In order to improve patient care, guidelines for clinical and therapeutic management should be based on high quality scientific evidence, such as the fifth edition of the European Glaucoma Society guidelines,

 which contains only references from high quality systematic reviews, landmark 

 trials and population-based studies. Randomised controlled trials (RCTs) are one the most reliable sources of this type of evidence because, if well conducted, they can produce unbiased and generalisable data on diagnosis and therapy, giving fundamental insights into patient management.

Precision management to revolutionise glaucoma diagnosis and treatment

The Early Manifest Glaucoma Trial (EMGT) and the United Kingdom Glaucoma Treatment Study (UKGTS) are two prospective RCTs comparing treatment versus no treatment in glaucoma patients. Taken together, the results from these trials help us to answer the question of what we should do after diagnosing glaucoma in a patient.

The EMGT investigated the effects of medical treatment and laser treatment on glaucoma progression. Two hundred and fifty-five patients were recruited between 1993 and 1997 on a population-screening basis and followed until 2013.

Previously untreated glaucoma patients with repeatable visual field (VF) defect and corresponding optic nerve damage in at least one eye were enrolled, including those with primary open-angle glaucoma (POAG), normal tension glaucoma (NTG) and pseudo-exfoliative (PXF) glaucoma. Patients with advanced VF damage and high intraocular pressure (mean IOP >30 mmHg or IOP >35 mmHg in at least one eye) were excluded.

Participants were randomly allocated to treatment or no treatment. Treatment consisted of a combination of laser trabeculoplasty and topical betaxolol. The primary outcome was glaucoma progression, measured quantitatively by VF deterioration or optic nerve head changes. Mean baseline IOP was 20.7 mmHg and VF mean deviation (MD) was −4.7 dB.

The IOP trend during follow-up was different between the two groups. In the treated arm, IOP decreased from 20.6 to 15.5 mmHg at 3 months, corresponding to a 25% reduction from baseline; this was maintained throughout the follow-up period. No IOP changes were observed in the untreated arm.

Survival analysis showed that the differences in VF progression between groups arose early and were maintained for the entire follow-up period. Progression was more frequent in the control group at any time point, occurred earlier in controls and increased over time in both arms.

The first analysis (in 2001) showed significantly differently progression in the two groups: 62% in the control group and 45% in the treatment group.

 At the end of the study, progression was detected in 59% of treated participants compared with 76% of control participants, with a hazard ratio of 0.6.

An IOP of >21 mmHg, PXF syndrome, glaucoma in both eyes, worse median baseline MD and older age were significantly associated with risk of progression. Among the longitudinal factors, progression was strongly associated with the magnitude of initial IOP change, IOP at 3 months of treatment and mean IOP during follow-up.

 Disc haemorrhages and lower central corneal thickness (CCT) were also associated with risk of progression but the latter only in patients with higher baseline IOP.

Study examines pairing phacoemulsification with implantation of stents

Alongside the valuable data about the impact of treatment on glaucoma progression gained from this study, the untreated group allowed us to follow the natural course of the disease. By analysing data from untreated patients who were followed for at least 6 years, Heijl et al. showed that the majority of subjects experienced minimal yearly IOP changes, with larger IOP changes in those with PXF glaucoma.

 Overall, IOP did not increase in the untreated arm and 68% of patients showed glaucoma progression.

Rate of progression, as well as median time to progression, was higher in patients with PXF syndrome, followed by high tension glaucoma and NTG (−3.13 dB/year compared with −1.31 dB/year in high tension glaucoma and −0.36 dB/year in NTG).5 Accordingly, PXF glaucoma has a higher risk of progression if untreated.

The United Kingdom Glaucoma Treatment Study

The UKGTS was conducted in 2014. It was designed to have several similarities to the EMGT (e.g., inclusion criteria), to make the results as comparable as possible. The UKGTS was the first multicentre RCT to evaluate treatment with latanoprost (Xalatan, Pfizer) 0.005% versus placebo in glaucoma patients (POAG, NTG and PXF glaucoma).

Patients were enrolled consecutively between 2007 and 2010 and the primary outcome was VF deterioration within 24 months. Such a short observational period was possible because the frequency interval of VF was clustered at the beginning and the end of the trial, to maximise the power to detect progression.

As in EMGT, enrolled subjects had newly diagnosed and untreated glaucoma, defined by VF defect and corresponding damage to the optic nerve head. Patients with moderate-to-advanced VF damage were excluded, as well as those with elevated IOP (>35 mmHg on two consecutive occasions in either eye or mean baseline IOP of ≥30 mmHg).

Mean IOP was 20.1 mmHg and 19.6 mmHg in the placebo and treated group, respectively. The median MD at baseline was 2.9 dB, which means the glaucoma tended to be at an earlier stage than in the EMGT (median EMGT MD was −4.1 dB).

Mean IOP reduction from baseline was 5 mmHg (20%) in the treated group and 1.4 mmHg in the placebo group. The strongest initial response was slightly reduced at 6 months and then remained stable during the rest of the study.

At 24 months, the percentage of patients who reached the primary endpoint was significantly different between arms: 25.6% of patients in the placebo group compared with 15.2% in the treatment group. Time to deterioration was also significantly longer in the treated group with consequently longer VF preservation and a hazard ratio of 0.44. These differences were already evident at 12 and 18 months.

