Large fluctuations in the central subfield thickness (CST) may predict worse visual acuity (VA) outcomes in patients with diabetic macular oedema (DMO),

 reported Matthew Starr, MD, and colleagues from the Wills Eye Hospital, Mid Atlantic Retina, Thomas Jefferson University, Philadelphia.

This conclusion was based on a post hoc analysis of a large cohort of eyes from the Diabetic Retinopathy Clinical Research Network protocols T and V clinical studies.

Starr and colleagues used the standard deviation of all of the recorded CSTs for each patient to quantify the fluctuations in the CSTs and the patients then were grouped into quartiles based on the standard deviations. The eyes were included in this analysis if a minimum of 3 CSTs and the 1-year VA were available. The main outcome measures were the VAs at the 1- and 2-year time points for each protocol, stratified by the standard deviation quartile, he explained.

The study reported significant differences in VAs in the 1,197 eyes included in the study based on the CST standard deviation quartile of protocols T and V with adjustment for the mean baseline VA, baseline CST, lens status, haemoglobin A1c, and treatment arm.

In protocol T, at week 52, a nonsignificant -1.61 letter difference in the Early Treatment Diabetic Retinopathy Study letters was seen between quartiles 1 and 4 (p = 0.0986). However, by week 104, the letter difference increased to −3.59 letters, which reached significance (p = 0.0066).

In protocol V, the letter differences were significant at both time points: at week 52, the difference was −3.04 letters between quartiles 1 and 4 (p < 0.0001) and at week 104, the difference was −2.35 letters (p = 0.0005).

The difference in the VAs based on CST fluctuations in these patients with DMO remained significant, even while adjusting for the mean baseline VA and CST levels, lens status, haemoglobin A1c, and treatment arm. “Eyes with larger fluctuations in CST had worse VA compared with eyes with the fewest CST fluctuations in both protocols,” they said.

Over time, such large fluctuations in CST may predict worse VA outcomes in patients with DMO.

1. Starr MR, Salabati M, Mahmoudzadeh R, et al. Fluctuations in central subfield thickness associated with worse visual outcomes in patients with diabetic macular oedema in clinical trial setting. 

https://doi.org/10.1016/j.ajo.2021.06.030

Articles

Eyes with larger fluctuations in central subfield thickness (CST) had worse VA compared with eyes with the fewest CST fluctuations in both protocols, according to investigators.

Central subfield thickness fluctuations in DMO may predict worse VA

Dr LaHood is an ophthalmologist specialising in refractive cataract and laser surgery in Adelaide, Australia. His research and teaching focus on the management of astigmatism. He is a consultant to Alcon and Zeiss.

This three-part series on using toric IOLs in cataract surgery is designed to provide some practical tips for success. 

, looked at patient selection and optimising biometry. 

, published in the November issue, covered the calculation of toric IOL sphere and cylinder power. In this final article in the series, I will examine the perioperative period and provide postoperative troubleshooting.

A toric IOL has maximum optical impact when aligned perfectly with the steep axis of the cornea. If it is a few degrees off, there is a decline in effect of astigmatic neutralisation. In general, most surgeons consider alignment within 10° to be accurate enough but in reality, a lot depends on the magnitude of astigmatism.

Misalignment of a high-power toric IOL can leave someone with a lot of residual astigmatism whereas misalignment of a very low cylinder power toric IOL may have a minimal effect. To align a toric IOL accurately, a reference mark must be used. There are many different methods of preoperative marking: ink markers, needle marking and even apps.

I prefer to use an intraoperative digital display system (Verion Digital Marker, Alcon or Callisto Eye, Carl Zeiss), not because these methods are more precise than manual marking but because they are more efficient and speed up the surgery. I do still make a manual mark on the eye in the sitting position prior to surgery as a back-up reference in case of difficulty with the digital system, but rarely need it.

Regarding manual marking, a single mark is adequate to align a Mendez ring. The human eye is incredibly good at halving things, so I will make a small mark inferiorly at the bottom of the cornea to split the cornea in half.

In the worst-case scenario, if your digital marking system fails, you have not pre-marked the eye and you still want to implant a toric IOL, I suggest that you still can safely do so. Simply look at the top of the cornea and identify the vascularised pannus. If you look at the midpoint of that pannus, this will be the midpoint vertically and you could drop a line down from that to halve the cornea.

If you look again at the widest point of the cornea and draw a line horizontally across it, you are going to give yourself an excellent surrogate marker; you could then use a Mendez ring and still be able to mark the axis to implant the toric IOL. You can safely use a toric even in this worst-case scenario.

The surgical technique of toric IOL implantation differs from standard cataract surgery because of the preoperative marking and the rotational placement of the lens. The IOL injection is similar to cataract surgery but I recommend being primed and ready to rotate quite rapidly as the IOL is expanding.

The unfolding of the IOL is a prime time to get it into a good position. Many will suggest, if you are using a C-loop haptic, to put it 5° before where you want it so that you can nudge it into the final resting position when you are doing the next steps of surgery. If you are using a plate haptic IOL, you can put it exactly where you want it because you can nudge it in either direction very easily.

I do not use a capsular tension ring unless necessary due to zonular instability, even in high myopes. I find that toric lenses from the major manufacturers have good rotational stability, and the need to rotate is extremely low.

If you do find that you have over-rotated your toric IOL past its intended position, there is no shame in turning it around again. Take your time. Inject some more viscoelastic into the capsular bag and use two instruments to completely rotate the lens all the way back to where you want it.

