Central retinal artery occlusion (CRAO) is a vision-threatening disorder for which there is no well-established treatment. Intra-arterial tissue plasminogen activator (tPA) has the potential to fill that gap but it has to be given in time, according to Dr Gareth Lema, Senior Faculty, Icahn School of Medicine at Mount Sinai, New York.

Dr Lema and colleagues believe that substantial loss of vision can be prevented by “timely treatment” of CRAO using intra-arterial tPA when it is administered within a window 6-12 hours at most after the onset of symptoms, as they reported previously.

This treatment, however, does not come without challenges. Time is retina; and minutes count. Patients often do not present in time for treatment or unnecessary delays diagnosis affect the eligibility for treatment. Acute painless unilateral vision loss is not often perceived as a possible stroke, Dr Lema pointed out. Even among doctors, only about a third of ophthalmologists refer patients for an emergent stroke evaluation.

If a patient presents to the emergency department on time, the only path to treatment is a full consult with an ophthalmologist, including a dilated exam.

The goal of this new protocol is to remove the diagnostic delay and decrease the time to treatment to within 3 to 6 hours after symptom onset, by eliminating the onsite ophthalmology consult.

In the previously mentioned study, Dr Lema recounted, visual acuity improvements were seen in 66% of the 15 patients treated with intra-arterial tPA, 53% had a 3-line improvement in vision, 4 patients who presented with counting fingers to no light perception vision improved to 20/80 vision or better. There were no major adverse events.

In the study, the mean tPA dose was 17 mg and the tPA was infused via a transfemoral arterial approach. The mean time to treatment was 8.83 hours (range, 5.5-12 hours).

Importantly, he pointed out, these improvements exceed those with the natural course of the disease and in some cases, “dramatic improvement” was achieved with earlier treatment.

Telemedicine, which was adopted by many ophthalmologists during the COVID-19 pandemic, can be instrumental in streamlining treatment of CRAO. To expedite the diagnosis, OCT machines were placed in three stroke centres within the Mount Sinai Health System. Scans are obtained by the stroke service and transmitted to a retina attending along with history and exam data, such a visual acuity and pupil exam. The diagnosis can be made in minutes and eligible patients can rapidly obtain treatment.

Dr Lema concluded, “CRAO is visually debilitating, but establishing collaborative relationships with our stroke colleagues and optimizing the evaluation can save vision by decreasing the time to treatment.”

Sobol EK, Sakai Y, Wheelwright D, et al. Intra-arterial tissue plasminogen activator for central retina arterial occlusion. Clin Ophthalmol 2021;15-601-8.

Articles

Intra-arterial tPA treatment could provide benefits for patients with central retinal artery occlusion. 

Study proves intra-arterial tissue plasminogen activator beneficial for treatment of central retinal artery occlusion

John Saharek, president of ImprimisRX, speaks with 

's David Hutton on three new products the company will be featuring during the American Academy of Ophthalmology's 2021 annual meeting, including:

 Moxi-Brom (moxifloxacin hydrochloride 0.5% and bromfenac sodium sesquihydrate 0.075%)

 Klarity-CL drops (cyclosporine 0.1% / loteprednol etabonate 0.2% ophthalmic suspension)

Tim-Brim-Dor-Bim (prednisolone acetate 1%, gatifloxacin 0.5%, bromfenac 0.075%).

The American Academy of Ophthalmology (AAO) annual meeting was held November 12 to 15 at the Ernest N. Morial Convention Centre in New Orleans, Louisiana, United States. The event included Subspecialty Days and a virtual component for remote participation.

Videos

ImprimisRx President John Saharek shares an update on a few of the company's latest products during AAO 2021. 

President John Saharek on the ImprimisRx pipeline, details 3 products

The American Academy of Ophthalmology (AAO) annual meeting is going live and will be held November 12 to 15 at the Ernest N. Morial Convention Centre in New Orleans, Louisiana.

The event will include Subspecialty Days and will also offer a virtual component.

According to Debra Rosencrance, vice president of meetings and exhibits at AAO, after being totally virtual in 2020, the biggest thing attendees can look forward to at this year’s meeting is being together.

