treated to prevent one case of PAC or AAC. It gets worse: 126 eyes would need to be iridotomized (if that wasn’t a word before, it is now) to prevent one case of PACG, assuming a 5-year progression risk of 35%. There’s always something valuable to glean from a study — and in any medical or scientific field, learning what not to do is just as important as learning what to do.

— Dr. Benjamin Xu Because it was a single-center study and located in China, all test patients were Chinese and between the ages of 50-70. The study randomized one eye to LPI and the other to no treatment at all. The primary outcome of the study was to note the incident of primary angle-closure disease (PACD).

Editor’s Note: The World Glaucoma E-Congress 2021 was held from June 30 to July 3. Reporting for this story took place during the event.

There was indeed a benefit of LPI in preventing PACD — incidence of the

September 2021

GENETICS, GENETICS, IMAGING IMAGING AND OTHER AND OTHER RESEARCH RESEARCH AREAS AREAS

New Developments in Ophthalmic Imaging Benefits Glaucoma by Tan Sher Lynn

xcerpts from the Developments in Imaging Symposium during the 5th Asia-Pacific Glaucoma Congress (APGC 2021) Lowering intraocular pressure (IOP) is currently the only clinically proven glaucoma intervention. Nevertheless, glaucomatous neurodegeneration may still occur after reducing IOP. Hence, there exists a need to decrease the severity of damage caused to the visual system beyond lowering IOP, according to Dr. Kevin Chan from the New York University School Of Medicine (USA).

Neuroimaging in glaucoma He and his research team focus on two major directions: One, to look for glaucoma involvement in the brain; and two, neurotherapeutics to slow down the disease beyond controlling eye pressure. To understand the brain’s visual system, they used functional magnetic resonance imaging (MRI), structural MRI and metabolic magnetic resonance (MR) spectroscopy to obtain structural and functional clinical ophthalmic measurements. For example, the blood-oxygenationlevel dependent (BOLD) functional MRI of the visual cortex suggested weaker brain functional responses in more advanced glaucoma patients. Meanwhile, by using upper field stimulation and lower field stimulation, they discovered that visual cortex activity is imparied prior to clinical vision loss in glaucoma. There were also developments in regard to hemodynamics in glaucoma, including the measurement of cerebral blood flow, cerebral blood

volume, cerebrovascular reactivity and cerebral metabolic rate of oxygenation consumption, as well as more advanced diffusion models to improve specificity to detect microstructural changes in glaucoma. These include diffusion kurtosis imaging, diffusion basis spectrum imaging and white matter tract integrity, which will help to improve structural and physiological

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characterization for more targeted treatment in the future.

OCT imaging challenges and improvements Today, fundus photography and optical coherence tomography (OCT) is the gold standard for glaucoma imaging. These

methods are used in most settings for diagnosis and follow-up. However, OCT imaging poses some principal challenges, including low contrast in the inner retina, significant floor effect in late stage disease, limited lateral resolution and no molecular contrast, according to Prof. Leo Schmetterer from the Singapore Eye Research Institute. “There are multiple ideas on how advanced technology may improve sensitivity for glaucoma imaging. One way to improve the molecular contrast in OCT images is to use polarization OCT. There is also the DARC (detection of apoptosing retinal cells) technology, which gives you an insight into the number of cells that actually die in a certain point of an investigation. And if we combine OCT with adaptive optics, then we can reach the resolution that is close to single cell imaging,” he said.

“OCTA can also provide information on ocular perfusion which may help to understand the mechanism of glaucoma damage in individual eyes, such as the evaluation of the influence of vascular pathology.” — Dr. Eun Ji Lee Meanwhile, Dr. Eun Ji Lee from the Seoul National University Bundang Hospital, South Korea, said that optical coherence tomography angiography (OCTA), a non-invasive imaging technique that generates volumetric angiography images in a matter of seconds, might be useful in the evaluation of glaucomatous damage, as well as in predicting its progression — specifically in eyes with advanced glaucoma or high myopia. “OCTA can also provide information on ocular perfusion which may help to understand the mechanism of glaucoma damage in individual eyes, such as the evaluation of the influence of vascular pathology,” she said.

OCT applications in glaucoma management In managing glaucoma, early diagnosis is essential. Detection of glaucoma progression is also very important as it helps to determine treatment decision and escalation. “Quality of life is closely associated with the location of optic nerve damage. When diagnosing glaucoma, in addition to looking into the optic nerve head, it is important to examine the retinal nerve fiber layer (RNFL) with OCT, as well as the retinal ganglion cells at the macula,” said Prof. Ki-Ho Park from the Seoul National University, South Korea. ”OCT imaging can detect localized RNFL defects in preperimetric glaucoma, which can be missed by spectral-domain OCT (SD-OCT) ganglion cell analysis because the defect is outside of the region of analysis. OCT imaging can also detect ganglion cell complex (GCC). “Wide-field imaging can be better than conventional deviation map analysis because it can detect RNFL defects located outside of the region of conventional macular or peripapillary scans. And OCT-based minimum rim width can be a useful tool to detect glaucoma,” he said, adding that OCTA can be used as a complementary tool in detecting RNFL defects and the region at risk.

DARC – a marker for early detection

She and her team investigated the clinical use of this method through the DARC project. The phase 1 clinical trial of DARC, published in June 2017, showed that DARC counts are significantly greater in patients who later showed increasing rates of disease progression. Phase 2 evaluated the efficacy of DARC in visualizing apoptotic retinal cells as in phase 1, but with single dosage (0.4mg of fluorescent-labelled annexin ANX776); increased subjects (n=113); and diseases (glaucoma, age-related macular degeneration, optic neuritis and Down’s syndrome). Images were recorded at baseline, 15min, 2h and 4h post-ANX776 admission.Central images of the optic nerve head and macula were recorded. The comparison of glaucoma progression via manual observer and convolutional neural network algorithm (CNN-algorithm) analysis showed that a significantly higher DARC count was seen in the progressing versus stable glaucoma group. “The positive predictive value (PPV) of DARC is 100% for predicting glaucoma progression, with all glaucoma patients with DARC count > 30 going on to progress with OCT RNFL at 18 months. “Taking this forward, we are keen on exploring new medications, and the use of intranasal DARC which rapidly enters the retina, is less invasive for patients and potentially requires smaller dosage (thus reducing cost),” she said.

DARC is a non-radioactive approach that uses fluorescent-labeled annexin V and high-resolution imaging to enable realtime detection of cellular apoptosis. “In early apoptosis, the cell membrane changes its structure — phosphatidylserine moves from the inside to the outside of the cell. Fluorescent labelled annexin V binds to the exposed phosphatidylserine. Individual apoptotic cells are visualised as white spots on the retina,” said Prof. Francesca Cordeiro from the Imperial College London, U.K., adding that experimental studies have shown that DARC can improve early detection of glaucoma.

Editor’s Note: The 5th Annual Asia-Pacific Glaucoma Congress (APGC 2021) was held virtually from June 4 to 8, 2021. Reporting for this story took place during the event.