If you are wanting to move just a few degrees in the opposite direction, it is possible but be wary of putting too much stress on the capsule. My tip is to slightly deflate the anterior chamber, which will allow easier “backwards” rotation of the IOL within the capsular bag.

A key time that you may encounter a little IOL rotation away from its intended position will be at the end of the case when you take the instruments out of the eye. Sometimes, if the incision has not perfectly sealed, shallowing of the anterior chamber will allow some movement of the toric IOL within the capsule.

I highly recommend being quick with your incision hydration, trying not to let the anterior chamber flatten and keeping things quite firm at the end of the case. This prevents setting up a cycle of IOL rotation, entering the eye, flattening the chamber and further movement, etc. I have noticed a major decrease in my need to hydrate the main incision after injecting the Clareon toric IOL with the AutonoMe injector and this has been helpful in leaving a stable anterior chamber at the conclusion of the case with little risk of early rotation.

If you notice any early rotation after you have finished the case, go back in and put the lens back where it needs to be. This is a lot easier to do while you are still in the operating theatre rather than seeing it the next day and wishing you had taken the extra few minutes.

Postoperative care of a toric IOL patient is identical to that following any other cataract surgery. I recommend seeing the patient at 1 day, 1 week and 6 weeks postoperatively. On Day 1, I start to look for any early and significant rotation. If I notice a lens with significant malrotation, I take the patient directly back to the operating theatre and put the lens in the originally intended position.

If I notice on Day 1 that the lens is off by a few degrees, I am not concerned because the patient may be completely happy and it is fine to wait and see. Also, if the lens has moved a little, it means that it is not particularly stuck to the capsule and is a somewhat mobile. I would rather wait for the capsule to become more condensed so that if I do choose to rotate the lens, it is more likely to stay in that position long term.

At the 6-week postoperative appointment, I audit my results, looking at lens position both in terms of axial position and depth within the eye. This is also when I would perform an accurate subjective refraction.

Even if the patient is happy, I recommend doing a subjective refraction. It will give you so much more information that you can use to improve your future results. I also take more optical biometry measurements for my records. These are handy if I want to consider any kind of toric rotation or lens exchange and provide me with postoperative anterior chamber depth.

If a patient has significant post-op astigmatic refractive error, I follow a structured decision-making tree by asking myself first whether the patient is happy. If the patient is unhappy, I want to do something for them. On the other hand, a happy patient with refractive error may be truly happy as they are or may prefer glasses anyway so do not try to fix things — instead, learn from what may have gone wrong in that case.

If you examine the patient and find the lens is exactly where you intended yet they still have some residual refractive error, you may ask yourself what you have done wrong, but the answer is likely nothing. Either the patient had significant change in their surgically induced astigmatism or their initial biometry was not quite right. This is now a situation that needs a little further investigation before treatment decisions can be made.

You simply need a subjective refraction and measurement of the axis and pseudophakic anterior chamber depth, along with knowledge of the sphere and cylinder power of the implanted toric IOL. Working out whether you can rotate the IOL to fix the residual astigmatism or if an IOL exchange may be needed can seem daunting.

You will need to use an online tool to help you with this, but a good rule of thumb is that if the spherical equivalent of the subjective refraction is close to zero then you should be able to rotate the current IOL into a more optimal position for the patient. Ultimately, the patient will have to decide whether they want to have another surgical procedure so that you can rotate the IOL or whether they can have laser treatment to the cornea.

My preference is to rotate the lens to a better position to get rid of the residual astigmatism if I can, and it is a simple solution. My colleague Dr Michael Goggin and I created an app called Toric Pro.1 Other calculators include astigmatismfix.com and the Barrett RX formula. All these resources can tell you whether you can rotate the lens for a better residual refractive outcome.

There will be some patients who do not want to undergo surgery again and there will be some eyes that you will not want to re-enter. Perhaps they had unstable zonules or it was a difficult operation. For these cases, laser vision correction can be a safe and effective option.

Again, the most important thing in this situation is an accurate subjective refraction as this is what will be used in planning the laser surgery. Most people will know a friendly laser surgeon who is happy to help with such cases.

One of the most important points to make about re-rotating an incorrectly positioned IOL is that it is not appropriate to simply put the IOL at the originally intended position if it is not there already. Once you have made an incision and implanted a toric IOL, you have changed the eye. Surgically induced astigmatism has altered the shape and you now know how deep the toric IOL sits.

You have new information and a new subjective refraction to work with. Do not be tempted to just go in and put the IOL back unless on Day 1 there is a large rotational change from intended. In this scenario, I think it is reasonable to go back and reposition, often with the added security of a capsular tension ring.

If at any stage you do have to go back inside the eye, it can be particularly stressful because you want to get it right this time and because this is not a common procedure. My suggestion, if going back into the eye early, is to free up the lens and take a minimalist approach.

Use a little viscoelastic but do not fill the bag. Rotate the lens to its new position — and I always gently press or tap the IOL against the capsule to maximise contact between optic material and capsule.

If going back into the eye much later, when capsular fibrosis has sandwiched the IOL in place, take your time and be kind to the zonules. I recommend putting a needle between the IOL and the capsule edge before visco-dissecting the two apart.

There are times when an IOL simply cannot be completely removed and haptics must be left inside the bag. It is always good to have a sulcus and anterior chamber IOL option on standby in case there are any complications with this relatively tricky procedure. Also, remember that if you find yourself having difficulty rotating a previously implanted toric IOL, there is no harm in backing out and deciding that the safest course of action is to instead perform laser vision correction surgery.

