CAKE POST (WGC 2021 Edition) - ISSUE 3

and on the Horizon

for New Drugs Treatments

by Brooke Herron

ew drugs and treatment paradigms are emerging in the continued search for better outcomes for glaucoma patients. These include advances in topical medications and drug delivery, as well as the potential for neuroregeneration and non-IOP lowering therapies.

On Day 3 of the World Glaucoma e-Congress (WGC 2021), these important innovations were covered in a session co-chaired by Drs. Tina Wong (Singapore) and Arthur Sit (USA).

New topical medications

Unmet needs exist for drugs that are safer, with more potent IOP-lowering effect, or a novel mechanism of action, said Prof. Makoto Aihara, from the University of Tokyo (Japan). During his presentation, he covered three drugs that may demonstrate this potential: 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. “This is a drug first approved in Japan, Korea and Taiwan,” shared Prof. Aihara, adding that it has a novel mechanism of action that differs from FP receptor agonists. “OMDI increases aqueous humor outflow via both uveoscleral and trabecular pathways,” he continued.

In the RENGE study, stable IOP was achieved over 52 weeks, with enhanced efficacy in combination with timolol. “In the low IOP

Ngroups, OMDI can reduce baseline IOP by 19.5% (-3.66 mmHg); in the high baseline groups OMDI can reduce IOP by 23.4% (-5.64 mmHg); and in the high baseline group with OMDI and timolol, the IOP reduction was 36.1% (-8.36 mmHg),” he shared. Importantly, OMDI has no cosmetic side effects like DUES and has the benefit to recover PAPS after switching from FP agonists without changing IOP. He said that this novel drug can help maintain not only quality of life, but also quality of vision.

Next, he covered two kinds of ROCK inhibitors: ripasudil 0.4% (Glanatec, Kowa Pharmaceutical, Japan) and netarsudil 0.02% (Rhopressa, Santen). “ROCK inhibitors directly improve trabecular outflow,” he shared, adding that netarsudil also has a function to reduce aqueous production. “ROCK inhibitors may be useful for the treatment of various ocular diseases,” said Dr. Aihara.

He continued: “In the future, we will have various types of combined drugs … these could be useful to keep patients adherent.”

Advances and challenges in drug delivery

“It’s an exciting time with SLT and laser trabeculotomy, MIGS and now drug delivery, rounding out our toolbox with the hope of dealing with issues of compliance,” began Dr. Paul Singh, from the Eye Centers of Racine and Kenosha (Wisconsin, USA).

There are a lot of products currently under investigation: some biodegradable and nonbiodegradable intracameral implants, and some are external as well, he shared. Dr. Singh then shared his experience with bimatoprost SR (DURYSTA, Allergan, an AbbVie company, Dublin, Ireland) which is approved in the U.S. and is a sustainedreleased, 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.

“Anybody who has some compliance issues is a good candidate,” said Dr. Singh.

He also mentioned several other new products, including OTX-TIC (travoprost implant; Ocular Therapeutix, Massachusetts, USA) for intracameral injection which is currently in phase 2 trials. “Envisia Therapeutics (North Carolina, USA) also has their product, which is a travoprost dissolvable implant and Glaukos (California, USA) has their iDose,” he shared. Dr. Singh also covered punctal plugs, a device that is placed under the eyelid Evolute (Mati Therapeutics, Austin Texas), TODDD (Amorphex, Massachusetts, USA) and an external (bimatoprost) ring from Allergan (an AbbVie company, Dublin, Ireland).

Is neuro-regeneration possible?

Rather than focusing on IOP, I’m particularly focused on the other side, which is retinal ganglion (RGC) cells and their axons that degenerate in glaucoma, said Dr. Jeffrey Goldberg (USA) from the Byers Eye Institute at Stanford University (California, USA).

“Our fundamental problem in the irreversibility of vision loss is that there’s no RGC regeneration after

optic nerve injury,” he explained. “The short time period and space between injury is critical … and 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.”

He said this is where we have an unmet need in glaucoma, and that’s in better treatments “beyond IOP.”

Dr. Goldberg continued that there is a new emerging trial design whereby sick (but not dead RCGs) can be protected and their function improved: “To get there, we want to incorporate improved patient selection and trial design with new exploratory biomarkers.”