September 2021

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GENETICS, IMAGING AND OTHER RESEARCH AREAS

The Role of Corneal Biomechanics in Glaucoma Diagnosis and Progression by Brooke Herron

laucoma is a multifactorial and complex disease and if left undiagnosed or untreated, it can result in optic nerve damage and visual field loss. Reducing intraocular pressure (IOP) plays a crucial part in preventing structural and functional damage from glaucoma, and as such, accurate IOP measurements are necessary to manage and treat the condition. However, this accuracy is influenced by the cornea’s biomechanical properties (e.g., corneal thickness and material stiffness).1

The role of corneal biomechanics in NTG According to Vinciguerra et al., data shows that differences in corneal biomechanics across individuals may have a greater impact on IOP measurement errors than corneal thickness or curvature.1 And although it’s the standard IOP measurement, Goldmann applanation tonometry (GAT) is known to be significantly affected by corneal biomechanical properties such as central corneal thickness (CCT): GAT

underestimates IOP in eyes with thin corneas and overestimates IOP in eyes with thick corneas.2 As a result, there have been numerous attempts using different devices to introduce an IOP estimate that takes corneal biomechanics into account.1 One such device is the dynamic Scheimpflug analyzer Corvis® ST (Oculus Optikgeräte GmbH, Wetzlar, Germany). This non-contact tonometer employs a biomechanically corrected IOP (bIOP) algorithm to produce IOP measurements with reduced biomechanical effect.1 A study from 20181 compared bIOP measures between the Corvis® ST and GAT in patients with primary open-angle glaucoma [both high (HTG) and normal tension (NTG)], ocular hypertension (OHT) and controls. The investigators measured CCT, GAT-IOP and bIOP; GATIOP was also adjusted for CCT (GATAdj). The authors found significant differences between GAT-IOP, GATAdj and bIOP in NTG and HTG, OHT and controls: “NTG corneas were significantly softer and more deformable compared with controls, OHT and HTG, as demonstrated by significantly lower

values of stiffness parameters.” This is related to the compensating factors that bIOP corrects for, namely, age, CCT and corneal biomechanics. Further, they noted that primary open-angle glaucoma (POAG) patients with softer or more compliant corneas are more deformed by the air puff and more likely to show visual field defects than those with stiffer corneas. These results show that it’s critical to utilize IOP estimates that are not affected by material properties, age and thickness — and importantly, that corneal biomechanics should be considered as an independent risk factor in clinical decision-making. “The abnormality of corneal biomechanics in NTG and the significant correlation with visual field parameters might suggest a new risk factor for the development or progression of NTG,” said the authors. Indeed, further evidence from a 2019 study by Pillunat et al., also showed that NTG patients have biomechanically different corneal behavior.2 In this study, the authors tested the ability of the Dresden biomechanical

September 2021

GENETICS, GENETICS, IMAGING IMAGING AND OTHER AND OTHER RESEARCH RESEARCH AREAS AREAS

glaucoma factor (DBGF) based on dynamic corneal response (DCR) deformation and corneal thickness parameters to discriminate between healthy and NTG eyes. Five Corvis® ST parameters were used in the DBGF calculation: deformation amplitude ratio progression, highest concavity time, pachymetry slope, the bIOP and pachymetry. In a threefold crossvalidation, the receiver operating characteristic (ROC) curve confirmed an area under the curve (AUC) of 0.814 with a sensitivity of 76% and a specificity of 77% using a logit cut-off value of a DBGF = 0.5, where normal eyes had a DBGF lower than 0.5 and NTG eyes had a DBGF higher than 0.5. These findings support the idea that NTG eyes behave biomechanically different compared to controls — and as the DBGF has the ability to discriminate between these two groups, it might be considered as a new possible screening method for NTG.

Biomechanically corrected IOP remains stable in LVC eyes Laser vision correction (LVC) procedures using flaps (like LASIK) can affect corneal biomechanics — but how do they affect bIOP? To find out, two studies compared changes in bIOP and DCRs between transepithelial PRK and FS-LASIK and SMILE and FS-LASIK. In a retrospective cases series, Lee et al. evaluated changes in bIOP and DCRs in 129 eyes of 129 patients before and after PRK (n=65) and LASIK (n= 64) and found that no significant differences in bIOP were noted before and after surgery when measured with the Corvis® ST. Results also showed that the changes in deformation amplitude ratio (2.0 mm) and integrated inverse radius were smaller in transepithelial PRK than femtosecond-assisted LASIK (P < 0.001), indicating less of a biomechanical effect with PRK. Further, the fact that “bIOP measurements remained almost unaltered after surgery is an indication that bIOP estimates are less influenced by changes in CCT and material properties than the uncorrected IOP measurements,” concluded the authors.3

Another retrospective case series compared the bIOP algorithm provided by the Corvis® ST with GAT-IOP before and after FS-LASIK and SMILE surgeries.4 Preoperatively, the GAT and Corvis® ST IOP values showed significant positive correlation with CCT ( P = 0.05 for LASIK; P = 0.003 for SMILE), with no significant correlation between bIOP and CCT (P > 0.05). Postoperatively, and compared with preoperative readings, there were significant decreases in GAT-IOP (-3.2 mmHg ± 3.4 [SD] and -3.2 ± 2.1 mmHg, respectively; both P < 0.001) and Corvis® ST IOP (-3.7 ± -2.1mmHg and 3.3 ± 2.0 mmHg, respectively, both P < 0.001); bIOP did not differ significantly (0.1 ± 2.1 mmHg and 0.8 ± 1.8 mmHg, respectively; P = 0.80 and P = 0.273, respectively). These results are important, noted the authors, as they “suggest that the bIOP algorithm should be able to compensate for the effect of laser surgeries on ocular biomechanics, including the loss of tissue caused by ablation and flap or cap cutting.”

Predicting OCT and visual field progression with corneal SPs It’s clear that corneal biomechanics are emerging as an increasingly important risk factor for the development and progression of POAG — and further research shows their importance in classifying risk glaucoma progression in suspect eyes. One prime example comes from Qassim et al., who investigated corneal stiffness parameters (SPs) for their association with a greater risk of glaucoma progression in POAG suspects.5 This study included 371 eyes of 228 POAG suspected patients with normal baseline Humphrey Visual Field (HVF; Carl Zeiss Meditec, Jena, Germany) results. The baseline corneal SPs were measured with the Corvis® ST, with baseline SP at first applanation (SP-A1) and highest concavity predicting the prospective outcome measures. The main outcome measures were the OCT rate of thinning of the retinal nerve fiber layer (RNFL) and ganglion cell

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inner plexiform layer (GCIPL). The authors noted that stiffness parameters correlated positively with CCT and this was adjusted for in all analyses. Results showed that “eyes with higher SP-A1 and thinner CCT (thin and stiff corneas) showed accelerated RNFL thinning by 0.72 μm/year relative to eyes with lower SP-A1 and thicker CCT (95% confidence interval [CI], 0.17-1.28; P = 0.011) and were at 2.9-fold higher likelihood of fast RNFL progression of more than 1 μm/year (95% CI, 1.4-6.1; P = 0.006).” Thus, eyes with a higher SP and a thinner CCT are at the highest risk of progression. The authors also observed consistent results with GCIPL thinning. “Furthermore, a higher SP-A1 was associated with a greater risk of visual field progression (P = 0.002), synergistic with thinner CCT (P = 0.010). Eyes with higher SP-A1 and thinner CCT were at 3.7-fold greater risk of visual field progression relative to eyes with thicker CCT and lower SP-A1 (95% CI, 1.3-10.5; P = 0.014),” noted the authors. “This provides further evidence for the importance of corneal biomechanical factors in stratifying risk of progression in glaucoma suspect eyes,” they concluded.