“We have noticed at our 2 recent in-person board meetings how much people enjoy just being together,” she said. “While virtual provided the opportunity to still see and hear great content, the networking is just not the same online as it is in person. That includes being able to walk the exhibit floor and experience the new technology.”

In New Orleans, AAO 2021 attendees can expect a new format based on strategic planning that was completed in early 2020.

“The meeting has been shortened by a day,” Rosencrance explained. “The session times have been standardized to allow for more and longer breaks. The opening session is now on Friday evening from 5 to 6:30 pm. This recreated meeting format will provide more opportunity for more networking either with colleagues or exhibitors.”

As the meeting will have a packed agenda, Rosencrance added that there will be a lot for those attending in person to take away, including the in-person experience.

“The hallway conversations with colleagues, catching up with friends, discussing the ophthalmic devices with exhibitors, and listening to world-renowned experts covering every facet of ophthalmology [are all part of the experience],” she pointed out. "Of particular note, this year marks the 20th anniversary of the Cataract Spotlight moderated by David F. Chang, MD, and Nicole Fram, MD.”

This popular and fast-paced symposium will focus on cataract complications, and features many of the world’s leading ophthalmic surgeons.

Another popular item on the agenda each year is Subspecialty Days, and with an array of subspecialties highlighted, Rosencrance noted that there is plenty to choose from.

“In retina, Mark Humayun, MD, [PhD,] will give the Charles L. Schepens Lecture on retinal implants on Friday, and on Saturday there will be a discussion on artificial intelligence,” she said. “In glaucoma, there is a discussion on lens and glaucoma as well as a MIGS [minimally invasive glaucoma surgery] case-based section. In cornea, you can hear about the battle of the bugs, and therapies on the horizon.”

In addition to retina, cornea, and glaucoma, Subspecialty Days feature neuro-ophthalmology, ocular oncology and pathology, ocular plastic surgery, paediatric ophthalmology, and refractive surgery.

Rosencrance also noted that the American Academy of Ophthalmic Executives practice management program will be ophthalmologists’ 1-stop resource for their entire practice team.

“There are courses on fundamentals of coding, how to start a private practice, leadership skills, personal and practice finances, contracting, and much more,” she said.

Another key attraction will be the host city of New Orleans. Rosencrance expects that attendees will enjoy everything the Big Easy has to offer.

“New Orleans is always a favourite location, especially for the US ophthalmologists,” she said. “There is no other city like New Orleans, with its unique blend of southern hospitality, rich history, and world-class restaurants.”

The region was hit by Hurricane Ida in late August, but New Orleans did not suffer the damage seen in some other areas, and power was restored within weeks.

“The central business district and the French Quarter did not have significant damage from Ida,” Rosencrance noted. “Power was restored much quicker than anticipated, with 99% of the city already back on by September 13. Restaurants, hotels, and attractions are open and ready for visitors.”

Although Ida’s impact hasn’t rocked the boat for attendees, the COVID-19 pandemic will make its presence felt in many ways during the event.

According to Rosencrance, all attendees, including health professionals, exhibitors, and academy staff, will have to show proof of vaccination to enter the convention centre. The AAO will be using the Clear Health Pass app.

“Attendees will be able to take a picture of their vaccine cards to upload to the app,” she said. “Once [they have been] verified, the app will provide a green check mark which will be used to enter the convention centre and to pick up your badge. In addition, masks will be required in the convention centre.”

Rosencrance added that this year’s meeting room setup will provide more physical distancing than usual as well.

As the academy returns to live meetings, Rosencrance said the preparation can be a daunting task under normal circumstances. This year, she noted, it is hard to gauge what attendance will be there due to a variety of factors.

“A lot of people’s crystal balls are cloudy these days, but we anticipate being down between 30% and 40% from a typical year,” she concluded. “Of course, we have financial benchmarks that we hope to meet, but just being able to bring the ophthalmology community safely together again will be a tremendous success.”

The American Academy of Ophthalmology's annual meeting will proceed November 12 to 15 in New Orleans, Louisiana.