I would like to encourage surgeons to implant toric IOLs more frequently. The tips and advice I have given in this series of three articles will help you plan for success and to be prepared for the rare occasions you must deal with failure.

Success is all about doing all the small steps well and minimising the chance of error. You will have to be a little more pedantic about reviewing preoperative results and considering postoperative data but the improvement in patient results will be worth it.

Giving due consideration to preoperative marking and the surgical technique in toric IOL implantation, as well as being diligent about reviewing postoperative results, can improve patient outcomes whilst minimising the chance of errors.

Toric IOLs for beginners: What to consider before and during surgery and in the postoperative period

Researchers at the University of Virginia School of Medicine have made a discovery linking lupus, a potentially debilitating autoimmune disorder, and macular degeneration, a leading cause of blindness.

The two diseases share a common contributor to harmful inflammation, the scientists found. The insights could let researchers develop new treatments for those diseases and other conditions driven by the newly discovered inflammation source.

“We were quite surprised at the common link between lupus and macular degeneration,” said Dr Jayakrishna Ambati of UVA’s Department of Ophthalmology and the founding director of UVA’s Center for Advanced Vision Science. “It appears that the new inflammatory pathway we identified could be therapeutically targeted for many chronic diseases.”

Dr Ambati and his collaborators have discovered an unknown role for an inflammasome – an agent of the immune system – called NLRC4-NLRP3. Inflammasomes play an important role in marshaling the body’s defenses to protect it from invaders such as viruses and bacteria.

In lupus and atrophic macular degeneration, however, it appears that NLRC4-NLRP3 contributes to harmful inflammation, the UVA researchers found. In lupus, it helps drive the hyperactive immune response that leads to symptoms such as joint pain, rash, fever and more. In macular degeneration, meanwhile, NRC4-NLRP3 appears to contribute to inflammation that destroys the vital light-sensing cells in the eye’s retina.

Dr Ambati’s new work helps explain why. The inflammasome, he found, is sent into action by a special class of genetic material called “short interspersed nuclear element RNAs,” or SINE RNAs. This type of RNA makes up more than 10% of our genomes, and it activates in response to cell stresses such as infection, genetic damage and aging. The resulting inflammation caused by SINE RNAs can be harmful in many chronic diseases.

SINE RNAs are elevated in both macular degeneration and lupus, Dr Ambati found. In addition to discovering the role of SINE RNA in the two diseases, Dr Ambati and his colleagues identified an unknown receptor for the SINE RNAs called DDX17. Scientists have been looking for this receptor for decades, and the new discovery helps them better understand the process that leads to the harmful inflammation.

“These findings indicate that blocking a single inflammasome might not be enough, and that targeting both the NLRC4 and NLRP3 inflammasomes would be a superior strategy,” Dr Ambati said.

Using this new information, scientists may be able to target the source of harmful inflammation in lupus, macular degeneration and other diseases driven by SINE RNAs. That could lead to new treatments to benefit patients, the UVA researchers say.

“We’re excited to have developed drugs called Kamuvudines that block this dual inflammasome, which we anticipate will be in clinical trials next year,” Dr Ambati said.

The researchers have published their findings in the scientific journal Science Immunology. The work is featured on the journal’s cover. The research team consisted of Shao-bin Wang, Siddharth Narendran, Shuichiro Hirahara, Akhil Varshney, Felipe Pereira, Ivana Apicella, Meenakshi Ambati, Vidya L. Ambati, Praveen Yerramothu, Kameshwari Ambati, Yosuke Nagasaka, Dionne Argyle, Peirong Huang, Kirstie L. Baker, Kenneth M. Marion, Kartik Gupta, Bo Liu, David R. Hinton, Scott W. Canna, Tamer Sallam, Srinivas R. Sadda, Nagaraj Kerur, Bradley D. Gelfand and Jayakrishna Ambati.

Jayakrishna Ambati is a co-founder of iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics and has done consulting work unrelated to the research. A full list of the authors’ disclosures is included in the paper.

The study was supported by the National Institutes of Health, grants DP1GM114862, R01EY028027, R01EY29799, R01EY031039, R01AI148741, R00EY024336, R21EY030651, R01EY028027, R01EY031039 and R01EY032512. It was also supported by the John Templeton Foundation, grant 60763; the UVA Strategic Investment Fund; the DuPont Guerry III professorship; a gift from Mr. and Mrs. Eli W. Tullis; the BrightFocus Foundation; and the Owens Family Foundation.

Inflammation link discovered between lupus and macular degeneration

Although many chronic medical conditions affecting the eyes can be effectively managed with oral medication, most chronic ocular conditions, such as diabetic retinopathy, macular degeneration, ocular inflammation, and glaucoma, require medication to be delivered locally, usually as eye drops or injections.

Despite their apparent ease of administration, incorrect and inconsistent use of eye drops is surprisingly prevalent. More than 90% of post-cataract patients self-administer their eye drops incorrectly, and about 30% of post-glaucoma surgery patients are nonadherent to topical treatment.

Fortunately, an increasing number of ophthalmic medications enable sustained drug delivery via intraocular or intracanalicular depots. For appropriate patients, there is significant benefit in terms of adherence, which may translate into improved efficacy and persistence with therapy. For example, in glaucoma, sustained delivery of bimatoprost via the recently-approved Durysta implant (bimatoprost implant 10 mcg, Allergan) substantially reduces the administration burden for patients while exposing target tissues to therapeutic levels of drug over several months.

Similarly, taking the example of chronic noninfectious ocular inflammation, sustained delivery of corticosteroids to the retina can offer a major advantage over conventional eye drops and frequent intra/periocular injections.