Is low vitamin D a risk factor for primary open angle glaucoma?

Increased risk of progression was associated with treatment allocation, glaucoma in both eyes, higher mean baseline IOP and disc haemorrhages at the baseline visit. History of heart attack and smoking habits were associated with risk of progression. Unlike in EMGT, age, CCT and severity of VF loss were not associated with risk of progression.

By combining the results from EMGT and UKGTS, common conclusions can be drawn and translated to clinical practice. Lowering IOP is effective in reducing disease progression in previously untreated patients with POAG, NTG and PXF glaucoma; the treatment’s efficacy depends on the patient’s pre-treatment IOP, with a stronger effect on higher baseline IOP values.

The rate of reduction is also crucial: each mmHg of IOP reduction decreases the risk of progression by a specific percentage. The lower the IOP reached—not only immediately after starting therapy but also during follow-up—the better the outcome.

When we analyse the results from RCTs, the statistical variability of data must be taken into account. We strongly need summary measures to draw overall conclusions and mean values of different parameters (such as mean annual IOP change, mean MD change, mean rate of progression), which represent the average behaviour of all participants, are usually reported.

However, there is a certain amount of variability around this value, corresponding to participants who have shown results that differ from the mean. Translating this statistical variability into clinical practice means that one must remember that any patient could be near the average or could be an outlier, showing a different behaviour from that expected, with regard to IOP changes, rate of progression and other parameters.

The EMGT and UKGTS trials provided extensive information on the natural history of glaucoma. When we look at survival analysis, we generally focus on differences between treated subjects and controls, but it also shows patients who progress despite treatment and controls who do not progress despite remaining untreated.

In the UKGTS, two-thirds of participants in the placebo group showed no VF deterioration during 24 months of follow-up and the same happened in 38% of untreated patients in EMGT.

 This suggests that patients with slight VF loss at baseline could be followed without treatment for a period. Then it becomes critical to assess the risk of progression of each patient, keeping in mind that the pattern could be difficult to predict and that the rate of progression may change over the period of observation.

In summary, besides stressing the importance of IOP reduction in preventing glaucoma progression, EMGT and UKGTS have shown that different factors affect the risk of disease progression. Looking for a particular target IOP or percentage IOP reduction is not the best option for all glaucoma subjects. Each patient must be considered as unique; only by quantifying the individual risk will it be possible to best tailor the treatment approach for each patient.

2. Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. 

3. Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. 

4. Leske MC, Heijl A, Hyman L, et al. Predictors of long-term progression in the early manifest glaucoma trial. 

5. Heijl A, Bengtsson B, Hyman L, et al. Natural history of open-angle glaucoma. 

Garway-Heath DF, Crabb DP, Bunce C, et al. Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial. 

Lascaratos G, Garway-Heath DF, Burton R, et al. The United Kingdom Glaucoma Treatment Study: a multicenter, randomized, double-masked, placebo-controlled trial: baseline characteristics. 

Dr Michelessi is a researcher at the Glaucoma Research Unit of the G.B. Bietti Foundation, Rome, Italy. Dr Giammaria is a research fellow in the Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Canada. Neither author reports any conflict of interest relevant to the subject matter.

Articles

Two randomised controlled trials, EMGT and UKGTS, have examined the factors affecting the risk of glaucoma progression. Global target IOPs are not the best option for all patients.

Using pivotal study data to guide glaucoma patient management decisions

Johnson + Johnson Vision announced today it is kicking off the availability of its TECNIS Eyhance Toric II IOL with TECNIS Simplicity Delivery System for the treatment of 

 allows for high-quality vision at both intermediate and far distances

 and is specifically engineered for rotational stability.

 The lens allows patients to achieve significantly improved intermediate vision, compared with a standard aspheric monofocal IOL, along with 20/20 distance vision.

According to Filomena Ribeiro, MD, PhD, FEBO, head director of ophthalmology at Hospital da Luz in Lisbon, Portugal, the haptic design and rotational stability of the TECNIS Eyhance Toric II IOL, has allowed her to offer her patients immediate improvements in their functional vision, while also correcting their astigmatism.

“Having implanted the TECNIS EyhanceToric II IOL, I can confidently say that this IOL is a game-changer in the monofocal category and in helping my patients get back to spending more time doing what they love,” she said in a statement.

Posterior corneal elevation: Is there a role for premium IOLs?

A survey of 17 leading European ophthalmologists found that their patients were satisfied with the lens.

 Meanwhile, more than 79% perceived their patients as being very satisfied with their intermediate and distance vision.

Additionally, 94% of those surveyed were very satisfied with the handling while implanting the lens, while nearly two thirds rated the overall performance of the lens as excellent compared to other toric IOLs.

 More than 80% also rated the rotational stability of the lens as excellent compared to other toric IOLs. All those surveyed said they were very likely to continue to use the lens in the future.

Ray tracing and IOL modelling in AMD patients

Erin McEachren, regional vice president, EMEA, Johnson + Johnson Surgical Vision, said the rollout offers the benefits of its most advanced monofocal IOL to cataract patients with astigmatism.