AAO 2021 kicks off in the Big Easy

By Prof. Robert P. Finger, Prof. Vincent Daien, Mr James S. Talks, Prof. Taiji Sakamoto, Prof. Bora M. Eldem, Dr Monica Lövestam-Adrian and Prof. Jean-François Korobelnik

It is well accepted that randomised controlled trials (RCTs) are the gold standard in establishing the efficacy of a clinical intervention. However, since such studies often have strict inclusion criteria and stringent requirements for patient follow-up, they often have greater patient adherence than that seen in the clinic and can exclude some of the types of patients routinely seen in day-to-day practice.

In addition, RCTs can be extremely expensive to conduct and study enrolment can be relatively slow compared with non-randomised studies.

 This is where data collected from routine clinical practice comes in. Such data enable the generation of real-world evidence (RWE), which can complement information from RCTs by providing insights regarding the safety and effectiveness of an intervention in broader patient populations under routine care conditions.

This evidence can be derived from real-world data from various sources, including electronic health or medical records (also referred to as EHR or EMR), patient registries, medical claims databases, retrospective or prospective observational studies or clinical audits (Table 1).

 RWE is increasingly being used to support drug approvals

 and in health technology assessments to support reimbursement.

In that respect, it is already guiding clinical practice. With a better understanding as to how to assess the quality of real-world studies, clinicians can use this evidence appropriately to inform their own clinical decision-making at both practice and patient level.

Abbreviations: CRVO, central retinal vein occlusion; DMO, diabetic macular oedema.

In ophthalmology, there is an increasing global evidence base that describes the use of intravitreal anti-vascular endothelial growth factors (anti-VEGF) in routine clinical practice.

 Such studies have shown that, in routine practice compared with RCTs, there is both a lack of adherence to, and undertreatment with, anti-VEGF therapy, including non-persistence, whereby patients do not continue therapy in the medium-to-long term.

This remains a significant barrier to optimising real-world outcomes for patients with chronic, progressive retinal conditions such as neovascular age-related macular degeneration (nAMD). Certainly, more RWE for effective strategies that can be employed at a clinic/ practice level to improve adherence and persistence to anti-VEGF agents would be welcomed.

In addition, there are inherent limitations to data collection in real-world clinical practice; as a result, RWE may vary in quality.

 This is partly because of heterogeneity in data gained from different sources and variability in both the application of RWE methodologies and the interpretation of the resulting evidence. Furthermore, depending on the RWE source, data may be inconsistently collected, misclassified or missed — this is known as information bias.

A recent systematic review analysed 64 real-world ophthalmology data sources from 16 countries for completeness of data relating to different outcomes and only ten scored highly.

 Most of these sources provided information on baseline status, clinical outcomes and treatment, but few collected data on economic and patient-reported burden.

Another issue within ophthalmology is how the treatment regimens, particularly for anti-VEGF agents, are described. Intravitreal aflibercept, brolucizumab, pegaptanib and ranibizumab have indications for retinal diseases, but in some European countries, bevacizumab is used and reimbursed off-label, despite jurisdictional ambiguity and, often, a legal risk for prescribing physicians.

Sometimes, there is a lack of clarity as to whether patients were treated with fixed dosing, pro re nata therapy or treat-and-extend dosing and the degree of adherence to those schedules.

 This makes understanding treatment effectiveness and comparing studies particularly challenging.

Although information bias may be one of the easiest types to identify and quantify, RWE is also prone to other biases. Therapies may be differently prescribed depending on patient and disease characteristics, leading to selection and channelling biases (for example, older patients or those with more advanced disease tending to receive one therapy over another).

In addition, patients or caregivers may be more likely to report only the most recent or impactful events, leading to recall bias; and, in some cases, events are more likely to be captured in one treatment group than another, resulting in detection biases.

 It is important that such limitations are recognised and RWE is interpreted in this context.

Introducing a novel RWE quality assessment tool

Throughout medical school and early in their medical careers, clinicians are taught how to assess the robustness of clinical studies, learning about randomisation, methods of blinding and different types of controls.