REFERENCES: 1.

Vinciguerra R, Rehman S, Vallabh NA, et al. Corneal biomechanics and biomechanically corrected intraocular pressure in primary open-angle glaucoma, ocular hypertension and controls. Br J Ophthalmol. 2020;104:121-126.

Pillunat KR, Herber R, Spoerl E, Erb C, Pillunat LE. A new biomechanical glaucoma factor to discriminate normal eyes from normal pressure glaucoma eyes. Acta Ophthalmol. 2019;97(7):e962-e967

Lee H, Roberts CJ, Kim TI, Ambrósio R, Elsheikh A, Yong Kang DS. Changes in biomechanically corrected intraocular pressure and dynamic corneal response parameters before and after transepithelial photorefractive keratectomy and femtosecond laser-assisted laser in situ keratomileusis. J Cataract Refract Surg. 2017;43(12):1495-1503.

Chen KJ, Joda A, Vinciguerra R, et al. Clinical evaluation of a new correction algorithm for dynamic Scheimpflug analyzer tonometry before and after laser in situ keratomileusis and smallincision lenticule extraction. J Cataract Refract Surg. 2018;44(5):581-588.

Qassim A, Mullany S, Abedi F, et al. Corneal Stiffness Parameters Are Predictive of Structural and Functional Progression in Glaucoma Suspect Eyes. Ophthalmology. 2021;128(7):993-1004.

GENETICS, IMAGING AND OTHER RESEARCH AREAS

Biomechanics and Imaging in Glaucoma by Sam McCommon

e, the ophthalmic-interested audience, were recently treated to a fascinating dive into the realm of ocular biomechanics. Prof. Michaël J.A. Girard, holder of many titles, including head of the ophthalmic engineering and innovation laboratory at Singapore National Eye Institute, led the discussion at the recent APAO 2021 Virtual, and there’s a lot to chew on here. Specifically, the discussion focused on imaging to assess ocular biomechanics, with a focus on glaucoma. As Prof. Girard explained, glaucoma is a biomechanical disorder, but we don’t fully understand how these biomechanics work and their impact on glaucoma. So, relying on data-centric engineering, Prof. Girard wondered if he could create a biomechanical stress test for the optic nerve head (ONH) to both assess the ONH’s robustness and predict visual field loss progression. As he put it, “If we could understand the mechanical behavior it might really help us diagnose or even prognose who’s going to compress and how fast.”

Testing, testing: Stress tests for glaucoma One significant way Prof. Girard and his team have observed biomechanical changes in glaucomatous eyes is with optical coherence tomography (OCT). They’ve observed ONH deformations when the IOP increases, for example from 16 to 45mmHg. Prof. Girard proposed performing a stress test using a dynamometer to check ONH deformation, and the team is currently testing hundreds of eyes. The large sample size shows a wide variety of deformations, meaning there’s a lot of information to glean. For now,

we know that deformations are linked with visual field loss. Interestingly, patients suffering ocular hypertension (OHT) have demonstrated fewer lamina cribrosa (LC) deformations and exhibit stiffer neural and connective tissues. Patients with both myopia and glaucoma, however, show the greatest extent of deformation. The higher the myopia and the higher the glaucoma, the greater the deformation. Additionally, the optic nerve can exert a force when the eye is rotated, leading to deformation and allowing for another type of stress test, dubbed optic nerve traction. There’s a good reason to have these different tests: Normal-tension glaucoma (NTG) patients are more sensitive to optic nerve traction, while high-tension glaucoma (HTG) patients are more sensitive to IOP changes. But what makes the ONH strong? As Prof. Girard demonstrated with OCT, the central retinal vessel trunk and branches may make the ONH robust.

The structural signal of glaucoma The shape — that is, the physical shape of the glaucomatous eye — has been one focus of advances in AI machine learning techniques. Interestingly, an algorithm that can detect and analyze the shape of ordinary objects like a cup, chair or couch, for example, can be used to detect differing shapes within eyes. This type of shape-detecting AI can then plot the eyes on a chart — with shape regions indicating a glaucomatous nerve head. At this point, glaucoma could be identified with a single number. And that’s not where it ends — that same number could help doctors understand

and prognose not only the patient’s glaucoma progression, but also myopia and its relationship to glaucoma. Prof. Girard and his team are also working on ways to image the optic disc drusen and create a biomechanical, OCT-based test for the iris. For example, the iris is stiffer and less permeable in primary angle-closure glaucoma (PACG) compared to healthy patients. That’s another area to investigate, and we’ll keep our eyes open for more information from Prof. Girard and his team. Kudos to all involved in this project, as nailing down the biomechanics of glaucoma would go a long way toward both treatment and prevention.

Editor’s Note: The 36th Asia-Pacific Academy of Ophthalmology (APAO 2021) Virtual Congress was held from Sept. 5-11. Reporting for this story took place during the event.

September 2021

GENETICS, IMAGING AND OTHER RESEARCH AREAS

Notable Gems of Glaucoma by Tan Sher Lynn

xperts discussed glaucoma related disorders and complications and ways of managing them during the Plenary Session on Day 2 of the 5th Annual Asia-Pacific Glaucoma Congress. Here are the highlights…

Pathophysiology of XFS and XFG According to Prof. Gábor Holló from the Semmelweis University in Hungary, pseudoexfoliation syndrome (XFS) is a systemic disorder caused by progressive accumulation of protein material called exfoliative or pseudoexfoliative material over various tissues. “In exfoliative syndrome with or without glaucoma, we can see the exfoliative material on the anterior lens surface in the center

and on the periphery when the pupil is dilated. We should consider XFS and pseudoexfoliative glaucoma (XFG) even in the earlier form of the disease,” he said. He noted that people who spend a lot of time outdoors under high radiation (like in the sun) have a much higher risk of developing pseudoexfoliation compared to those who do not spend much time outdoors. It is strongly correlated to the amount of UV radiation received, especially when young. Hence, he suggested that kids should wear UV-filtering glasses when outdoors to prevent the onset of XFS later in life. Approximately 30% of XFS developed into XFG within 10 years, with elevated intraocular pressure (IOP), which is usually higher than in primary open-

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“In exfoliative syndrome with or without glaucoma, we can see the exfoliative material on the anterior lens surface in the center and on the periphery when the pupil is dilated. We should consider XFS and pseudoexfoliative glaucoma (XFG) even in the earlier form of the disease.” — Prof. Gábor Holló angle glaucoma (POAG). IOP fluctuation is also greater than in POAG, and the

visual field is more severely damaged than in POAG at the time of diagnosis. He noted that having LOXL1 (gene) deficiency at the lamina cribrosa (LC) makes one susceptible to XFG. “LOXL1 deficiency negatively influences the elastic fibres providing support, therefore increasing the susceptibility for increased IOP. In XFG and POAG, we can see that the LC is significantly thinner. LC thinning is an early sign, with progressive thinning as the glaucoma advances.” The treatment of XFG is IOP-based. “XFG is treatable and significant intraocular pressure reduction is currently the only means of treatment for short and long-term variability. This can be done through early surgical interventions, fixed combination medications, and laser trabeculoplasty exfoliation, for example. However, specific treatment based on the pathophysiology of XFG is not available. Low target IOP and small diurnal/ long-term IOP fluctuation are to be targeted from the very beginning of the treatment,” he advised.