“It is an important first in Europe for the monofocal IOL category, as today most lenses in this category only correct vision to help patients with cataracts see things at a distance, and therefore do not improve the intermediate vision that is required for many important daily tasks,” McEachren said in a statement. “This is another breakthrough in meeting the ever-changing and evolving needs of our patients across Europe and the world.”

DOF2018CT4015 – Clinical evaluation of the TECNIS Eyhance Model ICB00 – 6-month clinical study. Sep 2018. Based on a clinical study, N=134 achieved mean 20/20 monocular pooled distance BCDVA.

TECNIS Eyhance Toric II IOL – Survey of 17 surgeons about experiences with DIU. May 2021. REF2021CT4156.

According to the company, more than 400 eyes of patients from 12 European countries have been fitted with the TECNIS Eyhance Toric II IOL, with surgeons surveyed noting that their patients are pleased with the results. 

Johnson + Johnson's TECNIS Eyhance Toric II IOL launches in Europe

 have a very high-tech and sophisticated optical system that works excellently when the cornea is in perfect condition. Therefore, they are contraindicated in patients who have corneal haze, scar or oedema.

A patient who has a posterior corneal elevation is susceptible to higher-order aberrations (HOAs) or early keratoconus. Consequently, many surgeons will refrain from using premium IOLs in such cases. As one of the first surgeons in Saudi Arabia to use a trifocal lens, I meticulously select my patients.

In Saudi Arabia, keratoconus is prevalent due to the dry atmosphere, seasonal allergies and consanguinity. However, not all patients have the same severity of disease. Some patients live their entire lives without knowing that they have keratoconus or without signs of the condition. Others present early with signs and symptoms.

Ray-tracing and IOL modeling in AMD patients

Many patients who present to me with the desire to be spectacle-free have questionable corneal tomography images. The first keratoconus patient I treated with a trifocal lens (AT LISA tri toric 939 M/MP; Carl Zeiss Meditec) was one of my colleagues, a 52-year-old physician with a mild but stable form of keratoconus.

Her central cornea seemed to be normal and the steepening was at the inferior part of the cornea, sparing the central 5-mm zone. The HOA at the 6-mm zone was 1.2 μm, outside the normally accepted range of up to 0.5 μm.

The patient was keen to try trifocal lenses, so after long discussion and counselling the procedure was undertaken. Postoperatively, she was incredibly happy, with uncorrected visual acuity 6/6 at near, distance and intermediate. She had no visually disturbing aberrations.

I then performed the same procedure on her sister, who suffers from subclinical keratoconus, and who also responded very well. That is when I began to consider premium IOLs for certain cases of keratoconus patients. I developed my own criteria for selection and, so far, patients have been very satisfied.

How to use topography-guided laser procedures to treat keratoconus

I have performed this procedure on four patients (eight eyes) with different categories of keratoconus but who all share one thing in common – the central 5-mm zone with an accepted range of HOA. It is not extremely high, but it is apparent that they do not have a normal posterior cornea.

During diagnosis, all patients undergo a routine, complete ophthalmic examination, which includes dry and wet refraction. Patients also undergo a meticulous clinical assessment and detailed history-taking, including family history, previous trauma, allergies, any spectacles changes and the frequency of these changes, and contact lens use. Next, we perform corneal tomography, which is key for diagnosing keratoconus and precisely shows the anterior corneal curvature and the posterior corneal curvature.

Using four-maps analysis, I perform the Belin Ambrosio Enhanced Ectasia analysis and I study them carefully. Then I check the elevation maps, both in the forms of best-fit sphere and the best-fit toric ellipsoid.

I compare the maps and see if the patient has good spectacle correction. If the patient does not have high central aberration, I then consider implanting a trifocal lens.

I speak with the patients about HOA photic phenomena and explain that they should anticipate some glare and halos over time. I even show them a picture of what glare and halo will look like so that they know what to expect in the coming weeks. I also discuss mental adaptation and how their vision might be adapted to some aberration.

The good thing about keratoconus patients is that they are already used to a minimum amount of light, glare and halos. If their central vision is okay, it is not exaggerated by premium lenses. In all my cases, glare and halos have turned out to be benign; however, I still like to set realistic expectations.

Corneal crosslinking outcomes appear to justify its use in paediatrics

I perform a routine phacoemulsification and painstakingly centre the IOL. The plate haptic design IOL centres itself easily and this is a strong point in favour of this design.

I like to place one suture to be sure that the lens does not move, especially if ectatic corneas have delayed healing or might have microleaks and fluctuation in eye pressure, which can change the lens position. If the patient is receiving a toric lens, I ensure that the anterior chamber maintains its stability.

The postoperative regimen is similar to that of a routine phaco procedure. I examine the patient and remove the suture within the first week and no later than 2 weeks from surgery. Then I reassess the patient’s vision at 2 weeks, 6 weeks and 3 months.

One step of utmost importance is assuring the patient that the lens is removable if he or she is not happy. I offer patients a lens removal within the first 6 weeks if the aberration is higher than anticipated, and this provides some reassurance for the patient.