Sustained-release steroids are available as biodegradable and nonbiodegradable implants with different active compounds and durations of effect. For short-term control of postoperative inflammation, Dextenza (dexamethasone ophthalmic insert 0.4 mg, Ocular Therapeutix) is an intracanalicular insert that releases steroid onto the ocular surface, and Dexycu (dexamethasone intraocular suspension 9%, EyePoint) is a controlled-release suspension that is injected into the posterior chamber. Both are bio-erodible and designed to release dexamethasone for the first month following surgery.

Another bio-erodible formulation of dexamethasone, Ozurdex (dexamethasone 0.7 mg, Allergan), is an intravitreal implant that lasts 3 to 6 months. For some patients with uveitis and uveitic macular oedema that have been unresponsive to previous treatments, Ozurdex offers greater drug release in the first 2 months, then tapers over the following few months. Patients also tend to like that it’s bio-erodible.

For other patients, a more consistent, longer-term release of drug is desirable, such as that offered by Yutiq (fluocinolone acetonide intravitreal implant 0.18 mg, EyePoint) and Iluvien (fluocinolone acetonide intravitreal implant 0.19 mg, Alimera), which are indicated in the US for noninfectious uveitis affecting the posterior segment and for diabetic macular oedema, respectively. Both are nonbiodegradable polymer conjugates injected intravitreally, which provide a continuous microdose of fluocinolone over about 3 years.

The Durasert sustained-release technology on which both Yutiq and Iluvien are based is also at work in Retisert (fluocinolone acetonide intravitreal implant 0.59 mg, Bausch + Lomb), which provides a higher dose of fluocinolone and must be implanted surgically, rather than as an in-office injection.

 Sustained-release anti-inflammatory agents.

A history of intraocular pressure elevation following topical steroid drops should be considered carefully when weighing the option of a sustained-release steroid implant. I tend to use shorter-acting sustained-release options (Dextenza, Dexycu) for short-term postoperative inflammation or in a patient whom I suspect may have a stronger response to steroids, which is generally a very safe way to go. If a longer extent of treatment is desired, I will generally start with a sustained-release steroid that has a shorter duration of effect first, such as Ozurdex, to make sure the patient is steroid tolerant before switching to a longer-acting implant, such as Yutiq.

Another issue to consider with intraocular implants is the potential for migration within the eye; when it occurs, it can be a problem. If the implant migrates forward from the vitreous, it can result in damage to anterior segment structures, with the potential to impact vision. Thus, intravitreal implants should be used with caution in patients who have a compromised posterior capsule or are aphakic.

Patients who receive regular—often monthly—anti-VEGF injections shoulder a significant burden in terms of time, expense, and invasiveness of treatment. A study from 2016 found that each injection appointment (including travel time) took an average of 4.5 hours, and 53% of working patients needed to take off at least 1 day per appointment.

 In my practice, I’ve found these injections to be especially challenging for working-age patients who are also trying to balance jobs, family obligations, and other health problems.

One approach to reduce this burden is the port delivery system (PDS), which entails a surgically placed, permanent, and refillable drug-releasing port. The ranibizumab PDS (Susvimo, Genentech) requires refills approximately every 15 months and has been FDA approved for wet age-related macular degeneration (AMD), and is in development for treatment of diabetic retinopathy and diabetic macular oedema.

Developing a successful sustained-release ophthalmic drug: Challenge accepted

Challenges with developing sustained-release drugs for the eye often amount to issues with safety—the reason many products ultimately fall off the path to approval. The general principle of local, sustained delivery to ocular tissues is sound; but often, in the case of intravitreal therapies, adverse events, such as inflammation, intraocular pressure increase, and corneal issues due to implant migration are where these drugs fail. Moreover, in many cases, efficacy of investigational sustained-release drugs is adequate, but noninferiority or superiority to existing formulations is difficult to demonstrate.

There is no doubt that local, sustained delivery works, particularly in the posterior segment. With the agents available to us today, our threshold for efficacy and safety of new alternatives is higher than it may have been 15 years ago. The recent example of abicipar is illustrative: 2-year results from a pair of phase 3 studies (CEDAR and SEQUOIA) indicated that abicipar, a DARPin anti-VEGF agent, was noninferior for achieving stable vision in people with wet AMD, with fewer injections when compared with ranibizumab.

However, the trials also showed abicipar had more clinically significant medication-related ocular adverse events when compared with ranibizumab.

 Ultimately, the FDA deemed the benefit-risk ratio with abicipar unfavourable.

Clinical trial process: Rigorous and necessary

A few late-stage clinical trials are currently exploring other novel techniques to prolong duration of efficacy of intravitreal injections. KSI-301 is an anti-VEGF monoclonal antibody conjugated with a large biopolymer.

In the phase 1 study, 55% of patients achieved a 6-month retreatment interval; top-line results from phase 3 trials for neovascular AMD, diabetic macular oedema, and retinal vein occlusion are expected to begin reading out in late 2021.

 GB-102 uses bioabsorbable micro­particles to encapsu­late sunitinib malate, a tyrosine kinase inhibitor that targets both VEGF-A and platelet-derived growth factor.

 This formulation may extend the intravitreal retreatment interval to 6 months, and a phase 2 trial in patients with neovascular AMD is underway.

However, one needs to keep in mind that despite promising early-phase results, several sustained-release agents have not fared as well in late-stage trials.

⁠ ⁠⁠When it comes to developing new ophthalmic drugs and devices, we must keep in mind that not everything can be tolerated inside the eye.