 It is similarly important to understand the quality of RWE.

RWE is becoming an increasingly important component of the overall evidence-based treatment of retinal diseases. However, clear guidance on how to assess the rigor of real-world studies and the conclusions and recommendations they generate in the field of ophthalmology is lacking. 

Abbreviations: GRACE, Good Research for Comparative Effectiveness; RWE, real-world evidence.

As shown in Figure 1, an RWE steering committee—a coalition of leading retinal specialists and methodological experts—recently developed a user-friendly framework assessing the quality of available RWE for retinal diseases, including nAMD, diabetic macular oedema and retinal vascular occlusion.

 The goal was to assist ophthalmologists in independently drawing relevant and reliable conclusions from RWE and understanding its applicability to their practice.

Abbreviations: DMO, diabetic macular oedema; ETDRS, Early Treatment Diabetic Retinopathy Study; nAMD, neovascular age-related macular degeneration; OCT, optical coherence tomography; RVO, retinal vein occlusion.

The Good Research for Comparative Effectiveness (GRACE) checklist was selected as the basis of the RWE quality assessment tool. This is an 11-item screening tool that evaluates methodology and reporting to identify high-quality observational comparative effectiveness research.

 The checklist has been extensively validated, has demonstrated strong sensitivity and specificity and can be successfully applied by a wide variety of users with different training backgrounds.

Although the checklist was developed specifically for comparative effectiveness research, many of the items were also considered applicable to non-comparative studies. It was adapted for the retinal diseases field by omitting items that were not considered relevant to a practical, clinically focused ophthalmology audience, and adapting or combining some items for easier application.

Considerations when assessing quality of RWE

The adaptation of the GRACE checklist to be more specific to, and relevant for, ophthalmologists has resulted in the development of the retinal diseases RWE quality assessment tool. Table 2 summarises the retinal disease-specific aspects of the checklist.

This addresses treatment details, how outcomes were assessed/quantified, descriptors of the study population and possible sources of bias. More details and examples of what to consider can be found in the full publication.

The purpose of the tool is to specifically assess the quality of RWE generated by a specific study in a population of patients with retinal disease. Caution should be exercised when comparing RWE across different retinal disease studies because of the heterogeneity mentioned previously regarding the different methodologies employed, as well as heterogeneity in patient populations, disease characteristics and treatment regimens.

RWE is a growing in importance as a source of information that, when evaluated appropriately, can help to support clinical decision-making. Regulators also increasingly accept that RWE may be needed in appraising post-marketing value. The retinal diseases RWE quality assessment tool can help clinicians to understand which findings from real-world studies are most robust and applicable to their practice.

Robert P. Finger, Vincent Daien, James S. Talks,Taiji Sakamoto,Bora M. Eldem,Monica Lövestam-Adrian and Jean-François Korobelnik

Prof. Finger is based at the Department of Ophthalmology, University of Bonn, Bonn, Germany; Prof. Daien at the Department of Ophthalmology, Gui De Chauliac Hospital, Montpellier, France and The Save Sight Institute, Sydney Medical School, The University of Sydney, Sydney, Australia; Mr Talks at the Department of Ophthalmology, Royal Victoria Inﬁrmary, Newcastle upon Tyne, UK; Prof. Sakamoto at the Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima and J-CREST, Japan; Prof. Eldem at the Faculty of Medicine, Ophthalmology Department, Hacettepe University, Ankara, Turkey; Dr Lövestam-Adrian at the Department of Ophthalmology, Lund University Hospital, SUS Lund, Sweden; and Prof. Korobelnik at CHU Bordeaux, Service d’Ophtalmologie, Bordeaux, France and the University of Bordeaux, INSERM, BPH, U1219, Bordeaux, France.

The authors have no commercial interests in relation to the article. Medical writing and editorial support for preparation of the article, under the guidance of the authors, was provided by ApotheCom, which was funded by Bayer Consumer Health.

1. Talks J, Daien V, Finger RP, et al. The use of real-world evidence for evaluating anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration. 