A 56-year-old breast cancer survivor with subclinical keratoconus wanted to treat herself after surviving her cancer by getting her eyesight back. She had heard about premium lenses and presented to me with a specific interest in trying them.

Considering her condition, I conducted an examination and determined that she was fine to move forward with the procedure. She told me that she was reborn after two things: recovering from breast cancer and being spectacle-free for the first time in her life.

A 48-year-old man in a sensitive diplomatic position presented to me and shared that his use of spectacles was causing some embarrassment because there are times when he was unable to wear them but still required to read things and he felt that this was disabling him. He was considering leaving his job due to his inability to focus.

He had posterior corneal elevation. The procedure was successful, and he has returned to work without anyone knowing that he had undergone the procedure.

Sometimes, surgeons can be afraid of technology because we do not know what is hidden behind it, and we refrain from exploring new advancements because we do not want our patients to have an unsatisfactory experience.

Given my recent experience with implanting premium lenses in challenging cases, I have changed my perspective and now view these opportunities as another way to give my patients a chance. With the confidence that I can exchange the lens with minimum complications as a backup plan and considering that there is no cost to the patient because I work in a government hospital, I have to ask myself why not.

In the end, the keratoconus patients who have received premium lenses are the happiest patients I have. This is probably because they are used to some amount of HOA so they adapt to their new IOLs faster and have higher tolerance than people with normal eyes.

Dr Al Saati is chief of the Anterior Segment Division at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. She has no financial disclosures to make regarding any of the lenses used in this case series.

It is widely accepted that patient selection is the key to success with premium IOLs. However, with care, premium IOLs can be implemented in challenging cases.

Bausch + Lomb and Clearside Biomedical Inc. announced that the U.S. Food and Drug Administration (FDA) has accepted the resubmitted New Drug Application for triamcinolone acetonide suprachoroidal injectable suspension (Xipere).

The agency determined that the filing is a Class 2 resubmission and assigned a Prescription Drug User Fee Act (PDUFA) action date of October 30, 2021, for the investigational therapy with a proposed indication of treatment of macular oedema associated with uveitis.

“If approved by the FDA, [triamcinolone acetonide suprachoroidal injectable suspension] would be the first therapy available utilising the suprachoroidal space for patients suffering from macular edema associated with uveitis, which is the leading cause of vision loss in people with uveitis,” said Yolande Barnard, vice president and general manager, US Pharmaceuticals, Bausch + Lomb, in a prepared statement.

“If approved, [this] would be our first commercial product and the first approved drug to be delivered into the suprachoroidal space (SCS),” added Clearside’s President and CEO George Lasezkay, PharmD, JD.

The novel treatment option is designed for suprachoroidal administration via Clearside’s proprietary SCS microinjector that provides access to the back of the eye, where sight-threatening disease often occurs.

An affiliate of Bausch Health acquired the exclusive license for the commercialisation and development of triamcinolone acetonide suprachoroidal injectable suspension in the United States and Canada in October 2019.

The Bausch Health affiliate also has exclusive options for the right to commercialise and develop the novel treatment option in the European Union, the United Kingdom, Australia and New Zealand, and/or South America and Mexico. Arctic Vision has the exclusive license for its commercialisation and development of in Greater China and South Korea. Triamcinolone acetonide suprachoroidal injectable suspension is not yet approved in any jurisdiction.

PDUFA action date of October 30, 2021, is assigned for investigational therapy with a proposed indication of treatment of macular edema associated with uveitis.

FDA accepts Bausch Health, Clearside Biomedical's resubmitted Xipere NDA 

This article was reviewed by Dr Kuldev Singh.

When performing glaucoma surgeries, considering slightly different twists to the procedure may help avoid potential complications. Dr Paul Palmberg, a professor of ophthalmology at Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine in Florida, United States, shared his view of the ocular anatomy, which he said helps him to avoid pitfalls and increase patient comfort.

When considering the conjunctiva, Tenon’s capsule and the sclera, careful techniques can be performed to avoid limbal leaks and bleeding in the conjunctival flap. Dr Palmberg explained that the ocular tissues are not islands but are attached to each other (i.e., the conjunctiva is attached to the limbus at the edge of the cornea and Tenon’s capsule is attached approximately 1–2 mm further to the posterior). He reminded surgeons of the blood supply in the conjunctiva and blood vessels on Tenon’s capsule and the scleral surface.

Bleeding inside Tenon’s capsule in the bleb can be avoided if incisions are made only at the insertions of the conjunctiva and Tenon’s capsule. The best route is to get under Tenon’s capsule and not inside it.

Dr Palmberg noted that the capsule is thicker at the 10 o’clock to 2 o’clock and 4 o’clock to 8 o’clock positions. When starting a surgery, he advised using a lateral incision through the conjunctiva and Tenon’s capsule and everting the tissues so that the tips of the scissors can be positioned sufficiently far from the limbus; this facilitates getting under both the conjunctiva and Tenon’s capsule and down to the bare sclera to take a bite with a suture.

As the operation progresses, the surgeon can continue around, everting the conjunctiva and Tenon’s capsule. “The scissors are passing through the potential space under Tenon’s capsule all the way around,” Dr Palmberg said.