And there is some real-world data on neuroprotection in glaucoma. “First, the United Kingdom Glaucoma Treatment Study (UK-GTS) showed that eye pressure lowering with latanoprost does indeed protect patients from visual field (VF) progression compared with placebo,” he said. “Another good example of trial design is the Lowtension Glaucoma Treatment Study (LoGTS) where brimonidine was directly compared to timolol with eye pressure lowering, but instead VF was the outcome and showed that brimonidine conferred visual field protection.”

In conclusion, Dr. Goldberg said that “neurotrophic factors, rho-kinase inhibition and other strong candidates are ready for neuroprotection testing in glaucoma.”

Non-IOP lowering treatments for glaucoma

While 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.

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.

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.

Eye Stent Amazed The Malaysian Experience with MIGS

by Joanna Lee

The iStent (Glaukos, California, USA) has been around since the device’s first generation FDA approval in 2012. It has high safety and suitability for patients with IOP in the low twenties and who are on multiple medications. Now that this particular MIGS device has found its way across the world, we’re taking a peek at how Malaysian doctors are using it. On Day 3 of the World Glaucoma e-Congress (WGC 2021), three experts from the Malaysian Glaucoma Society shared their insights on MIGS procedures, and namely, on devices like the iStent Inject (Glaukos, California, USA) and XEN Gel Stent (Allergan, an AbbVie company, Dublin, Ireland).

For JOAG

Assoc. Prof. Dr. Norshamsiah Md Din from the National University of Malaysia touched on her experience using iStent implants for both juvenile open angle glaucoma (JOAG) and Posner Schlossman Syndrome (PSS) patients. One case study presented was a 33-yearold patient who was diagnosed with JOAG in 2015. The iStent had helped lower his IOP to the mid-teens until late 2020, when a new iStent was inserted in both eyes in January 2021.

Unfortunately, the vision was lost in the phakic patient’s left eye. She cautioned that one has to be careful to protect the patient from lens touch in a short and quick procedure. She said the efficacy of iStent in PSS is unclear, even though it seemed promising, as her patient stopped developing complications (side effects from preservatives) before the iStent. “Whenever you insert the iStent, always under-promise but over-deliver,” Dr. Norshamsiah said.

More on MIGS

Next, Kuala Lumpur Hospital glaucoma fellow Dr. Tan Li Mun spoke about the soft and flexible porcinederived collagen gelatin XEN Gel Stent. While it is not usually used with angle-closure glaucoma or on eyes with inflammation, she brought up the case study of a 40-year-old male patient with iridocorneal endothelial (ICE) syndrome who had presented with IOP of 40 mmHg and who had fluctuating IOP on four anti-glaucoma medications and oral acetazolamide.

His vision ranged between 6/9 to 6/24. They did an implant of XEN Gel Stent (ab externo) and postoperatively, the patient had a reduced IOP of 10 mmHg with a deep anterior chamber. He was given subconjunctival 5 FU (5 gm/0.1 ml) at 2, 4 and 6 weeks after the procedure. The outcome at 6 months was a VA of 6/9 with an IOP of 15 mmHg.

Promising XEN outcomes

In the second case, Kuala Lumpur Hospital glaucoma specialist Dr. Roslina Muji discussed the management of glaucoma in uveitis. Deeming it a challenge — especially with young patients and involving complex medication and intraocular scarring — the use of XEN Gel Stent implant for

uveitic glaucoma offers a safe and effective option (apart from a short surgical time and minimal anterior segment disturbance). It also has a low incidence of post-op hypotony, she said. When inserting the XEN Gel Stent, her tips were: “Choose an area not affected by phaco wound (preplan the XEN site); avoid the PAS (peripheral anterior synechiae); and reform AC with viscoelastic before inserting the gel stent.

If combined with phacoemulsification, XEN seems to be effective in lowering IOP for 12 months, she said, citing a 2019 study combining XEN implantation and phacoemulsification in Chinese eyes.

Her take home message was that the XEN Gel Stent has shown promising outcomes. The IOP lowering effects are similar to traditional incisional surgery such as trabeculectomy or tube shunt surgery, but with fewer risks, she said. However, physician comfort and individual surgical preference may dictate which method would be used in practice.

Glaucoma Challenges from Diagnosis to Therapy

Are we right at the crossroad?

Myopia and glaucoma are increasing worldwide; however, East Asia is further down this particular path than nearly anywhere else. In this session on Day 3 of the World Glaucoma e-Congress (WGC 2021), four specialists from Taiwan provide their knowledge and experience of treating glaucoma that’s helpful and informative for everyone, no matter if you work in Buenos Aires, Paris or Beijing.