As much as I want my patients to have access to more treatment options—particularly those that work over months and even years—we know in advance that a lot of these drugs won’t make it to market, and I believe this fact confirms we are running clinical trials very well. Our highly selective and rigorous FDA-approval process should make physicians and patients feel confident in the medications that are available on the market and being used to treat them.

I am glad there are partnerships that bring physicians, research groups, and pharma together, working hard to bring new and better treatment options to patients, investigating drugs and their adverse events thoroughly before the public has access to them. Patients with chronic medical conditions deserve to have treatment options that are both effective and convenient to use long-term.

Dr Reddy has no financial disclosures related to this content.

1. An JA, Kasner O, Samek DA, et al. Evaluation of eyedrop administration by inexperienced patients after cataract surgery. 

. 2014;40(11):1857-1861. doi:10.1016/j.jcrs.2014.02.037

2. Okeke CO, Quigley HA, Jampel HD, et al. Adherence with topical glaucoma medication monitored electronically the Travatan Dosing Aid study. 

. 2009;116(2):191-199. doi:10.1016/j.ophtha.2008.09.004

3. Tyson SL, Bafna S, Gira JP, et al. Multicenter randomized phase 3 study of a sustained-release intracanalicular dexamethasone insert for treatment of ocular inflammation and pain after cataract surgery. 

. 2019;45(2):204-212. Published correction appears in 

4. Sivaprasad S, Oyetunde S. Impact of injection therapy on retinal patients with diabetic macular edema or retinal vein occlusion. 

. 2016;10:939-946. doi:10.2147/OPTH.S100168

5. Khurana RN, Kunimoto D, Yoon YH, et al. Two-year results of the phase 3 randomized controlled study of abicipar in neovascular age-related macular degeneration. 

. 2021;128(7):1027-1038. doi:10.1016/j.ophtha.2020.11.017

6. Do DV. Extended durability in exudative retinal diseases using the novel intravitreal anti-VEGF antibody biopolymer conjugate KSI-301. Presented at: Angiogenesis, Exudation, and DegenerationMeeting; February8, 2020; Miami, FL.

7. A study to evaluate the efficacy, durability, and safety of KSI-301 compared to aflibercept in patients with macular edema due to retinal vein occlusion (RVO) (BEACON). ClinicalTrials.gov. Updated August 23, 2021. Accessed October 7, 2021. https://clinicaltrials.gov/ct2/show/NCT04592419?term=KSI-301&draw=2

8. A study to evaluate the efficacy and safety of KSI-301, an anti-VEGF antibody biopolymer conjugate, versus aflibercept in patients with neovascular (Wet) age-related macular degeneration (DAZZLE). ClinicalTrials.gov. Updated November 19, 2020. Accessed October 7, 2021. https://clinicaltrials.gov/ct2/show/NCT04049266?term=KSI-301&draw=2&rank=5

9. Baker-Schena L. Drug delivery for the posterior segment. American Academy of Ophthalmology. Accessed June 14, 2021. https://www.aao.org/eyenet/article/drug-delivery-for-the-posterior-segment

10. Samanta A, Aziz AA, Jhingan M, et al. Emerging therapies in nonexudative age-related macular degeneration in 2020. 

. 2021;10(4):408-416. doi:10.1097/APO.0000000000000355

11. Allergan, an AbbVie company, and molecular partners receive complete response letter from FDA on biologics license application for Abicipar pegol. News release. AbbVie; June 26, 2020. Accessed October 7. 2021. https://www.prnewswire.com/news-releases/allergan-an-abbvie-company-and-molecular-partners-receive-complete-response-letter-from-fda-on-biologics-license-application-for-abicipar-pegol-301084188.html

12. Vantipalli S, Sall KN, Stein E, et al. Evaluation of the safety and efficacy of OTX-TP, an intracanalicular travoprost insert, for the treatment of patients with open-angle glaucoma or ocular hypertension: a phase 3 study. 

Current options, challenges in developing novel therapies.

Exploring sustained drug delivery options in ophthalmology

Cheryl Guttman Krader is a contributor to Dermatology Times, Ophthalmology Times, and Urology Times.

Measures of functional vision, which refers to a person’s ability to use vision to perceive the environment and function in daily life, are needed to establish benefit of novel gene therapies for inherited retinal dystrophies (IRDs). To that end, a novel standardized orientation and mobility (O&M) course, the multiluminance mobility test (MLMT), was developed and validated to assess the response to treatment with AAV2-hRPE65 for patients with vision loss due to biallelic mutations in 

Researchers are now working to develop a virtual reality orientation and mobility (VR-O&M) test that could overcome the practical challenges associated with reliance on a physical course. In a recently published paper, Dr Tomas S. Aleman and colleagues reported on a study that provided proof-of-concept data supporting the use of a VR-O&M system to evaluate the potential for functional vision improvement using investigational therapies for IRDs.

“Our initial findings support further investment in time and resources to refine and validate the VR-O&M technique as an alternative to physical mobility courses,” said Dr Aleman, Irene Heinz-Given and John LaPorte Research Associate Professor in the Department of Ophthalmology at the Perelman School of Medicine, University of Pennsylvania in Philadelphia.

“Once basic VR-O&M tests are validated, the limitations of the current designs, such as lack of standardization and the inability of the VR instruments to explore the full range of our visual abilities, will need to be addressed,” he said.

Dr Aleman said plans were being made to evaluate the effects of gene therapy in an ocular disease, such as 

-LCA. It became obvious that a measure of the patient’s real-life behaviour was desirable and needed for endorsement of the safety and efficacy of the treatment by regulatory bodies, such as the FDA. The idea of the MLMT obstacle course was pursued as a paradigm that could determine whether the treatment had a positive effect on visual behaviour in a real-world simulated environment.