A radial incision then can be made at the side and spread back through the intermuscular septum to each side of the superior rectus muscle. Sponges soaked with mitomycin C (MMC) can be placed through the openings in the intermuscular septum and along the limbus to apply the MMC widely and facilitate extensive spreading of the drug.

The technique described was developed by Prof. Sir Peng Khaw, who saw a marked decrease in bleb problems in paediatric cases from 20% to 0%. He used the fornix flap with wide MMC application instead of a limbus-based flap with local MMC application.

“The limbus-based procedure resulted in a focal, highly elevated, thin and highly vulnerable bleb,” Dr Palmberg said. He added that, following his use of the fornix-based procedure, his bleb-related complications decreased from approximately 8% to 1% at 5-year follow-up.

Straightforward procedures for leaking blebs: No incision required

Another advantage of the fornix-based procedure involves aqueous drainage through Tenon’s capsule on each side of the superior rectus muscle; because the fluid can drain much more freely through lymphatics in the conjunctiva and Tenon’s capsule further back, a much more comfortable bleb forms.

In contrast, when a limbus-based flap is created, scars form at the incisions in the conjunctiva and Tenon’s capsule—the so-called ‘ring of steel’ that blocks posterior drainage. “Wide application of the MMC under a fornix flap avoids a ‘ring of steel’: that is, scarring, which can delimit the bleb posteriorly,” Dr Palmberg said.

Dr Palmberg uses 10-0 nylon to make a bite immediately peripheral to the cornea, down through the sclera and across and upwards; he also closes each side with a bite in the sclera and up through the conjunctiva (square wave bites). He pulls tightly down on this to impale over the needle, comes back out and takes another bite that is tied down under the conjunctiva and run out to the tip, and then takes a bite at the apex and passes it back underneath, tying a knot that is buried under the flap.

Considering the best surgical approach in angle closure patients

He repeats the same process on the other side. “In this way, the vector forces in this area are pulling to the sides—but not across where the conjunctiva should balloon up—without compressing Tenon’s capsule,” he said. “Fluid then can flow [backwards] through Tenon’s capsule.”

The manner with which the bites are made in the sclera is not to be taken lightly; these are square wave bites and not skimming bites. A vertical bite should be taken down with 10-0 nylon, moved across, and then brought back up as vertically as possible through the conjunctiva and down, with the knot tied underneath.

“The needle should not be parallel to the surface as it enters the sclera, because this is a skimming bite that is shallow upon entrance and exit,” Dr Palmberg said. “This puts tension on the thin sclera on the two sides and eventually tears and loosens, all of which cause leaking blebs 3 days postoperatively.”

Using a valve-like trabeculectomy with MMC can help avoid hypotony in the early and late phases postoperatively, when sutures dissolve. A valve-like incision when possible, and/or the scleral flap resistance, can be adjusted intraoperatively to set the intraocular pressure at equilibrium flow.

In this technique, Dr Palmberg makes a 3-mm-wide tunnel incision out to 1 mm in the cornea and then uses a Kelly Descemet Membrane Punch 0.75 mm to make a canal in the tunnel. He checks the pressure at equilibrium flow by filling the anterior chamber with balanced salt solution. At equilibrium, the pressure is approximately 4 to 6 mmHg, which is estimated by pushing on the cornea with a 30-gauge cannula.

After two 10-0 nylon stitches are placed in the flap and the flow is at equilibrium, the cornea is pressed again, and the pressure is approximately 8 to 12 mmHg. This avoids hypotony early and late when the sutures dissolve and avoids the need for an iridectomy. Additionally, there is less astigmatism because the sutures in the flap are not tight, there is no cost to the procedure and there is no net visual field loss.

Dr Palmberg has no financial interest in this subject matter.

Careful study of ocular anatomy can help surgeons avoid problems related to glaucoma procedures and achieve better results for patients. 

Eliminating the potential land mines in glaucoma surgery

Cataract surgery is performed more often than any other surgery in Europe, with the use of prophylactic antibiotics procedures being commonplace. Whilst such drugs are vital for preventing and treating infection, the antimicrobial resistance crisis threatens to undermine the progress that has been made in preventing deaths from infection and has become an urgent healthcare priority.

I asked ophthalmologist Dr Marco Coassin to tell me more about endophthalmitis, a type of inflammation of the internal eye tissues that can occur due to infection, and the delicate balance between minimising the risk of postoperative infection and taking responsibility for helping to manage and reduce antibiotic resistance.

Should patients be made aware that they could develop endophthalmitis following cataract surgery?

Whilst I do not believe that patients should be worried about developing endophthalmitis, they do need to be aware of this sight-threatening disease, even if the chances of developing it after cataract surgery are statistically low. According to various reports, the incidence of postoperative endophthalmitis is in the range of 0.03–0.7%: as a surgeon, I might see one endophthalmitis case per every 1,000 cataracts I operate on.

Study: Identifying link between endophthalmitis, coronavirus

The problem is that patients are often unaware that, even if rare, endophthalmitis might occur in perfectly operated eyes – and be devastating for their vision. This may be due to the unwillingness of doctors to worry their patients before an otherwise straightforward surgery.