OCT artifacts and their influence

Dr. Linda Yi-Chieh Poon, from Kaohsiung Chang Gung Memorial Hospital (Taiwan) gave a presentation about the prevalence of optical coherence tomography (OCT) artifacts in high myopia and its influence on glaucoma diagnosis.

Taiwan has a relatively high prevalence of high myopic patients who are at risk of glaucoma, and OCT is indispensable in its diagnosis. However, artifacts in OCT scans occur in up to 46% of glaucoma patients receiving circumpapillary retinal nerve fiber layer (RNFL) scans, leading to erroneous measurements of RNFL thickness on final printout.

In a study of 220 patients, they discovered that glaucoma and myopia are predictors of OCT artifacts and the likelihood of inaccurate RNFL thickness measurement increases along with higher myopia and glaucoma severity. They concluded that careful inspection of RNFL segmentations and OCT images for the individual patient, instead of relying on machine generated RNFL thickness, is the most important thing to avoid false clinical interpretation.

Risk factors in myopic POAG

Dr. Yi-Chun Chen from the Cathay General Hospital (Taiwan) spoke about

the risk factors for visual field (VF) progression in myopic primary open-angle glaucoma (POAG).

by Chris Higginson

Dr. Chen felt that the risk factors for central VF progression in myopic eyes with POAG have not been well investigated, so her team investigated the factors associated with central VF progression in myopic eyes with POAG.

Her conclusion was that the presence of disc hemorrhage (DH) is associated with faster progression rate of global and central VF. Also, patients with a smaller degree of optic disc rotation were associated with a faster progression rate of inferior-central VF. In addition, eyes with inferior optic disc rotation associated with superior VF defect had a faster progression rate in the superiorperipheral VF. In her opinion, because central VF is strongly related to quality of life, the central VF of myopic POAG patients should be monitored more carefully if there is no significant optic disc rotation and in the presence of DH.

Managing advanced glaucoma

The management of patients with advanced glaucoma was presented by Dr. Chien-Chia Su from National Taiwan University Hospital.

In Dr. Su’s experience, in advanced glaucoma, circumpapillary capillary density and macular vessel density may provide a better estimation of glaucoma

progression than current structural GPA (guided progression analysis), such as RNFL and GCC (ganglion cell complex) due to the variability in visual acuity. She went on to say that macular damage is associated with a decline of central visual function as well as an increased glare in advanced glaucoma patients. However, macular vessel density and the 10-2 VF can be excellent tools for structure function assessment.

Finally, visual rehabilitation not only enhances the quality of life, but is essential for functional improvement in advanced glaucoma patients. In Taiwan, a good connection between assistive device centers — which can provide tools and technology to help patients function well — and clinicians, may strengthen social welfare and improve quality of life of patients suffering from poor vision.

XEN in East Asia

Dr. Mei-Ju Chen, from the Taipei Veterans General Hospital (Taiwan) gave a presentation about the management, safety of and efficacy of XEN Gel Stent (Allergan, an AbbVie company, Dublin, Ireland) for open-angle glaucoma in East Asian eyes.

The XEN is a 6 mm gel implant that can provide communication between the anterior chamber and subconjunctival space and is used in cases of openangle glaucoma. She advised that, “XEN is less invasive than trabeculectomy; however, once the XEN is in, it is vital to do a gonioscopy in the first week to see if there is any steroid response, if the bleb is flat, or there is an internal ostium occlusion.”

In a study of XEN implants on East Asian eyes, Dr. Chen concluded that it effectively reduced both IOP and medication levels, with no serious complications. However, almost half of the eyes required some form of wound modification post-op.

Sri Lanka Symposium Highlights Need for More Ophthalmologists

by Andrew Sweeney

One of the great things about big ophthalmology conferences — like the World Glaucoma e-Congress (WGC 2021) — is that we get an opportunity to learn in detail about how clinicians operate in different countries. This year has provided a remarkable number of symposiums focusing on the activity of glaucoma associations around the world. We’ve learned from doctors in Japan, South Korea, Sudan and others, and we’ve come out better for it.