Bleb-related “pain in the neck” A bleb is an insult to the otherwise perfect surface of the eye, and they are associated with many complications. One of them is bleb dysesthesia, which happens in 10-15% of cases, according to Dr. Tarek Shaarawy from the University of Geneva, Switzerland. “Blebs come in different forms and shapes, and not every one of them are as perfect as what we like it to be,” he said. Sharing his experience on managing problematic blebs, Dr. Shaarawy said that before he operates on a patient, he would first assess for conjunctival health, thickness and mobility. Making a snip at the conjunctiva and doing a hydrodissection allows him to understand if the conjunctival is atrophic or not. He showed various blebs which are problematic, including one that is totally atrophic and avascular, which would lead to what is called a “sweating bleb.” Adding a bit of fluorescence to the bleb allows the one to see that it is

actually leaking at various places. Another case is a bleb that encroaches on the limbus and invades the surface of the cornea. “This sort of bleb will cause discomfort and dysesthesia. Luckily, we can manage it easily by separating it from the cornea and excising the area,” explained Dr. Shaarawy. Some blebs may look fine initially, but when a little pressure is applied on the globe, it will begin to leak profusely. In some instances, there’s no need to excise the whole bleb. “If you consider the bleb as a house, and the leakage is at the roof, there’s no need to deconstruct the whole house, just remove the roof and rebuild it,” he said. Needling a bleb, the alternative to surgically revising it, is one of the most treacherous procedures. There’s a risk of perforating the conjunctiva and hence, Dr. Shaarawy would usually needle the bleb one or two times.

The eye’s waste removal system and its implications in glaucoma Prof. Neeru Gupta from the University of Toronto, noted that until physicians can cure glaucoma, the goal is to delay visual decline or disease progression. “In glaucoma, there is progressive loss of retinal ganglion cells and axons, resulting in focal rim thinning and nerve fiber layer defect. Once vision is lost, it is irreversible. We rely a lot on clinical biomarkers such as IOP, optic nerve and visual field, for the diagnosis and treatment of open angle glaucoma,” noted Prof. Gupta. Lowering IOP is the only proven method of slowing the rate of glaucoma injury. Medications work by reducing aqueous humor production, increasing drainage at the trabecular network (conventional method) or increasing uveoscleral (unconventional pathway). Using sheep and mouse models, Prof. Gupta and her colleagues proved that lymphatic drainage is a pathway that the eye has¹, and that the flow can be measured2 and manipulated3 to improve the eye’s condition.

structural changes) in our clinic, we need to keep in mind that everything we are looking at is bathed in a rich environment of fluid that is filled with waste, metabolic active molecules and things that keep these tissues together and working well. Secondly, there’s a rich system in the eye, which is the lymphatic system that serves as a route for the fluid and waste to drain out of the eye,” she said. She also noted that there was evidence that cerebrospinal fluid (CSF) enters into the optic nerve via a glymphatic pathway. Using similar experiments as the DBA/2J mouse model of high IOP and progressive loss of retinal ganglion cells, she and her teammates demonstrated that there is reduced CSF inflow into the optic nerve in glaucoma.4 “At the level of the optic nerve, it appears to have impairment of the glymphatic system and optic nerve waste removal. It’s very exciting to consider this environment and fluid as a new target for glaucoma therapy,” she said.

REFERENCES: 1.

Yücel YH, Johnston MG, Ly T, et al. Identification of lymphatics in the ciliary body of the human eye: a novel "uveolymphatic" outflow pathway. Exp Eye Res. 2009;89(5):810-9.

Kim M, Johnston MG, Gupta N, et al. A model to measure lymphatic drainage from the eye. Exp Eye Res. 2011;93(5):586-91.

Tam ALC, Gupta N, Zhang Z, Yücel YH. Quantum dots trace lymphatic drainage from the mouse eye. Nanotechnology. 2011;22(42):425101.

Mathieu E, Gupta N, Paczka-Giorgi LA, et al. Reduced Cerebrospinal Fluid Inflow to the Optic Nerve in Glaucoma. Invest Ophthalmol Vis Sci. 2018;59(15):5876-5884.

Editor’s Note: The 5th Annual Asia-Pacific Glaucoma Congress (APGC 2021) was held virtually from June 4 to 8, 2021. Reporting for this story took place during the event.

“When we are evaluating glaucoma (looking at the optic nerve and

September 2021

GLAUCOMA HOT TOPICS

Cataracts and Glaucoma and Surgeries, Oh My! by Ankita Umapathy

Combining surgeries is best reserved for visually significant cataracts and advanced/central visual field loss.” Continued refinement and evolution of glaucoma surgeries will impact these considerations, so watch this space! The rest of the symposium focused on combining cataract surgery with various types of glaucoma surgeries. Dr. Ishtiaque Anwar from Bangladesh Eye Hospital and Institute, began by showcasing videos combining cataract surgery and tube shunts, like the Ahmed Glaucoma Valve (AGV; New World Medical, California, USA). In typical cases, he performs valve implantation, phacoemulsification, and then tube insertion. When working with small pupils, he recommends iris hooks to allow sufficient dilatation for rhexis, phacoemulsification and intraocular lens (IOL) implantation.

hile perhaps not as scary as lions and tigers and bears (oh my!), the lack of consensus on the surgical management of coexisting cataracts in patients with glaucoma is pretty darn intimidating. So, we followed the yellow brick road to the 5th Annual Asia-Pacific Glaucoma Congress. Turns out the Cataracts and Glaucoma symposium had deep insights into this hotly contested topic all along!

To combine or not combine: That is the question

Dr. Sek Tien Hok from Mount Elizabeth Novena and Gleneagles Hospitals, Singapore, cited an American Academy of Ophthalmology (AAO) study that found phacoemulsification reduced long-term intraocular pressure (IOP) and medication use, in primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma patients. In fact, clear lens extraction is recommended as first-line treatment for primary angleclosure glaucoma (PACG). For these reasons, combined surgeries can be advantageous, though not without complications.

Cataract and glaucoma surgeries can be combined or performed sequentially. However, trabeculectomy alone may accelerate cataract formation, and phacoemulsification performed after filtering surgery could reduce bleb function.

His rules of thumb are, “if the cataract is not visually significant, perform glaucoma surgery and delay cataract surgery. Phacoemulsification alone, or together with minimally invasive glaucoma surgery (MIGS), may be sufficient for less advanced glaucoma.