A surgeon’s overconfidence may play a role too: a “this is not going to happen to me” kind of attitude is not uncommon for those who perform hundreds of operations each year. This pairs with the very high expectations that patients now have towards modern cataract surgery. They expect a rapid, simple procedure, resulting in crystal clear postoperative vision.

What are the causes, characteristics and outcomes of the condition?

The main causative agents in post-cataract endophthalmitis are common bacteria that may normally be found in the ocular surface and periocular tissues. They may enter the eye through the surgical incision used to remove the cataract and cause massive, uncontrollable intraocular inflammation.

 account for up to 94% of the cases. Symptoms may start within 3 days after the surgery and include rapid worsening of visual acuity, ocular pain and discharge. Signs include conjunctival hyperaemia, corneal oedema, anterior and posterior intraocular inflammation with hypopyon, vitritis and retinal alterations.

Examining the stability of a new aspheric IOL in cataract patients

Diagnosis may be cumbersome and requires invasive procedures for collecting specimens for microbiologic cultures. And treatment may be painful and require intraocular injections or vitreoretinal surgery.

The outcomes can be quite dramatic. Only half of the infected eyes retain a visual acuity of better than 20/40 and up to one third will end up with extremely poor vision (worse than 20/200). We know that certain pathogens, such as 

and Gram-negative bacteria, are related to worse visual outcomes. Older individuals, patients with diabetes or those with other severe systemic comorbidities usually have the poorest prognosis.

What can be done to avoid the chances of infection?

There are four approaches I take to reduce the chance of endophthalmitis occurring in my cataract patients. Firstly, I rely on pharmacological prophylaxis: the ESCRS endophthalmitis study

 demonstrated that intracameral cefuroxime at the end of surgery dramatically reduces the risk of intraocular infection. The addition of postoperative antibiotics in the form of eye drops can help lower the incidence of endophthalmitis even further.

Controlling postop pain, inflammation in cataract patients: drug delivery vs drops

Secondly, since corneal wound leakage is a leading factor for postoperative infection, I am very meticulous in correctly shaping corneal incisions and in carefully sealing them at the end of cataract surgery. Thirdly, I identify patients who might be at higher risk for infection, such as those with immunosuppression, diabetes or intraoperative complications. And finally, I carefully monitor patients’ postoperative behaviour.

What can you as an ophthalmologist do to help prevent antimicrobial resistance from developing?

We need to be aware that our small actions—routinely prescribing antibiotic eye drops after cataract surgery—may have a huge impact in terms of global health. More than 4 million cataract surgeries are performed each year in Europe. Since virtually all cataract surgeons use intra- or postoperative antibiotics, it is calculated that this amounts to more than 60 million days per year of antibiotic exposure. If the way we use antibiotics does not improve, it has been estimated that 10 million people will die as a consequence of antimicrobial resistance by 2050.

Looking at 10 years of dry eye disease flares

We should use the antibiotic that has the largest spectrum of action and prescribe the shortest duration of therapy. Efficiently and rapidly eliminating the pathogen reduces the risk of developing resistance. I personally use levofloxacin four times a day for one week, usually in fixed combination with dexamethasone.

After one week, I then prescribe dexamethasone alone or a different anti-inflammatory eye drop. You do not need more than one week of antibiotic after surgery and tapering the antibiotic does not make any sense: it just increases the risk of resistance.

Dr Coassin is an associate professor of Ophthalmology at the University Campus Bio-Medico in

Rome, Italy. He receives lecture fees from Bausch & Lomb, GlaxoSmithKline and Santen, and clinical research grants from Bausch & Lomb, NTC, Santen, Sintetica and Thea.

Whilst endophthalmitis following cataract surgery can lead to serious vision outcomes, there are ways of minimising the risk of it occurring whilst also being mindful of the need to prescribe antibiotics in a way that does not worsen antimicrobial resistance.

Considering antibiotics use in postoperative endophthalmitis 

This article was reviewed by Dr Isabelle Audo.

 has increased exponentially in recent years and several gene therapy clinical trials for retinal diseases are open, enrolling or have recently been completed. Dr Isabelle Audo recently described the highlights in therapies that involve sub-retinal gene delivery, optogenetics, antisense oligonucleotide (AON) and clustered regularly interspaced short palindromic repeat (CRISPR) Cas9. Dr Audo is a professor of ophthalmology in the Department of Genetics at Institut de la Vision, CHNO des Quinze-Vingts in Paris, France.

Choroideraemia, which involves damage to the blood vessels of the choroid and degeneration of the photoreceptor cells, is an X-linked disorder that has a frequency of about 1/50,000 individuals. The disorder is linked to a mutation in the CHM gene.

Several studies have been performed to evaluate gene replacement therapy using vectors designed for subretinal delivery to treat this disease. One Phase 1/2 study conducted by Spark Therapeutics is evaluating sub-retinal injection of the adeno-associated virus (AAV2) vector; no results have been forthcoming thus far.

Gene therapy heralds new era for inherited retinal diseases

A few Phase 1/2 studies have been conducted in Europe and the United States. One such study, conducted by Biogen (formerly NightStar Therapeutics) in the United Kingdom, reported results obtained with a sub-retinal injection of a low-dose vector (AAV2) to treat six patients. The investigators reported a mean visual gain of 3.8 letters and a dark-adapted increase in sensitivity of 2.3 dB with no significant visual loss.