2. Okada M, Mitchell P, Finger PM, et al. Non-adherence or non-persistence to intravitreal injection therapy for neovascular age-related macular degeneration: a mixed-methods systematic review. 

3. Lauer MS and D’Agostino RB Sr. The randomized registry trial--the next disruptive technology in clinical research? 

4. United States Food and Drug Administration. Real-world data (RWD) and real-world evidence (RWE) are playing an increasing role in health care decisions. 2020; Available from: https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence.

5. Egan C, Zhu H, Lee A, et al. The United Kingdom Diabetic Retinopathy Electronic Medical Record Users Group, Report 1: baseline characteristics and visual acuity outcomes in eyes treated with intravitreal injections of ranibizumab for diabetic macular oedema. 

6. Bhandari S, Nguyen V, Fraser-Bell S, et al. Ranibizumab or aflibercept for diabetic macular edema: comparison of 1-year outcomes from the Fight Retinal Blindness! registry. 

7. Rayess N, Vail D and Mruthyunjaya P. Rates of reoperation in 10,114 patients with epiretinal membranes treated by vitrectomy with or without inner limiting membrane peeling. 

8. Faramawi MF, Delhey LM, Chancellor JR and Sallam AB. The influence of diabetes status on the rate of cataract surgery following pars plana vitrectomy. 

9. Calster JV, JacobJ, Wirix M, et al. A Belgian retrospective study in patients treated for macular edema secondary to CRVO: 1-year real-world intravitreal aflibercept data. Presented at EURETINA 2018.

10. Korobelnik JF, Daien V, Faure C, et al. Real-world outcomes following 12 months of intravitreal aflibercept monotherapy in patients with diabetic macular edema in France: results from the APOLLON study. 

11. Fajgenbaum MAP, Neffendof, JE, Wong RS, et al. Intraoperative and postoperative complications in phacovitrectomy for epiretinal membrane and macular hole: a clinical audit of 1,000 consecutive eyes. 

12. Bolislis WR, Fay M and Kühler TC. Use of real-world data for new drug applications and line extensions. 

13. Leahy TP, Ramagopalan S and Sammon C. The use of UK primary care databases in health technology assessments carried out by the National Institute for health and care excellence (NICE). 

14. Finger RP, Daien V, Talks, JS, et al. A novel tool to assess the quality of RWE to guide the management of retinal disease. 

15. Daien V, Eldem BM, Talks JS, et al. Real-world data in retinal diseases treated with anti-vascular endothelial growth factor (anti-VEGF) therapy–a systematic approach to identify and characterize data sources. 

16. Bro T, Derebacka M, Jørstad ØK, Grzybowski A. Off-label use of bevacizumab for wet age-related macular degeneration in Europe. 

17. Blonde L, Khunti K, Harris, SB, et al. Interpretation and impact of real-world clinical data for the practicing clinician. 

18. Moher D, Jaded AR, Nichol G, et al. Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists. 

19. Dreyer NA, Bryant A andVelentgas P. The GRACE Checklist: a validated assessment tool for high quality observational studies of comparative effectiveness. 

A recently developed tool can help ophthalmologists to assess the quality of findings from real-world studies in retinal diseases. This will help them decide which results are most robust and applicable to their practice. 

Assessing the quality of real-world evidence in retinal diseases 

Dr Timothy G. Murray discusses his talk at ASRS entitled, “

Combined MIVS/Phacoemulsification for Concomitant Management of Retinal Pathology With Cataract: 5-Year Followup of a Large, Consecutive Case Series.”

 The presentation took place on 11 October, 2021.

Dr Murray practices as a retina specialist at Miami Children’s Hospital, Baptist Health System and Jackson Memorial Hospital. He is also the Founding Director/CEO of Ocular Oncology and Retina of Miami Florida (MOOR).

 So it's kind of exciting to be able to speak at ASRS. And one of my big interests has been combining anterior and posterior segment surgery together for our patients, so that they can have surgery, one procedure that allows them the best ability to recover their vision with the least risk. And that was what we presented here, showing five-year followup data on one of the largest series of patients ever to be reported.