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However, the key to combined surgeries is flexibility, as Dr. Anwar then demonstrated by reversing the procedures with a more complicated case. With subluxated cataracts, it is important to first stabilize the rhexis, enlarge the pupil if needed, perform hydrodissection, and place a capsular tension ring (CTR) in the bag. He advised appropriate management of any vitreous prolapse and elevated vitreous pressure before proceeding with AGV implantation, centering the rhexis, IOL implantation and finally, tube insertion.

A winning combination? Next, Dr. Masaki Tanito from Shimane University, Japan, spoke about combining cataract surgery with Tanito microhook trabeculotomy (TMH). As TMH may deliver milder IOP and medication reduction than filtration surgeries in POAG patients, Dr. Tanito instructed that “procedure selection should be based on target IOP.”

In contrast to phacotrabeculectomy, he showcased that cataract surgery did not affect IOP reduction achieved by TMH. Indeed, TMH with cataract surgery provided greater IOP and medication reduction than the iStent (Glaukos, California, USA) with cataract surgery. Based on his previous work, Dr. Tanito recommended that “older patients with visually significant cataracts may be the best candidates for TMH in combination with cataract surgery, given the greater IOP reducing effect of cataract surgery in subjects over 70 years.” Moreover, TMH does not induce remarkable corneal astigmatism compared to other filtration surgeries, allowing toric IOL use in combined TMH and cataract surgery, particularly, when corneal astigmatism exists preoperatively. Ab externo implantation of the XEN Gel Stent (Allergan, an AbbVie company, Dublin, Ireland) is also an excellent option for cataract surgeons as it can be placed superiorly/superotemporally via the main superior wound. The procedure is simple, does not require a goniolens, is compatible with hazy corneas or anterior chamber (AC) IOLs, and scleral anchoring prevents stent migration. Dr. Norshamsiah Md Din from the Universiti Kebangsaan Malaysia, shared tips for the combined surgery with elegant videos. After deploying the stent following IOL implantation, she advised: “Remove the viscoelastic with care — the newly implanted stent can be wobbly and dislocate with AC

turbulence. Viscoelastic can be removed prior to XEN implantation in case of toric lens use, whereby it is crucial to empty the bag of viscoelastic.” Though postoperative hypotony is expected, this eventually stabilizes. Subconjunctival scarring can be treated with 5-fluorouracil and dexamethasone alone, or require bleb needling, depending on IOP and bleb morphology. When performing three needlings (on average) after three months postoperative, with small cystic blebs, Dr. Din recommends frequently checking IOP, whilst cutting fibrous subconjunctival tissue with a twirling motion, until aqueous drainage is reinstated and the desired IOP is achieved.

Investigating outcomes In investigating the refractive outcomes of combined surgeries, Dr. Sang Woo Park from Chonnam National University Medical School and Hospital, South Korea, explained the influence of postoperative changes in IOP, AC structure, and axial length. In acute PAC (APAC) patients, he found that duration of the acute attack affected refractive outcomes, consequently recommending prompt IOP normalization after APAC onset. Postoperative myopic shifts were prevalent in both OAG and ACG eyes, with preoperative lens vault (LV) — but not axial length or glaucoma type — being the only factor associated with unstable

postoperative refractive outcomes. In long-term studies, Dr. Park found that both phacoemulsification and phacotrabeculectomy groups had similar stable outcomes of prediction error, suggesting phacotrabeculectomy to be an effective treatment for glaucoma patients. However, elderly patients or those with large LV may be predisposed to unstable prediction error after phacotrabeculectomy. Finally, Dr. Syed Imtiaz Ali from Isra University, Pakistan, closed out the symposium with preoperative, intraoperative and postoperative tips for cataract surgery in pseudoexfoliation syndrome (PXF) patients. As phacoemulsification lowers IOP and potentially reduces the incidence of newly diagnosed glaucoma in PXF patients, Dr. Ali’s main tip was performing cataract surgery early in disease management. Preoperative considerations included the surgical outcome of the fellow eye, thorough patient education on surgical outcomes and risks, identifying PXF material, assessing pupil size, and looking for signs of zonular weakness and phacodonesis prior to pupillary dilatation. Intraoperatively, he suggests maintaining a large pupil size, being aware of capsular wrinkling upon attempted puncture (which could denote zonular weakness), and late CTR implantation. In postoperative management, Dr. Ali advises looking out for possible IOP spikes, which are higher and more sustained in PXF; a higher inflammatory response, potentially requiring medical management; and anterior capsular contraction, which could necessitate YAG laser use.

Editor’s Note: The 5th Annual Asia-Pacific Glaucoma Congress (APGC 2021) was held virtually from June 4 to 8, 2021. Reporting for this story took place during the event.

Tame the beast of combined cataract and glaucoma surgery with these expert tips.

September 2021

GLAUCOMA HOT TOPICS

Glaucoma Management in the Era of Artificial Intelligence by Ankita Umapathy

xperts shared their thoughts on the use and potential of artificial intelligence (AI) in glaucoma management during the 5th Asia-Pacific Glaucoma Congress on June 6, 2021.

use information in each pixel to identify gender, refractive error, blood pressure, etc., from fundus photographs. This cannot be done by human eyes,” she said.

According to Dr. Yu-Chieh Ko from the Taipei Veterans General Hospital, Taiwan, when it comes to diagnosis and management of glaucoma, AI can do as well as — or even better than — humans. “Humans tend to collapse visual information; while computers can

She noted that AI can assist in providing effective population-based screening, early diagnosis, mapping structure-function correlation, and detecting or forecasting glaucoma — all key components in glaucoma management. “By integrating AI in the care delivery system to optimize resource utilization, we can improve the quality of care,” she said.

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The potential of AI

Meanwhile, Dr. Siamak Yousefi, assistant professor at the University of Tennessee Health Science Center, USA, said that ophthalmology is one of the imaging intensive fields of medicine with great potential for AI models. “The use of AI in glaucoma is advancing very fast. However, most models are geared toward screening and diagnosis. As such, more innovative AI models are needed to address progression and monitoring for enhanced treatment planning. Contrary to emerging deep learning models, unsupervised learning may generate interpretable models with explainable outcomes,” he said.

Challenges in AI implementation Nevertheless, various challenges of implementing AI in glaucoma exist, according to Prof. Leopold Schmetterer from the Singapore Eye Research Institute. These include dataset shift, accidental fitting of confounders, unintended discriminatory bias, and generalization to new populations. There are also logistical difficulties in implementation, as well as sociocultural changes and patient perception that need to be addressed. “In terms of real world challenges, we have a significant number of nongradable images, depending on the fundus camera used; training, skills and quality control on site; and study population, particularly on the degree of cataract. “There is a need for validating deep learning systems in prospective cohorts. This needs to be paralleled by human-computer interaction (HCI) studies to evaluate live data, including clinicians, in a contextual environment. Implementation is largely dependent on the health care system and there is no general approach that would fit all settings. And it’s important to collect post-marketing performance data to

really understand the benefits and problems of such systems,” he advised. Meanwhile, Dr. Fei Li from the Zhongshan Ophthalmic Center, China, noted that glaucoma diagnosis relies on multi-imaging data, including fundus photos, OCT scans and visual fields. “An ideal algorithm diagnosis system for glaucoma should be able to evaluate different images and data, and at the same time combine the features of the data. We hope to strengthen the algorithms with more functions, such as data transfer, prediction of progression and enhancement of the interpretability of the algorithms,” he said.