Longer follow-up at 3–5 years in the six patients showed improved vision by 21 and 18 letters in two patients and stable vision in three patients. One patient treated with the lowest study dose lost 29 letters in the treated eye and 18 letters in the fellow eye.

Non-viral gene therapy eases treatment burden in wet AMD

Three studies of choroideraemia are ongoing. The Phase 2 REGENERATE trial in the UK includes 30 patients with early-stage disease, with normal vision and large areas of preserved central retina. The study is testing the long-term efficacy of the AAV2-REP1 vector in two patient cohorts.

The multicentre Phase 2 GEMINI trial in Europe and the US is evaluating the safety and efficacy of treatment and includes 15 patients treated bilaterally. The Phase 3 STAR trial includes 140 patients with more advanced choroideraemia who received low or high doses or remained untreated; the primary endpoint is the best-corrected visual acuity (BCVA) at 1 year, and the secondary end points are the status of the functional and structural parameters.

Retinitis pigmentosa (RP) treatment is being evaluated in two studies in which gene therapy is used to induce a new function in the cells (optogenetics). Dr Audo explained that the idea behind this technology is to transform the relatively well-preserved bipolar and mainly retinal ganglion cells into photoreceptor cells using a very basic photopigment that upon activation can change the polarity of the cells.

Initial data from AGTC-501 subretinal gene therapy for X-linked RP demonstrates safety, efficacy

Two studies are currently testing the safety and efficacy of this approach. In the first, a Phase 1/2 non-randomised dose-escalation study, Allergan, in conjunction with RetroSense Therapeutics, is testing one injection of three doses of AAV2 vector into the vitreous cavity in 21 patients; the vector is over-expressing a channelrhodopsin that is sensitive to a short wavelength of light. The primary outcome in this ongoing trial is safety; no results have been released.

GenSight Biologics is conducting a second ongoing Phase 1/2a non-randomised dose-escalation study of one intravitreal injection of the rAAV2.7m8 vector, which over-expresses channelrhodopsin in a long wavelength of light. Patients wear goggles that amplify light to increase the sensitivity and the effect of the opsin used to transduce the ganglion cells. Thus far, no major side effects have been reported in either study.

Patients are currently being enrolled in studies of RP, RP in Usher syndrome and Leber congenital amaurosis (LCA) in which AON therapy is being evaluated. As Dr Audo explained, this technology, which specifically targets gene defects, uses small RNA molecules that can target a specific sequence and hybridise to the messenger RNA (mRNA), which results in either masking or silencing of a mutation or modifying the splicing of the mRNA to produce an exon skip.

Several studies evaluating this technology are ongoing. The trials address the CEP290 deep intronic mutation, which is a common mutation between exons 26 and 27 that leads to LCA. The mutation produces a mis-splicing of the gene, resulting in truncation of the protein. The goal of AON therapy is silencing of the mutation, thus restoring the normal splicing and protein.

Treatment with voretigene neparvovec-rzyl results in foveal morphologic changes in LCA

One Phase 1/2, multiple-dose dose-escalation study has been completed. The study

 included adult and paediatric cohorts treated with low and medium doses. The main adverse events included development of cataract, cystoid macular oedema and retinal thinning. The investigators reported functional efficacy resulting from delivery of the AON with improvement in the BCVA, retinal sensitivity and mobility tests in patients with LCA.

The ILLUMINATE study is a Phase 2b/3 trial that involves multiple sequential injections in one eye of sepofarsen (ProQR Therapeutics), with the second eye treated after 1 year, in patients with LCA. Two doses of sepofarsen are being evaluated and compared with sham dosing. Recruitment is completed; results are not expected until 1 year after the first injection.

Another AON study conducted by ProQR Therapeutics, the STELLAR study, is evaluating the technology to treat RP in Usher syndrome by triggering USH2A mRNA. Exon 13 is the site of very frequently occurring mutations. “With delivery of AON therapy QR-421, the idea is to modify the splicing of exon 13 to cause the exon to be skipped and therefore avoid its mutation,” Dr Audo reported.

Linking patient imaging to AAO IRIS Registry clinical data

Using this technology, some functional recovery has been reported in a zebrafish model (unpublished data).In the ongoing Phase 1/2 STELLAR clinical trial involving patients with Usher 2a, patients are receiving one low, medium or high dose and the results are being compared to sham treatment. Patient enrolment is completed and results are expected at the end of 2021.

Another ongoing study by ProQR Therapeutics triggers the most common mutation in the US in autosomic-dominant RP and the rhodopsin gene: the P23H mutation. The goal is to inactivate this mutation, which is responsible for a dominant negative effect.

This technology is used to correct the genomic sequence. The BRILLIANCE study, conducted by Editas Medicine and Allergan, is using AV vectors to deliver CRISPR to trigger a deep intronic mutation on the CEP290 gene. The goal is to create a specific double-strand break that will silence or correct the mutation. This is the first human trial to use CRISPR/Cas9 

. “This is a very exciting moment,” Dr Audo said.

MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014;383:1129-1137.