The course requires availability of a large space that is not available in most eye clinics. In addition, assembling the course is time-consuming and not easy.

Limitations for modifying luminance and obstacle size and position in ways that will accommodate testing of the diverse patterns of visual dysfunction and spectrum of severity of vision loss in patients with IRDs is another drawback of a physical course. Furthermore, test performance scoring is done manually by observers who review videos of the testing. The process is time-consuming and the observers must be masked to avoid bias, as patient confidentiality is not maintained in the recording.

A VR-O&M test using a commercially available headset and custom-designed software was pursued as a more flexible alternative.

“A VR testing paradigm requires a much smaller physical space, allows the opportunity for easily introducing virtually unlimited number of environmental modifications, and performance parameters are automatically detected and quantified,” Dr Aleman said. He added that the testing still involves a patient walking through a physical space, but the required area is much smaller than with the MLMT.

In developing the software for the VR-O&M, Dr Aleman and colleagues evaluated several different configurations in cohorts of both normally sighted control subjects and patients with 

-associated Leber congenital amaurosis (LCA). The test itself is similar to the MLMT, as it requires patients to follow arrows through a course while avoiding collisions with randomly placed obstacles. Subjects are fitted with hand trackers and foot trackers to record information. Performance on the VR-O&M course is scored based on the number of collisions and time taken to reach the course exit.

After testing the various configurations, a protocol was selected for further evaluation in 3 patients with 

-LCA, including 2 patients who performed the testing before and after receiving gene therapy. Results from the controls and the patients with LCA from testing done prior to gene therapy showed differences between the 2 groups in the illumination level needed to navigate the obstacle course as well as in the number of collisions that occurred and total time needed for completing the course.

Compared with their pretreatment performance, the patients who were retested after receiving gene therapy demonstrated improvements in required illumination, number of collisions, and total navigation time that corresponded with their improvements in cone- and rod-mediated sensitivities.

Aleman is a coauthor on intellectual property describing the virtual reality mobility test (PCT/US2019/ 029173 pending). He has no other relevant financial interests to disclose.

1. Aleman TS, Miller AJ, Maguire KH, et al. A virtual reality orientation and mobility test for inherited retinal degenerations: testing a proof-of-concept after gene therapy. 

 2021;15:939-952. doi:10.2147/OPTH.S292527

According to investigators, the virtual reality option could overcome hurdles associated with reliance on a physical course.

Study finds virtual reality paradigm viable for orientation, mobility testing

Korean investigators reported that poor kidney function negatively impacts the response to intravitreal bevacizumab injections (Avastin, Genentech Inc.) and intravitreal dexamethasone implantation (Ozurdex, Allergan) in patients with diabetic macular oedema (DMO).

Renal function may be a possible indicator of the patient response to treatment in this population, according to Dr Hyeseong Hwang from the Department of Ophthalmology, Chungbuk National University Hospital, College of Medicine, Chungbuk National University, Cheongju, Korea, and colleagues.

The clinicians reached this conclusion after reviewing the medical records of 117 treatment-naïve patients with DMO patients who were treated with intravitreal injections of bevacizumab. The investigators then classified the patients based on the response to that treatment, and those who were refractory to bevacizumab then received the intravitreal dexamethasone implant.

The patient population then was assessed to identify a relationship between systemic factors and the treatment response to both bevacizumab and dexamethasone.

Assessment of systemic factors in DMO patients

Dr Hwang reported that among the 117 previously untreated patients with DMO, 61 eyes (52.14%) responded to the bevacizumab injections. An intravitreal dexamethasone implant was inserted in 23 of the 56 eyes were did not respond to the bevacizumab treatment; of these, 17 (73.91%) responded to the dexamethasone implant.

The investigators commented that among the various systemic factors of the patients with diabetes, renal function, i.e., the blood urea nitrogen, creatinine, and estimated glomerular filtration rate values, showed a significant (p<0.05) negative correlation with improvement in the central subfield retinal thickness following treatment.

They also reported that there was no difference in the haemoglobin A1C levels regarding the treatment response to both bevacizumab and dexamethasone.

Based on this work, the authors concluded, “The renal function was significantly worse in patients with a poor response to [bevacizumab and dexamethasone]. Renal function could be used as a possible predictor for treatment response in certain patients with DMO. Furthermore, for patients with DMO with poor responses to anti-vascular endothelial growth factor or steroid treatments, assessment of renal function could help explain the poor treatment response.”

1. Hwang H, Lee H, Kim, Jin Y, et al. Systemic factors and early treatment response to intravitreal injection for diabetic macular edema. The role of renal function. Retina. 2021;41:1275-82; doi: 10.1097/IAE.0000000000003012

Assessment of renal function could help explain the treatment response for patients with diabetic macular oedema.

Renal function could be a predictor for poor treatment response in patients with DMO

Corneal collagen crosslinking (CXL) to increase corneal biomechanical strength has become the standard of care for eyes with the progressive disease keratoconus. The procedure is very effective at halting the ectatic process and thus reducing the risk for eventual corneal transplantation.

Because of the corneal flattening that occurs with CXL, patients can also benefit from some improvement in uncorrected and best-corrected visual acuity (UCVA and BCVA). Nevertheless, irregularity of the anterior corneal surface persisting despite CXL limits the improvement to visual acuity (VA) and is also associated with higher order aberrations (HOAs) that degrade the quality of vision.