Starting an AI project Dr. Daniel Ting, head of AI and digital innovation of the Singapore National Eye Centre, noted that the application of AI in ophthalmology is limitless. “The Internet of Things (IoT) creates a highly interconnected digital ecosystem, enabling real data collection at scale, AI and deep learning training, risk modelling and outcomes prediction. This can be further encrypted by blockchain technology to ensure data privacy and security,” he said.

He also remarked that AI can help physicians “see” what can’t be seen on fundus photographs and OCT images, such as cardiovascular risk factors and age. Sharing tips on starting an AI project, he said that the first thing is to ask the right questions. This includes knowing the market size, how accessible it is, reviewing enough literature to know what is going on in the market, and what is the value-add of AI. The second thing to do is to identify the right data. “Can we access the data in a rightful manner? How can we extract them? What is the size, type (numerical values, text, image or gene), diversity, or phenotype of the data that we have? “Third, you need to identify the right partner, which includes the clinical and technical teams. Fourth is to understand the right concepts. This involves designing an excellent clinical and digital operational flow, identifying the appropriate machine learning or deep learning techniques, determining the appropriate operating threshold, validating the AI algorithm using a robust statistical analysis method and listing down the limitations/caveats of the AI algorithm. “Last but not least, is the right enabler (ecosystem). This includes the implementation of the AI algorithm, evaluation of the outcome (i.e., clinical, health economics, patients’ and users’ experience), and whether there’s commercial potential for it,” he concluded.

Editor’s Note: The 5th Annual Asia-Pacific Glaucoma Congress (APGC 2021) was held virtually from June 4 to 8, 2021. Reporting for this story took place during the event.

Could AI be an ophthalmologist’s partner in glaucoma management and diagnosis?

September 2021

GLAUCOMA HOT TOPICS

New Insights into an Older Operation Trabeculectomy Complications

rabeculectomy is no “spring chicken.” Indeed, the procedure has been used since the 1960s, making it a “dinosaur” — albeit an effective, IOP-lowering one — compared to newer technologies and techniques, like MIGS (minimally invasive glaucoma surgery). The fact that it’s still regularly performed attests to its efficacy; however, it can be a challenging procedure and as such, can result in a myriad of intra- and postoperative complications. And although it’s still the most commonly used glaucoma surgery, a 2015 clinical study* said: “Trabeculectomy is a surgical procedure associated with numerous complications, so much so that the follow-up and the management of the aforementioned complications are

by Brooke Herron

sometimes more laborious than the surgery itself.” Ouchie, indeed. Thankfully, there is a worldwide network of experienced ophthalmologists and glaucoma specialists dedicated to enhancing knowledge and sharing their skills when it comes to preventing and management of complications following trabeculectomy. At the recent World Glaucoma e-Congress (WGC 2021), some of these renowned experts shared their insights and best practices.

Intraoperative complication: Conjunctival leaks Conjunctival leaks can be split into intraoperative leaks, such as conjunctival buttonholes, and postoperative leaks, said Assoc. Prof.

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Shamira Perera, from Singapore National Eye Centre. They are often caused by poor visualization or by the inappropriate use of instruments (i.e., toothed forceps). “Close inspection and careful handling of the tissues are essential to minimize extension of the holes that are formed and it’s important to close these in layers, first utilizing Tenon’s and then conjunctiva,” explained Assoc. Prof. Perera. “I prefer to use a crossstitch technique, with a 10-0 nylon. Unfortunately, once this is done, it can lead to some scarring at that point,” he added. Assoc. Prof. Perera also explained that occasionally, there can also be leakage at the limbus and this can be difficult to avoid — but it can be done

by careful adjustment of tension in the purse-string sutures … and this is bolstered by a limbal mattress suture. “The point of the mattress suture is to provide complete, conjunctival watertight closure and this is important to maintain the posterior drainage of fluid.” He then presented a study he coauthored which found that bleb leaks were quite uncommon in both trabeculectomy and phacotrabeculectomy. “That didn’t change whether the original disease was POAG (primary open-angle glaucoma) or PACG (primary angle-closure glaucoma),” continued Assoc. Prof. Perera, adding that they remained at around under 1%. “Bleb leaks are important postoperatively because they can be associated with bleb infection and eyes with bleb infection are 26x more likely to have a leak at the time of infection,” he continued, adding that importantly, 4% of patients develop a bleb-related complication (e.g., bleb leaks, blebitis or bleb-related endophthalmitis). “Of course, prevention is better than the cure. What we used to do wrong in the olden times was a focal treatment with MMC and the inability to reappose Tenon’s,” said Assoc. Prof. Perera. “Nowadays, this is done better with a wider extension of MMC injection or use by sponges, this can limit these types of conjunctival leaks.”

Blebs, blebs and more blebs The success of trabeculectomy depends on the direct drainage of aqueous humor into the conjunctival filtering bleb — but if that drainage pathway is obstructed bleb failure occurs — which results in postoperative IOP elevation, shared Dr. Masaru Inatani from the University of Fukui (Japan). During his presentation, Dr. Masaru detailed how to manage a dysfunctional bleb, which covered bleb needling (and how to do it), reoperation and other tips. “When I perform bleb needling, I prefer an avascular bleb because I can see the scleral flap and avoid the risk of bleeding and re-obstruction. On the other hand, if the bleb is thick and vascular, I do not choose bleb needling;

I recommend re-operation with tube shunt surgery, using the Baerveldt implant,” he shared, adding that he recommends the same operation if the scleral flap is invisible. Bleb dysesthesia is an uncommon complication of glaucoma filtration surgery where a well-functioning but large filtering bleb with adequate IOP control causes ocular discomfort due to the effect of interrupted tear film distribution over the bleb and cornea, explained Dr. Tomas Grippo, Grippo Glaucoma & Cataract Center (Argentina). Its pathophysiology isn’t fully elucidated but he described two potential mechanisms: a hypocellular tissue response (probably related to the use of antimetabolites) create an avascular bleb that reaches a larger size, and connective tissue hypertrophy caused by an extensive scarring reaction in a susceptible eye. He continued that conservative management usually only helps in mild cases: “It is an uncommon complication that very likely needs surgery due to failure of medical treatment … and aggressive surgical techniques removing bleb tissue may be less effective in terms of subsequent IOP control. Meanwhile, techniques that preserve bleb conjunctiva show the possibility of excellent success in correcting the dysesthesia, while preserving the filtering function.” Bleb-related infections (BRI) are another complication that can have sight-threatening complications, shared Dr. Catherine Liu, from the National Yang-Ming University School of Medicine (Taipei, Taiwan). She said that it’s crucial to be alert of the danger in eyes with a history of trabeculectomy and an immediate workup and prompt and intensive treatment is required.