Day 3 offered another country-focused symposium: Glaucoma Interest Group of the College of Ophthalmologists of Sri Lanka — Breakthroughs to Combat Dilemmas in Glaucoma Care in Sri Lanka. Yes, the WGC does seem to favor symposium names running on the longer side, but why not — and perhaps the greater the content, the longer the name. Here, experts covered a wide variety of issues pertaining to glaucoma in Sri Lanka, an island nation south of India with a population of just under 22 million.

92 ophthalmologists for 22 million people

A key speaker during the symposium was Dr. Dilruwani Aryasingha, a consultant

ophthalmologist at the Golden Key Eye and ENT Hospital (Colombo, Sri Lanka), who gave a general outline of ophthalmology in her country, along with the state of glaucoma treatment.

She reported on various shortcomings: there are only 45 eye units operating in Sri Lanka; laser for trabeculoplasty is unavailable; and only six units have imaging facilities. This is compounded by the fact that there are only 92 consultant ophthalmologists working on the island.

According to Dr. Aryasingha, the prevalence of glaucoma provides challenges — especially as many patients live in isolated, rural communities and are often economically disadvantaged. Among those aged 40 and over, 1.7% are blind and 2.1% are affected by glaucoma. And despite disease severity, many patients are non-compliant due to issues like cost of treatment, errors in drop installation, and lack of available facilities. Regarding treatment, the first choice has shifted from beta-blockers to prostaglandin analogs, which only became available in 2016.

Next, Dr. Lalitha Senarath, chairperson of the College of Ophthalmologists of

Sri Lanka, discussed the specificities of glaucoma and provided in-depth knowledge on some of the most common varieties. Dr. Senarath said neovascular glaucoma as wellrepresented in Sri Lankan patients, which is frequently caused by retinal vein occlusion, unattended proliferative diabetic retinopathy and chronic retinal detachment, among other reasons. Inflammatory glaucoma, characterized by an open-angle, is often encountered along with signs of acute anterior uveitis and high intraocular pressure (IOP).

Not your “garden variety” glaucoma

Postoperative glaucoma is also a major issue; this is frequently encountered in patients who underwent a surgical procedure at the hands of a less-thanexperienced clinician. This highlights the need for more highly trained ophthalmologists in a country with a very high patient-to-doctor ratio, especially in rural regions. Finally, traumatic glaucoma is also well-represented among the patient cohort, which may occur for a variety of reasons including inflammation due to iridocyclitis, intraocular hemorrhage or subluxated lenses.

Make sure you watch the rest of the symposium to learn more about Sri Lankan ophthalmology. In the meantime, we hope that more resources can be allocated to the country’s health system to address the shortage of trained staff. This applies to resources and medications too, because with more of those, perhaps access to treatment can be improved.

What’s the chance they’ve had access to glaucoma treatment?

uncommon complication that very likely needs surgery due to failure of medical treatment,” he said. “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.”

The final presenter was Dr. Catherine Liu, from the National Yang-Ming University School of Medicine (Taipei, Taiwan), who shared details on blebrelated infections (BRI). She said that “BRI may have visionthreatening consequences, so it’s crucial to be alert of the danger in eyes with history of trabeculectomy,” she explained, concluding that an immediate workup and prompt and intensive treatment is required.

Prevention and Management of Complications Following Trabeculectomy

by Brooke Herron

Other complications

Trabeculectomy is an old operation — but it’s a very effective one, began Dr. Franz Grehn (Germany), who co-chaired the session along with Dr. Eugenio Maul (Chile). “We can have success with this operation if we can manage and avoid complications.”

According to Dr. Maul, trabeculectomy will remain the cornerstone of glaucoma surgery, at least for the next few years. “Proper management in the postoperative period is what forges a glaucoma surgeon’s character,” said Dr. Maul.

So, what are some of the complications — and how are they best managed? This topic was explored in depth on Day 3 of the World Glaucoma e-Congress (WGC 2021).

Conjunctival leaks

Assoc. Prof. Shamira Perera, from Singapore National Eye Centre, said that conjunctival leaks can occur intraoperatively (e.g., conjunctival buttonholes) and occasionally, they can also occur at the limbus.

“In our series, we found that bleb leaks are quite uncommon in both trabeculectomy and phacotrabeculectomy, and didn’t change

whether the original disease was POAG or PACG,” shared Assoc. Prof. Perera, adding that they remained around 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.