The efficacy of the Athens Protocol, combining partial topography-guidedphotorefractive keratectomy (PRK) and CXL for stabilising keratectasia and improving VA, was first reported in the literature in 2010 and its long-term benefits have been shown in eyes with 10 years of follow-up.

 Although many investigators have reported on their experience with combined topography-guided PRK and CXL to treat eyes with keratoconus, widespread knowledge about its effects on HOAs is more limited.

We have been performing partial topography-guided surface ablation with CXL for visual rehabilitation and stabilisation of eyes with keratoconus. Our experience shows the benefits of using the surface ablation technique for regularising the anterior corneal surface, reducing HOAs and improving visual function.

The HOAs that are predominantly elevated in eyes with keratoconus are vertical and total coma.

 Coma is associated with a “comet-like” blur of the perceived image

 and it can be particularly disabling for patients. Spectacles and contact lenses correct errors in sphere and cylinder in eyes with keratoconus and thus improve VA, but these modalities do not address HOAs.

HOAs can be reduced with a wavefront-guided corneal ablation, but this technique is not the most appropriate for treating eyes with keratoconus because of limitations such as the challenge of obtaining a reliable wavefront map. Corneal topography, which is a static measurement, provides more reproducible data, and topography-guided PRK reduces HOAs by regularising the anterior corneal surface.

Ablation depth with excimer laser treatment is limited in eyes with keratoconus because of their thinner and inherently biomechanically weaker corneas; therefore the aim of the treatment is not to reach emmetropia but to normalise the anterior surface. The treatment results in improved BCVA secondary to the induced reduction in coma and reduction in spherical equivalent of manifest refractive error.

We perform subjective refraction and cycloplegic refraction according to our standardised protocols, with a focus on measuring the complete astigmatic error. Because of the inability to obtain an accurate clinical refraction in eyes with keratoconus, especially for moderate to advanced disease, we rely greatly on topographic imaging for the data.

To fully characterise the corneal surface, we use both a Scheimpflug topographer (Pentacam HR, Oculus) and a Placido imaging modality (ATLAS 9000, Carl Zeiss). Dual imaging also allows us to analyse HOAs with both Zernike and Fourier reconstructions. To evaluate the axis of the vertical coma and correctly identify the axis of astigmatism with Scheimpflug-based imaging, we turn off all HOAs except those related to coma (N8, N9, N18 and N19).

The topography scan and the irregularity data map generated by the 22 Placido discs of the ATLAS 9000 are transferred to the dedicated treatment planning station (CRS Master, Carl Zeiss) for the excimer laser (MEL 90, Carl Zeiss). The optical zone, treatment refraction and Z axes are adjusted to keep the ablation depth to a maximum of 50 microns.

The treatment begins with alcohol-assisted epithelial removal using 20% alcohol applied for 40 seconds. The ablation excimer pattern is then applied by the MEL 90. Mitomycin C 0.02% is applied to the ablated corneal surface with a soaked sponge for 30 seconds followed by copious irrigation with chilled balanced salt solution.

This is followed by the cross-linking procedure. Riboflavin 0.1% saline, HPMC (VibeX Rapid, Glaukos) is applied every minute for a total of 10 minutes. Ultraviolet-A light (10 mW/cm2) is delivered for 4.5 minutes, corresponding to a total energy of 2.7 J/cm2.

Postoperative management includes a bandage contact lens, topical dexamethasone 0.1% and topical ofloxacin 0.3% for 2 weeks. The following case highlights our approach and how it improves refraction, UCVA and coma.

A 39-year-old man presented with an interest in having laser vision surgery to correct his low myopia. He reported that he was managing with contact lenses and spectacles, but he found those options inconvenient because he was in the military.

His refraction was –0.75/–1.75×155 logMAR 0.00 OD and –0.75/–0.50×20 logMAR 0.00 OS. Slit-lamp evaluation showed a few corneal guttata. There were no other abnormal findings on clinical examination.

 Topographic maps and keratoconus staging results OD (left) and OS (right) suggest keratoconus.

On corneal topography, the front surface axial curvature maps for both eyes showed vertical asymmetry that strongly suggested keratoconus (Figure 1). Total HOA root mean square (RMS) was 0.617 μm OD and 0.601 μm OS (Figure 2).

. Preoperative Zernike HOA analysis OD (left) and OS (right).

Minimum corneal thickness was 545 μm OD and 543 μm OS. Treatment with topography-guided PRK plus CXL was recommended and the patient consented. Figure 3 shows the planned ablation patterns. The ablations were done with a 6.5 mm optical zone and expected depths of 37 μm OD and 25 μm OS.

 Planned ablation patterns OD (left) and OS (right).

Complete corneal re-epithelialisation was achieved at the 1-week follow-up visit. At 3 weeks, there was no evidence of corneal haze or other adverse sequelae, and the patient’s UCVA had improved to logMAR 0.22 OD and 0.24 OS.

At 3 months after the procedure, the patient’s UCVA was logMAR 0.00 OD and logMAR 0.50 OS. Visual acuity in the left eye improved to logMAR 0.00 with a refraction of –1.25/–0.50×113.

 Normalisation of the anterior corneal surface OD (left) and OS (right) at 3 months after topography-guided PRK combined with prophylactic CXL.

Corneal topography showed normalisation of the axial curvature maps OU, no evidence of ectasia and a small amount of regular astigmatism OS (Figure 4). Total HOA RMS had decreased to 0.445 μm OD and 0.447 μm OS (Figure 5), providing further evidence of the treatment’s benefit for regularising the anterior corneal surface.