Edwards TL, Jolly JK, Groppe M, et al. Visual acuity after retinal gene therapy for choroideremia. N Engl J Med. 2016; 374:1996-1998.

Xue K, Jolly JK, Barnard AR, et al. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. Nat Med. 2018;24:1507-1512.

Godfrey C, Desviat LR, Smedsrød B, et al. Delivery is key: lessons learnt from developing splice-switching antisense therapies. EMBO Mol Med. 2017;9:545-557.

Cideciyan AV, Jacobson SG, Drack AV, et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med. 2019;25:225-228.

Dr Audo is a consultant for Novartis, Biogen-Nightstar, MeiraGTX-Janssen, Roche, SparingVision and ViGeneron.

Investigators are conducting retinal gene therapy trials that offer potential new treatments for inherited causes of vision loss.

Retinal gene therapy clinical trials are addressing disease at core

This article was reviewed by Dr Amy K. Hutchinson.

As myopia rates continue to soar to epidemic levels worldwide, research has found that the use of orthokeratology and multifocal contact lenses provide clinically meaningful reductions in progression of the refractive error. Ophthalmologist Dr Amy K. Hutchinson recently commented on this. “Both lens types are thought to have a similar mechanism of action to slow myopic progression, and that mechanism is to eliminate peripheral hyperopic defocus and induce peripheral myopic defocus,” she said.

Peripheral hyperopic defocus occurs when myopia is corrected by monovision glasses or contact lenses. The central light rays focus on the fovea and provide a clear image, but peripheral light rays focus behind the plane of the retina, which is thought to play a role in myopia progression, she explained.

Genetics analysis may predict myopia in children

According to Dr Hutchinson, in support of this, clinical observations show a “significant reduction in myopia progression when bifocal glasses, multifocal contact lenses or overnight orthokeratology lenses are used to reduce the peripheral hyperopic defocus”. When measuring myopia progression, the result is expressed as the percentage of the changes in dioptric progression or axial lengthening between a treatment and control group; a 50% slowing is considered ideal and over 30% acceptable.

The centre distance design is used most often in multifocal lenses, in which the central area of the lens focuses the image on the fovea. “The peripheral area has a more positive power resulting from either distinct concentric rings or a gradual progressive increase toward the periphery,” Dr Hutchinson explained. This design provides the wearer with clear central vision and both eliminates the peripheral hyperopic defocus and introduces peripheral myopic defocus, which decreases the stimulus for myopic progression associated with monovision glasses and contact lenses.

Exploring possibilities of myopia prevention and control in the US

Currently, the MiSight multifocal contact lens by Cooper Vision is the only United States Food and Drug Administration-approved contact lens for myopia control. It has concentric peripheral rings that include a +2.00 D add. In a 3-year study, the lens slowed myopia progression in children (aged 8-12 years; refractive errors up to -4.0 D) by 59% and axial elongation by 52% compared with age-matched control children.

Other spherical and toric multifocal lenses are available for off-label use. Dr Hutchinson noted that evidence has suggested that higher add powers may result in better control of myopia progression. These lenses have been shown to slow myopia progression by -9.7–70% and slow axial elongation by 0–79%.

Orthokeratology lenses are worn overnight and temporarily reshape the cornea. “This technology uses a reverse-geometry rigid gas-permeable contact lens in which the base curve radius is flatter than the central corneal curvature, and the secondary curve is steeper than the base curve radius,” said Dr Hutchinson.

The central corneal flattening focuses the image on the fovea and eliminates the need for the patient to wear correction during the day. The lens steepens the mid-peripheral cornea and induces myopic defocus on the peripheral retina, thus controlling the myopia.

AAO: Myopia progression slowed with orthokeratology, multifocal lenses

The lenses, which are most useful for patients with low to moderate myopia, have demonstrated a 30–80% slowing of axial elongation. Slowing of the dioptric progression is not usually reported because the lenses cause a temporary shift in the refractive shift. There is some evidence that these lenses might be useful to treat anisometropia as well.

In the US, orthokeratology lenses are approved for wear overnight but not for myopia control, whilst in Europe, the Menicon Bloom lens (Menicon) is CE-marked for the control of myopia progression, one version being for nightly use and a second type designed for daily use.

However, safety with overnight contact lens wear has been a pervasive concern. There has only been one large retrospective study to estimate the incidence of microbial keratitis associated with overnight orthokeratology lens wear.

Based on the upper confidence interval of this study, the expected incidence of microbial keratitis is no more than 50 per 10,000 patient years, or 1 in 200 years of wear. However, avoiding the use of tap water is recommended. Overall, despite the reported success with contact lens wear to slow myopia progression, questions remain unanswered, including the ideal time to begin treatment, recommended treatment duration and what the rate of rebound myopia is with discontinuation of contact lens wear.

Dr Hutchinson is professor of ophthalmology and director of paediatric ophthalmology, Emory University School of Medicine, Atlanta, Georgia, US, and chief of ophthalmology at Children’s Healthcare of Atlanta. She has no financial interest in this subject matter.

Orthokeratology and multifocal contact lenses provide clinically meaningful reductions in progression of myopia, research shows, but some questions, such as the ideal treatment duration, remain unanswered.

Myopia progression can be slowed with multifocal and orthokeratology lenses

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