Blebs, blebs and more blebs

In trabeculectomy, if the drainage pathway is obstructed, bleb failure occurs — which results in postoperative IOP elevation, shared Dr. Masaru Inatani from the University of Fukui (Japan). He then detailed how to manage a dysfunctional bleb, which covered bleb needling (and how to do it), reoperation and other tips. One takeaway? An avascular dysfunctional bleb is a good indication for bleb needling because the needle easily approaches the scleral flap. We recommend watching a replay of his talk for more on these key insights.

Bleb dysesthesia — including its definition, symptoms, risk factors, pathophysiology and therapeutic approaches — was covered by Dr. Tomas Grippo, Grippo Glaucoma & Cataract Center (Argentina). “It is an

Next, Dr. Julian Garcia Feijoo, from the Hospital Clinico San Carlos (Madrid, Spain) shared his experience treating hypotony and provided some useful tips.

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). She said that treatment requires a unicameral eye with communication between the AC and vitreous cavity.

Bench to Bedside

Reflections on Crossing the “Valley of Death”

by Chris Higginson

There are other ways to treat high IOP other than surgery or medicines that attack the problem directly. Neuroprotection, in whatever its form, helps to treat glaucoma by protecting the optical nerve and potentially finding a “back door” to glaucoma treatment. On Day 3 of the World Glaucoma e-Congress (WGC 2021), experts convened in a session dedicated to this topic.

Clinical neuroprotection trials

Dr. Robert Weinreb, from the University of California, San Diego (USA), spoke about the lessons and reflections from neuroprotection clinical trials. A number of trials, both clinical and pre-clinical, have already been done into glaucoma neuroprotection.

Pre-study planning, with detailed modelling and verification using real world data is important, as well as selecting appropriate endpoints whether it be VF, optical disc or something else. Study design is vital and researchers must consider several questions including: who are the target patients, how will they be recruited and where will the trials be performed? He says it’s also important to consider how researchers will monitor patient enrollment, and the need for reading centers and a post-trial analysis plan.

After examining all of the research done so far, both in clinical and preclinical, Dr. Weinreb believes glaucoma neuroprotection clinical trials can be done, both at a reasonable cost and with good numbers of patients. In conclusion, a neuroprotective drug for the treatment of glaucoma can and will be found, and will help to preserve the vision of countless individuals throughout the world.

Preclinical evidence for neuroprotection

Dr. Kathryn Bollinger from the Medical College of Georgia at Augusta University, (USA), gave a presentation on preclinical

evidence for neuroprotection.

Although we may think of neuroprotection as an intervention independent of intraocular pressure (IOP) reduction that prevents retinal ganglion cell (RGC) death, it is possible for a single therapeutic (such as telmisartan, among others) to have both IOP lowering properties as well as neuroprotective effects.

Multiple investigators continue to identify new mechanisms and targets for neuroprotection across classic neurodegenerative diseases, including glaucoma. Many of the recently identified therapeutic candidates for neuroprotection in glaucoma address or mitigate common features of classic neurodegenerative diseases including Alzheimer’s and Parkinson’s. This is because glaucoma bears hallmark features of these classic progressive neurodegenerative diseases with cellular and molecular changes that include mitochondrial dysfunction and neurotrophin withdrawal, among others.

In conclusion, very interesting preclinical evidence has been reported in support of several candidates for neuroprotection, but in many cases clinical trials of potential therapeutic strategies are

ongoing, so it’s an exciting time for the fields of neuroprotection and glaucoma.

Nicotinamide and RGCs

Assoc. Prof. Pete Williams from the St. Erik Eye hospital (Sweden) spoke about nicotinamide (NAM; a vitamin B3 analogue) – an emerging hope for lab patients.

NAD (nicotinamide adenine dinucleotide) is an important metabolite for energy production and cellular homeostasis that helps to keep RGCs alive. The precursor in its production is NAM, but the production decreases both with age and high IOP. So, in order to produce more NAD, Assoc. Prof. Williams gave patients doses of NAM in the hope it would produce more NAD and keep RGCs alive. The trials went well and they found that by restoring NAD, mitochondrial health was improved and RGCs were protected from degeneration. He believes that by targeting neuronal metabolic decline in this way may offer a safe, neuroprotective treatment for glaucoma and other age-related neurodegenerative conditions and ophthalmic degenerations.

RCTs in Sweden, Australia and Singapore are scheduled to enroll in 2021/22.