 Postoperative Zernike HOA analysis OD (left) and OS (right).

The patient underwent an enhancement excimer laser procedure in the left eye at 12 months after the initial treatment, with an excellent result. At his last available follow-up, 6 weeks after the enhancement, UCVA in the left eye was logMAR 0.10. The patient was very satisfied with his visual outcome.

Early detection of keratoconus allows CXL to be performed when VA is still reasonably good and optimises prognosis for the patient. As in this case, patients with early keratoconus causing decreased vision often present for a refractive surgery consultation that enables diagnosis of their corneal disorder. The good outcomes that can be achieved for patients with keratoconus highlight the need to consider the implementation of screening programmes for this condition, as diagnosis and treatment at early stages can achieve excellent unaided acuities.

This case also highlights the efficacy of the topography-guided PRK procedure for normalising the anterior surface of the cornea and reducing coma in eyes with keratoconus. Recent reports substantiate its benefit for improving visual quality.

 We have also used topography-guided surface ablation techniques successfully for visual rehabilitation in eyes with irregular astigmatism and elevated HOAs related to conditions other than keratoconus, including in eyes with a history of trauma or infectious keratitis.

Regardless of the indication, patients need to be consented appropriately to establish realistic expectations for the outcome, depending on the severity of their condition and including the high probability of needing more than one laser treatment. In our experience, patients who elect to undergo the surgery are gratified by their improved visual quality.

David F. Anderson, PhD, FRCOphth, FEBO, MB, BS, CCST, and Aris Konstantopoulos, MB, ChB, MSc, FRCOphth, PhD

Drs Anderson and Konstantopoulos are both based at the Laser Vision Eye Centre, Nuffield Health Wessex Hospital, Hampshire, UK. They have no relevant financial interests to disclose.

1. Krueger RR, Kanellopoulos AJ. Stability of simultaneous topography-guided photorefractive keratectomy and riboflavin/UVA cross-linking for progressive keratoconus: case reports. 

2. Kanellopoulos AJ. Ten-year outcomes of progressive keratoconus management with the Athens Protocol (topography-guided partial-refraction PRK combined with CXL). 

3. Iselin KC, Baenninger PB, Bachmann LM, et al. Changes in higher order aberrations after central corneal regularization - a comparative two-year analysis of a semi-automated topography-guided photorefractive keratectomy combined with corneal cross-linking. 

4. Maeda N, Fujikado T, Kuroda T, et al. Wavefront aberrations measured with Hartmann-Shack sensor in patients with keratoconus. 

5. Alió JL, Shabayek MH. Corneal higher order aberrations: a method to grade keratoconus. 

6. Hefner-Shahar H, Erdinest N. High-order aberrations in keratoconus. 

7. El-Massry AA, Dowidar AM, Massoud TH, Tadros BGD. Evaluation of the effect of corneal collagen cross-linking for keratoconus on the ocular higher-order aberrations. 

8. Zhang Y, Chen Y. Topography-guided corneal surface laser ablation combined with simultaneous accelerated corneal collagen cross-linking for treatment of keratoconus. 

Partial topography-guided surface ablation, combined with corneal collagen crosslinking when visual acuity is still quite good, optimises prognosis for the patient with keratoconus.

Optimising visual function in keratoconus

At the 2021 American Academy of Ophthalmology annual meeting, Dr Ted Leng presented his talk entitled “Variations in Vitreoretinal Physician Utilization of Ancillary Testing: An IRIS Registry Analysis” during Retina Specialty Day. The IRIS Registry Analysis considered how many ancillary tests were ordered on a per patient basis, accounting for a variety of factors to identify patterns.

 This is a really exciting study that we conducted using the American Academy of Ophthalmology’s IRIS registry, given just a large amount of data that's in there. And as a retinal physician, we are super reliant on ancillary testing in our everyday practices to see, you know, which patients have retinal disease and how we're managing them.

So what we wanted to do in this study was to look at the utilization of ancillary tests by retinal physicians in the United States on retinal patients.

To go into some more detail, this was a three-year study, where we looked at retinal physicians from January 2018 to December 2020. And look at the amount of OCTs, fundus photographs and fluorescein angiograms they were performing. And then we normalized that data and looked at how physicians in different regions throughout the United States were using these tests, whether certain payers like Medicare or non-Medicare were utilizing these tests, and then also different practice settings, such as academic medical centres versus non-academic medical centres.

What we found was actually quite interesting. Once we did normalize the data, we did see that physicians in the Midwest region—and we use the four regions of the US Census Bureau—so the Midwestern states actually were performing more OCTs on a per patient basis than physicians in other regions. Medicare patients were getting more OCTS on a per patient basis per year than non-Medicare patients. And lastly, patients cared for in a non-academic medical centre, were getting more OCTs on a per patient basis than that not.

So I think, while those results in and of themselves are interesting, we then delve deeper into trying to ask why we saw these differences in practice patterns amongst retinal physicians. And one of the things that we looked into was the volume of wet macular degeneration patients as a kind of benchmark to see if that affected the use of OCT-A, for example.

So what we did was we asked, does a physician who sees more wet AMD patients per year use more OCT or less OCT than someone who doesn't do as many wet macular degeneration patients.

Dr Ted Leng discusses his presentation, “Variations in Vitreoretinal Physician Utilization of Ancillary Testing: An IRIS Registry Analysis” during Retina Specialty Day at AAO 2021.

Delving into ancillary testing frequency based on the IRIS registry

Electronic health records: how the pandemic highlighted the future of practice management

Investigating best practices for MicroPulse transscleral therapy for glaucoma