Other complications Hypotony occurs when IOP drops to less than 5-6 mmHg, shared Dr. Julian Garcia Feijoo, from the Hospital Clinico San Carlos (Madrid, Spain). “However, this is a definition based on numbers and it’s very important to consider the clinical relevance of the patient’s low IOP … it’s also important to differentiate between early and late

hypotony,” he explained. Preoperatively, he said to remember to consider the risk factors for the patient. “During surgery, be very careful and gentle and check the wound,” he shared, adding to use extra care in cases of high myopia, angle-closure with a shallow anterior chamber (AC) or high IOP. “If you are not completely happy this is the best moment to act — so don’t wait.” “The aim is to avoid complications that could impact the long-term vision of the patient. Experience will help you decide in which cases you can start with conservative treatment and when patients need aggressive treatment from the beginning,” he concluded. Another issue is malignant glaucoma, which has been described as a secondary angle-closure glaucoma with a posterior pushing mechanism and usually occurs after incisional surgery or after a laser procedure, said Dr. Jody Piltz-Seymour, from the University of Pennsylvania (USA). Thankfully, she said it’s uncommon and “the key to recognizing malignant glaucoma is the central shallowing of the anterior chamber from the forward displacement of the lens iris diaphragm.” She concluded: “Treatment requires a unicameral eye with communication between the anterior chamber and vitreous cavity.”

* Ramona B, Monica P, Paul-Eduard S, Speranta S, Calin-Petru T. Intraoperative and postoperative complications in trabeculectomy, Clinical study. Rom J Ophthalmol. 2015; 59(4): 243–247.

September 2021

GLAUCOMA HOT TOPICS

Diagnosing Glaucoma with AI and Detecting Progression by Tan Sher Lynn

xperts shared interesting insights into glaucoma progression during the World Glaucoma Association Symposium at the 5th Asia-Pacific Glaucoma Congress.

Compensation technology and digital staining Dr. Michael Girard, an associate professor at the Duke-NUS Medical School, noted that glaucoma is a biomechanical disorder. Common tests used to diagnose glaucoma and predict its progression include tonometry, ophthalmoscopy, gonioscopy, perimetry, pachymetry and optical coherence tomography (OCT). “But none of these tools take into account the physical phenomena of glaucoma. In OCT, a considerable amount of information is left unexplored.

to remove artefacts and improve deep tissue visibility (referring to this as compensation technology). Using this technology, and with collaboration with other researchers, more than 50 papers have been published that show the identification of a plethora of structural parameters which have strong diagnosis power in glaucoma.

and digital staining, we can have comprehensive structural analysis which allows us to diagnose glaucoma easily and with good accuracy from a single scan of the optic nerve,” he said.

“AI and deep learning also help to remove noise and shadows in OCT images. Using AI, you can interpret an OCT image and know the location of collagen, cells, connective tissue, blood vessels, etc. This can be done across multiple machines such as the Spectralis, Cirrus and Atlantis,” he said.

Meanwhile, Dr. Monisha Nongpiur, an associate professor at Singapore Eye Research Institute, noted that the visual field (VF) is an important marker for early detection of glaucoma.

Dr. Girard and his team have worked over the years to develop algorithms

They also created 3D digital staining technology, which helps physicians to understand and visualize 3D structures in the eye, and obtain access to various structural parameters of the optic nerve easily. “With image restoration

| September 2021

Visual field as marker of progression

“Glaucoma progression can be observed by looking at changes in the optic disc or VF. Visual field progression can be evaluated clinically, which involves looking at sequential charts for new defects, deepening or expansion of existing defects, or generalized depression. Another approach is change analysis, which is event-based analysis or trend-based analysis,” she said.

“Event analysis detects the changes in the threshold sensitivity at a particular test location. Trend analysis on the other hand, quantifies the rate of progression. It is measured by performing linear regression analysis of global indices or individual test points. The advantages and disadvantages of the two approaches complement each other, and as such, can be used together to guide the assessment of visual fields clinically for an early and accurate detection of progression.” According to her, location of VF progression also affects different functional performance and hence the patient’s quality of life. As such, it is important to pay attention to the damaged areas of the visual field, not just doing global analyses. Her study on the spatial distribution of VF damage in primary angle-closure glaucoma (PACG)1 revealed that the superior hemifield is affected more severely. “Damage is relatively more in the nasal region, followed by the arcuate and finally the central regions. Our study shows more peripheral involvement with relative preservation of the central area in PACG and this differs from what we know in normal tension glaucoma (NTG) where VF defects are closer to fixation,” she said, adding that a modulated treatment is important to slow down disease progression, and the rate of progression and age should be considered as well.

Contrast sensitivity for progression detection

Government Medical College and Hospital, Chandigarh, India, shared her thoughts on contrast sensitivity for detecting progression and said that a patient can have impaired contrast sensitivity (CS) despite having good visual acuity. “Changes in CS have been detected prior to visible damage to retinal nerve fiber layer (RNFL), or defects shown on the visual field printout. As such, assessing monocular CS might be more useful in monitoring the progression of functional visual loss than testing VF,” she said. Dr. Ichhpujani and her colleagues did an assessment of CS using the Spaeth Richman Contrast Sensitivity Test (SPARCS) and Pelli Robson Chart Test (PR)2 and found that SPARCS has the potential to differentiate between different grades of glaucoma patients and healthy controls better than the PR test. “Dr. Waisbourd recently used the CS to monitor VF progression3 and found that patients with rapid VF progression had significant decrease in CS, as detected by SPARCS but not by PR. This highlights the need for both central and peripheral CS assessment when looking for progression in patients. The researchers also found that CS in the left upper area of vision for both eyes correlated most strongly with the thickness of the inferior quadrant of the RNFL. These fibers project to the temporal portion of the right occipital lobe, implying a potential center for contrast perception in this area. So, CS can also be used along with OCT to notice worsening at an early stage,” she said.

Dr. Ichhpujani and her colleagues followed-up with a few patients who had moderate to advanced glaucoma for about two years using SPARCS and found that correlations between SPARCS and mean deviation (MD) as well as pattern standard deviation (PSD) were nonlinear.4 “SPARCS scores correlated better with each other than MD and PSD, indicating robustness of CS in assessing damage,” she noted. “In conclusion, I would like to say that different CS tests exist, with no clear consensus on which method is optimal. But at least we should start checking CS as regularly as we do with VF and OCT. Giving extra focus on CS of patients with advanced glaucoma by checking both central and peripheral CS would definitely provide additional insights into functional loss or progression,” she advised.

REFERENCES: 1.

Verma S, Nongpiur ME, Atalay E, et al. Visual Field Progression in Patients with Primary Angle-Closure Glaucoma Using Pointwise Linear Regression Analysis. Ophthalmology. 2017;124(7):1065-1071.

Thakur S, Ichhpujani P, Kumar S, et al. Assessment of contrast sensitivity by Spaeth Richman Contrast Sensitivity Test and Pelli Robson Chart Test in patients with varying severity of glaucoma. Eye (Lond). 2018; 32(8):1392-1400.

Waisbourd M, Sanvicente CT, Coleman HM, et al. Vision-related Performance and Quality of Life of Patients With Rapid Glaucoma Progression. J Glaucoma. 2019;28(3):216-222.

Ichhpujani P, Singh T, Thakur S, et al. Assessing glaucoma deterioration using Spaeth/Richman contrast sensitivity test. Ther Adv Ophthalmol. 2020;12:2515841420977412.