ROCK inhibitors

Prof. Hidenobu Tanihara, from Kumamoto University (Japan), spoke about ROCK (Rho Kinase) inhibitors — from bench side to bedside.

ROCK inhibitors cause significant IOP reduction by improving the conventional aqueous outflow pathway. In patients with POAG and ocular hypotension, clinical trials confirmed the IOP-lowering effects of ROCK inhibitors (such as ripasudil) although there was a high incidence of conjunctival hyperemia, which disappeared quickly.

He believes that steroid-induced glaucoma may be responsive to ROCK inhibitors because the steroid itself activates rho-ROCK signalling. His team’s clinical studies showed the efficacy and safety of ROCK inhibitors such as ripasudil, in patients with secondary, steroid-induced uveitis and exfoliation glaucomas.

Normal Tension Glaucoma

If it’s not the pressure, then what is it?

by Joanna Lee

They say diamonds are produced under pressure. So, amidst the hard pressed search for answers as to why normal tension glaucoma (NTG) happens, brilliant gems were discovered during a session on Day 3 of the World Glaucoma e-Congress (WGC 2021) which explored various perspectives from around the world regarding the causes.

Is it in your genes?

Dr. Janey Wiggs (USA) position was: “Blame it on your parents (and their genes)!” NTG seems to be more prevalent in Asians, she gave an example before explaining how NTG GWAS (genome-wide association studies) could find NTG in specific loci. Two genes, OPTN and TBK1 cause familial forms of early-onset NTG.

Surprisingly, NTG may also be associated with systemic neurodegenerative disease like Alzheimer’s disease. OPTN and TBK1 are also associated with amyotrophic lateral sclerosis (ALS) while Azheimer’s disease genes may contribute to POAG and in particular, NTG. So far, many GWAS loci identified thus far were involved in IOP, Dr. Wiggs said. A larger NTG GWAS and other studies to identify novel NTG genes are needed in order to better understand how genes contribute to disease.

Is it the ocular blood flow?

For Dr. Yukihiro Shiga, it’s all about the ocular blood flow. His argument was that “ocular blood flow assessment might help clinicians to predict the risk of visual function deterioration

in glaucoma.” In looking at how ocular blood flow is related to vision impairment, he and his colleagues are focusing on the model of the pericyte. As pericytes play a role in regulating blood supply, Dr. Shiga’s colleagues at DiPolo Lab (Quebec, Canada) have discovered its role in mediating capillary diameter regulation, thus, pericytes might be considered as a potential therapeutic target in glaucoma, he said.

Is it laminar biomechanics or the optic nerve?

Dr. Crawford Downs (USA) expounded on the support system (the lamina cribrosa) for the optic nerve head. According to him, laminar biomechanics are driven by IOP and cerebrospinal fluid pressure (CSFP) dynamics while blood flow is also thought to play a critical role in optic nerve head homeostasis.

“Laminar mechanical strains are a function of the translaminar pressure and the local structure and material properties of the laminar microstructure,” he said. Strains can be high, even at normal levels of IOP, and the response is eye-specific. IOP and CSFP could still be the primary drivers of glaucomatous axon damage, acting through eye-specific laminar biomechanics, even at ‘normal’ IOP levels.

Is it pressure from the other side?

The next presenter’s perspective is in

line with Dr. Down’s pointing to the lamina cribrosa. “It’s the pressure from the other side (CSF pressure)” was China’s Dr. Ningli Wang’s take on this, based on his presentation Prospective and Retrospective studies from Tongren and Duke, which demonstrates how trans-laminar cribrosa pressure difference (TLCPD) plays a role in NTG. He brought the audience through the various evolutions of studies involving the lamina cribrosa including showing a new therapy to rebalance the trans-laminar cribrosa pressure gradient.

It’s the eyeball pressure!?

Finally, Dr. Debbie Kamal puts the cause onto the very pressure of the eyeball itself. The UK-based doctor asserted that pressure lowering remains the only effective means of controlling progressive NTG, even when the baseline IOP is within the “normal” range.

“Most studies suggest that at least a 25%-30% reduction in IOP is necessary,” she said, adding that if the starting IOP is in the mid-teens this would be a therapeutic challenge. She demonstrated her point through her study (Jayaram et al., 2016)* which also showed how trabeculectomy is effective at lowering IOP by 25% or more.