It was kind of interesting; patients had really bad vision when they entered because I have a practice that has some complex surgical patients. So about 20/200 vision when they started. And then by three years, the patient's vision had improved to 20/40, which is, which is what we look at as driving vision, and they were able to maintain that through five years. So I think it was very, very exciting to have the long-term followup with this kind of combined surgery for the first time.

I think the problem is in the United States, it's very difficult to combine surgeries that include intersegment cataract surgery with posterior segment vitrectomy. It's interesting that our international colleagues do this routinely. So I think the idea here is as our younger doctors are training and they're outstandingly competent in both these areas, that they're now able to provide that to their patients. And this gives some support for the ability to do that in a very safe way, but also in a very sustainable way for our patients.

The American Society of Retina Specialists (ASRS) hosted its 39th Annual Scientific Meeting from the 8th to the 12th of October, 2021, at the JW Marriott San Antonio Hill Country Resort and Spa in San Antonio, Texas.

According to ASRS, its 2021 scientific programme offered attendees innovations in retina science, clinical practice and surgery with 148 papers, 165 posters, 46 papers on demand, and 69 films, as well as a wide range of networking opportunities and the chance to exchange ideas and perspectives with peers.

Dr Timothy G. Murray discusses the 5-year followup data from a large, consecutive case series of combined anterior and posterior segment surgery and the benefits of a single procedure for the recovery of vision and decreased risk.

5-year followup data for study on combining anterior and posterior segment surgery

The onset of the COVID-19 pandemic had a profound effect on medicine and eyecare worldwide. In a recent study, Dr Ningli Wang, director of Beijing Tongren Eye Center, China, described its impact on ophthalmology in China.

Ophthalmologists as a group had the highest risk of contracting the COVID-19 virus because of the close proximity between clinicians and patients during ocular examinations. To define the risk, Dr Wang and his colleagues sent a cross-sectional case-control questionnaire to 10 hospitals to investigate the incidence and distribution of symptomatic virus in eye professionals in Wuhan, China, between 26 February and 20 March 2020.

The questionnaire collected information on demographics, personal protective equipment and hand hygiene. “The goal was to improve safety among eye professionals working during the pandemic,” Dr Wang said. The results showed that two of the 10 hospitals in the area covered by the study were hit especially hard because they were situated close by (4.5 km) to the Hunan Seafood Wholesale Market, where the early viral outbreak was reported.

“The overall incidence of symptomatic COVID-19 was 2.52% among eye professions as compared with 2.27% among all healthcare workers, indicating the higher risk of contracting the virus among ophthalmologists,” Dr Wang said. In the hospitals surveyed, 28 cases of the virus were found in eye professionals.

The risk factors identified for the incidence of COVID-19 among ophthalmologists were older age, longer time in practice, lack of sleep, lack of protective equipment and higher rates of contact with patients with suspected or confirmed COVID-19. “The incidence of COVID-19 peaked during the early phase of the pandemic and decreased significantly 2 weeks after lockdown,” Dr Wang said. During lockdown, only cases requiring emergent care were examined in clinics.

The ocular manifestations of COVID-19 were keratoconjunctivitis; scleritis; uveitis; central retinal vein occlusion; optic neuritis; cranial nerve palsy; and Miller Fisher syndrome. The clinical signs lacked specificity, however, and were seen as either the initial manifestation, concomitant with other symptoms, or the only symptom. This presentation increased the difficulty in diagnosing COVID-19 infection.

Dr Wang explained that the prevalence rate of conjunctivitis and/or conjunctival congestion was 8%; other prevalence rates were foreign body sensation at 6%, increased secretion at 10% and ocular itching at 9%. However, the ocular symptoms were present less often than other symptoms, such as fever, coughing and fatigue.

Chinese practice patterns and precautions

Dr Wang reported that the most important practices for ophthalmologists are disinfecting hands and equipment after examinations, use of a protective shield, alternative examination methods to ensure safe distancing and ventilation. For other healthcare workers, the safety measures included using personal protective equipment, checking temperatures at least twice daily, stopping working in the presence of symptoms and maintaining a distance of 1.5 m from patients during visits.