Dr. Parul Ichhpujani from the

Editor’s Note: The 5th Annual Asia-Pacific Glaucoma Congress (APGC 2021) was held virtually from June 4 to 8, 2021. Reporting for this story took place during the event.

Each step brings us closer to understanding glaucoma and thus, improving patient outcomes.

September 2021

GLAUCOMA HOT TOPICS

On Shunts and Gene the Right Therapy Finding Therapy Matters by April Ingram

t the 5th Asia-Pacific Glaucoma Congress, Dr. Seng Kheong Fang from the International Specialists Eye Centre — ISEC (Malaysia) and Prof. Clement Tham from the Chinese University of Hong Kong (CUHK), cochaired the virtual plenary session. Here are some of the highlights…

On microshunts: Development and results The first of three expert speakers was Dr. Paul Palmberg, MD, PhD, professor of ophthalmology at the Bascom Palmer Eye Institute and University of Miami School of Medicine in the United States. Dr. Palmberg began by sharing how the current weapons in the glaucoma treatment arsenal can cause collateral damage and require considerable training, equipment and material costs — all of which highlight the need for the microshunt's development. He also discussed why microshunts may have advantages over MIGS. For example, MIGS typically yield IOPs in the upper teens — which may not optimize visual fields — and that they usually aren’t able to eliminate the need for ongoing medication use. The concept of microshunts continued with Dr. Francisco Fantes (Miami, Florida, USA) who asked if a small diameter tube could be substituted for the scleral flap in filtering surgery. It’s just plumbing, right? Dr. Palmberg explained how tube dimensions and surface effects deliver desired pressure gradients, noting that the material the tubes are made from are also key.

dosing (0.4 mg/ml for 3 minutes) can also improve IOP outcomes. Importantly, in the U.S. FDA randomized trial comparing InnFocus MicroShuntMMC to trabeculectomyMMC, also showed less hypotony, fewer bleb leaks and lens changes in the InnFocus eyes. In addition to the MMC dosing, Dr. Palmberg highlighted other keys to success, such as placing the tip of the microshunts under Tenon’s capsule to avoid formation of a fibrotic cap (and blocking the tube); placement of the microshunts at 10:30 or 1:30, 45° from the vertical, because this is where Tenon’s capsule is thinner; and lastly after priming, don’t forget to test equilibrium IOP, and avoid pinching the tube by the fins.

Results from an early study show an immediate reduction in IOP to ~11 mmHg that was maintained for 4 years; he then shared how mitomycin C (MMC)

Dr. Palmberg also shared study results confirming why sustained IOP reduction matters and is correlated with visual field improvements, adding how microshunts are a more ideal treatment choice for patients with higher risk of hypotony, leaks or cataract progression, and also those who are losing ganglion cells more rapidly than as anticipated with normal aging.

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Wait, how would we know about the ganglion cells? Excitingly, on the horizon there is a test for detecting apoptosing retinal cells from Dr. Maria Carderio. Finally, Dr. Palmberg summarized the advancements being made in glaucoma care, leading to individualized treatment plans.

On aqueous shunts The second expert speaker was Dr. Keith Barton, consultant ophthalmologist and director of Glaucoma Service at Moorfields Eye Hospital in London, United Kingdom. His talk was entitled, The Role of Aqueous Shunts in the Era of MIGS. Dr. Barton began by reviewing the four broad groups of MIGS,

low enough. Although there have been claims in the Advanced Glaucoma Intervention Study (AGIS) that any IOP <18 mmHg prevented progression, Dr. Barton refutes this, noting that the study did not show that. He explained that the role of primary trabeculectomy is for those at a high risk of visual loss who do not have other failure risk factors.

therapies and their actions. He explained the mechanism of Rhokinase inhibitors allow for the opening of pathways and improved outflow, which effectively lowers IOP. Next, Dr. Kaufman shared how nitric oxide (NO) donation is changing glaucoma treatment, by increasing outflow facility (and that NO also inhibits the Rho pathway).

He continued that tubes work in almost anyone — except low-risk primary cases, where the trabeculectomies work well … and it all depends on which tubes you use. He also reviewed the data from the Primary Tube vs. Trabeculectomy Study (PTVT) showed no significant difference in cumulative rate of surgical failure after 3 years; however, the probability of failure at 1 year was significantly higher for those that received tubes.

Further, he reviewed mechanoreception of the trabecular meshwork, specifically that it is a responsive, self-aware, selfregulating tissue/organ. Dr. Kaufman shared data from the ARTEMIS studies of the bimatoprost SR implant, highlighting that after 3 treatments, >80% remained treatment free for at least 1 year.

In addition, there was a lower IOP and less medications in the trabeculectomy group after 3 years, which was significant. The 5-year outcomes will be presented at the 2021 AAO meeting.

Schlemm’s canal, subconjunctival drainage, suprachoroidal and cryoballoon (CB) ablation, and the associated procedures. He shared highlights from the International Glaucoma Surgical Registry (IGSR) and how the data is particularly useful in comparing different types of procedures. Dr. Barton noted that even with the advancements of safe, less invasive procedures, trabeculectomies and drainage devices remain the most common. Thus, he asked: What is the role of the tube? Dr. Barton reviewed data from some prominent studies showing that although the microshunt and MIGS procedures were efficacious and less invasive, their efficacy in reducing IOP was of lesser degree than with trabeculectomy, which may be influential in the management of more advanced patients. He acknowledged that there is debate about what a target IOP is, and whether a lower IOP is

Dr. Barton added that primary tubes are not usually indicated in POAG with no other failure risk factors, unless followup is likely challenging and postop manipulation is likely impossible. But more importantly, tubes can be used in secondary glaucomas and other primary situations when a trabeculectomy has no hope of success. He shared case videos demonstrating different tube procedures and potential issues, providing helpful pearls and surgical tips, noting that with increasing MIGS use, and declining trabeculectomy, more patients will likely require tubes.

Next, Dr. Kaufman explained how MIGS technology is being used in gene therapy, so not to take something out, but rather as delivery systems. Gene therapy for glaucoma will involve a viral vector that will transfer a gene to the target cell to either block the Rho pathway, or a gene that disconnects actin from myosin, which will result in relaxation of the cells and cell adhesion to the extracellular matrix. Another device reviewed by Dr. Kaufman by encapsulated cell therapy (ECT), in which cells continuously produce the therapeutic protein which diffuses out of the implant at the target site. Dr. Kaufman summarized the strategies and targets for gene therapy, as well as acknowledging the constraints and challenges that remain in the development of these exciting therapies.

Gene therapy in glaucoma The final speaker of the session was Paul Kaufman, MD, the Ernst H. Bárány professor of ocular pharmacology and chair-emeritus of the Department of Ophthalmology & Visual Sciences at the University of Wisconsin School of Medicine and Public Health, in Madison, Wisconsin, United States. He presented Updates on Medical and Gene Therapy for Glaucoma.

Editor’s Note: The 5th Annual Asia-Pacific Glaucoma Congress (APGC 2021) was held virtually on June 4 to 8, 2021. Reporting for this story took place during the event.

Dr. Kaufman began with a brief historical summary of the medical

September 2021

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