As a follow- up study to this, Dr. Kamal’s colleagues at Moorfields Eye Hospital (London, United Kingdom) collected 10year data that also showed cumulative surgical success in lowering the IOP by 30% or more after trabeculectomy. Their findings were subsequently presented a few years ago at the American Academy of Ophthalmology (AAO) meeting, titled Long Term Trabeculectomy Outcomes in Normal Tension Glaucoma Patients.

* Jayaram H, Strouthidis NG, Kamal DS. Trabeculectomy for normal tension glaucoma: outcomes using the Moorfields Safer Surgery technique. Br J Ophthalmol. 2016;100(3):332-8.

Walking a Tightrope The Challenge of Diverging Opinions

by Brooke Herron

Debates are great — but in medicine, we need more than an expert opinion to determine the course of treatment. This is where randomized controlled trials (RCTs) come into play. Loaded topics — like to MIGS or not to MIGS and early versus late treatment — were some of the debates covered in a session from Glaucoma Organization of the Austrian Ophthalmological Society and Glaucoma Group of the Swiss Society of Ophthalmology, which was co-chaired by Drs. Gordana Sunaric-Megevand (Switzerland) and Anton Hommer (Austria).

The pros and cons of pro and con sessions

According to Prof. Leopold Schmetterer from the Singapore Eye Research Institute, there are certain takeaways we can obtain from pro-con debates. “We can discuss novel ideas for RCTs according to gaps in knowledge … and the question of how can we implement RCTs into clinical practice? And an important question is what is the difference between efficacy and effectiveness in a real world setting?”

These were interesting points to keep in mind as the session continued.

Early versus late onset treatment

Presenting on the pro side of early

treatment was Assoc. Prof. Gerhard Garhöfer from the Medical University of Vienna (Austria). He said that early changes in visual field (VF) already reflect considerable loss of ganglion cells and pronounced VF loss is associated with faster progression. He concluded: “Early treatment should be considered to provide lifetime preservation of visual function and quality of life.”

Arguing for late onset treatment was Dr. Marc Töteberg-Harms from University Hospital Zurich (Switzerland). He provided an example from a study on ocular hypertension (OHT): “If we treat OHT too early, we would unnecessarily treat a lot of patients which never develop glaucoma.”

In early to moderate glaucoma, he suggested treating as much as needed to achieve the target pressure, but not more. In regard to surgery, he said no matter which procedure you look at, the higher the IOP reduction you want to achieve, the higher the risk and the higher the complications will be.”

SLT as first line therapy or not?

Dr. Frances Meier-Gibbons from University Eye Clinic of Bern (Switzerland) said that in her opinion, subthreshold laser therapy (SLT) is a valuable first-line therapy for mild to moderate open-angle glaucoma and progressing OHT. She also recommends SLT for non-adherent patients with

ocular surface disease. “It offers IOP lowering similar to a beta blocker with few side effects,” she continued. “And the LiGHT trial shows that at 36 months an efficacy of 78.2% and lower costs than in the medication arm.”

On the con side was Dr. Anton Hommer from the Medical University of Vienna, who noted that he does perform SLT. But what does he see as disadvantages? “The LiGHT study does not provide superiority of SLT considering efficacy, side effects or cost. It’s not a lifelong solution and the IOP level for success was 20% laser versus 30% medications — so you should compare it in a better way,” he concluded.

MIGS we distrust versus MIGS we trust

MIGS (minimally invasive glaucoma surgery) is one of the biggest buzzwords in glaucoma — and we don’t have room here to cover the valuable discussion provided by Dr. Gordana Sunaric-Megevand, from Eye Centre Florissant (Geneva, Switzerland) and Prof. Dr. Clemens Vass, from the Medical University of Vienna (Austria). Instead, we’ll leave you with a few main takeaways, so make sure to catch the replay later!

According to Dr. Sunaric-Megevand, there are eight unsolved problems with MIGS, these include definition, indication, efficacy, safety, reported data, availability, conflicts of interest and costeffectiveness. “As of today, we cannot yet trust in MIGS — there are still too many unsolved problems and questions.”

On the other hand, Dr. Vass shared that MIGS may be recommended for selected cases and that MIGS is safe. “MIGS may be a good choice if you don’t need a low pressure and medication is not a problem.”

Of course, there is a trade-off between a safe and effective surgery and MIGS is not suitable to reach a low pressure of 10 mmHg. “The cost of the implant may be argued as a negative point … but it depends on the medical system of the country, there may be even cost-effectiveness with MIGS,” he concluded.

A Multifaceted Disease in A Multinational Country

Insights from the Russian Glaucoma Society

for myopia, and we know myopia is correlated with glaucoma — but unfortunately, the effect of the surgery makes glaucoma hard to diagnose. Dr. Antonov gave some advice about how to diagnose glaucoma in patients who have had the surgery.

by Chris Higginson

With one foot in Asia and the other in Europe, advances in Russian ophthalmology shouldn’t go unnoticed by the rest of the world. In this session on Day 3 of the World Glaucoma e-Congress (WGC 2021), four experts bring us up to speed on glaucoma research in Russia.

Neuroimaging the brain of glaucoma patients

To begin, Dr. Ilmira Gazivova, from the Federal Budgetary Institution of Science (Russia) discussed neuroimages of the brain in glaucoma studies.

Dr. Gazivova shared: “We know that glaucoma affects more than just the brain’s visual pathways, which means that we can scan the brain for it in the same way as other neurodegenerative diseases. We know that patients with POAG are up to five times more likely to suffer from other neurodegenerative diseases such as Alzheimer’s and Parkinson’s than others.”

Qualitative analysis suggests that glucose metabolism in the neurons of patients with POAG indicate an affinity with other neurodegenerative diseases.This suggests that the basis of visual, cognitive, autonomic disorders associated with changes in function of the central nervous system may well be the same as that of patients with POAG, and therefore more research in this direction should be continued.

The effect of pseudoexfoliation syndrome on glaucoma

Dr. Andrey Brezhnev from Kursk State Medical University (Russia) discussed pseudoexfoliation syndrome (PXS): from genetics to glaucoma surgery.

PXS is an age-related generalized disorder of the extracellular matrix,

characterized by excessive production and progressive accumulation of a fibrillar extracellular material in extraocular tissues. It has a related form of glaucoma called pseudoexfoliation glaucoma (PXG) which is 20x more prevalent in PXS patients than glaucoma is in the general public.

PXS is widespread in the population of Central Russia and is a complex, multifactorial disease that includes a combination of genetic and non-genetic factors. Treating PXS and PXG is difficult as it requires consistent monitoring of its many clinical features, such as high IOP level, diurnal fluctuation, its fast rate of progression, resistance to therapy and more. It has a host of clinical manifestations and associations, including cerebrovascular and sensorineural disorders, hearing loss and heart disease, all of which necessitate the further studying to improve early diagnosis and assessment.

PXG is a special form of PXS that requires, in addition to standard technologies, the development of new, specific approaches to early diagnosis, monitoring, as well as medical and surgical corrections.

Glaucoma in patients with keratorefractive surgery

Dr. Alexey Antonov from the Research Institute of Eye Diseases (Russia) discussed glaucoma diagnosis in patients with prior keratorefractive surgery.

Keratorefractive surgery is a treatment

In patients who have had photorefractive keratectomy, keratomileusis and small incision lenticule extraction (SMILE), corneal-compensated IOP is the best way to get reliable tonometric value, whereas rebound tonometry in the central zone of the cornea is the most reliable method of measuring IOP after radial keratotomy.

The control of keratotopography and refraction in patients who have undergone refractive surgery can allow the indirect identification of changes in the ophthalmotonus. It should be remembered that a longterm hypermetropic shift after radial keratotomy, as well as a myopic shift after LASIK, are both symptoms of unstable hydrodynamics in the eye, and suggest a patient with possible glaucoma.

Drug delivery as a method of treatment of glaucomatous optic neuropathy

Dr. Eugeny Egorov, from Pirogov Russian National Research Medical University (Russia), discussed targeted drug delivery as a method of treatment of glaucomatous optic neuropathy.

Dr. Egorov believes that the large volume, vitreous structure, direct vitreoretinal and vitreal-ocular nerve head contacts make the pars plana the optimal deposit place for bioactive substances (BAS) and drugs and for treatment of diseases of the posterior segment of the eye. It is the best place for bioactive substance generation and drug spreading into the eye by nonpenetrative methods.

Its size and position means that it’s possible to establish vasoactive mediators and a drug depot that provides a stable and uniform release of drugs and BAS to the hard-to-reach structures of the posterior segment of the eye. Its use has the possibility of repeated outpatient treatment, reduction of the cost of treatment, reduction of the injection frequency and reduction of the risk of systemic side effects.