For the general public, there is a low risk of contracting COVID-19 through ocular transmission; wearing a mask, careful hand washing and wearing goggles in high-risk areas are important safety precautions. Dr Wang cautioned that the exact mechanisms of ocular transmission and ocular damage are unknown.

“Long-term ocular complications need further observation,” he said. “Ocular equipment manufacturers can add protective shields to the equipment. The Chinese consensus for COVID-19 eye disease will be released and the Chinese experiences shared with ophthalmologists worldwide.”

This article is adapted from Dr Wang’s presentation at the Glaucoma Research Foundation New Horizons Forum. He has no financial interest in this subject matter.

Ophthalmologists’ close proximity to patients put them at higher risk of contracting the virus.

The impact of COVID-19 on Chinese ophthalmology at the start of the pandemic

Chronic pain is a common and often debilitating condition. According to Brandon Baksh, from the University of Miami, Florida, United States, chronic pain syndromes can be localised to the head and face and involve the trigeminal system: for example, in migraine and trigeminal neuralgia. Mr Baksh noted that chronic pain syndromes can also be widespread, such as in fibromyalgia, or localised to areas outside the head and face, such as back pain.

Nerve abnormalities have been linked to chronic pain syndromes. “As eye care providers,” he said, “we can assess this link between nerve abnormalities and chronic pain.” Corneal sensitivity—which, according to Mr Baksh, can be measured in a clinic—is altered in several eye conditions. However, its relationship with chronic pain conditions outside the eye is not clear.

To learn more about how chronic pain conditions outside the eye impact corneal sensitivity, the authors investigated whether individuals with chronic trigeminal pain conditions have differences in corneal sensitivity compared with individuals who have chronic pain conditions not localised to the trigeminal system.

The investigators’ hypothesis was that patients with chronic trigeminal pain have differences in corneal mechanical detection thresholds compared with those who have chronic pain conditions that are not localised to the trigeminal system.

A cross-sectional study that included south Florida veterans with chronic pain conditions (> 3 months’ duration) who had been seen at an eye clinic was performed. The study included 568 individuals with one or more chronic pain conditions. The mean age was 61+/-10.5 years. Of the group, 89% were male, 44% self-identified as White and 25% self-identified as Hispanic.

The main independent variables were pain diagnoses and locations, as recorded by the participants in a survey. The main dependent variable was corneal mechanical detection threshold, which was assessed using a modified Belmonte aesthesiometer.

To assess confounding variables, data were collected on demographics, dry eye symptoms and signs, mental health indices, systemic comorbidities and quality-of-life indices. Individuals were split into two groups based on their pain diagnosis:

Group 1 (trigeminal pain) — chronic pain conditions that involved the trigeminal system

Group 2 (other pain) — chronic pain conditions that were not localised to the trigeminal system

Corneal mechanical threshold was assessed with a modified Belmonte aesthesiometer:

Pulses of air at room temperature were used on the right eye;

They started at 10 mL/min with 15-second waits between pulses;

Pulses increased by 10 mL/min until the patient could feel them;

This was repeated a second time and the mean was used; and

If the difference between the two trials was greater than 20, a third reading was done.

Mr Baksh noted that a lower detection threshold using the Belmonte aesthesiometer meant a higher corneal sensitivity.

Other categorical variables that are associated with a lower corneal mechanical detection threshold. Note that a lower result = higher sensitivity.

In terms of the statistics used, continuous variables were assessed via the independent t test. Correlations were assessed via Pearson 

 coefficient and categorical variables were assessed via chi-square test. All reported 

 < 0.05 was considered statistically significant.

In the study, the mean corneal mechanical detection threshold was 81+/-38 mL/min, with a range of 10 to 240 mL/min. The authors found that the trigeminal pain group (n = 122) had a lower mean corneal mechanical detection threshold (i.e., higher sensitivity) of 73+/-31, compared with the other pain group (n = 446, mean threshold 84+/-40). This was statistically significant. The groups shown in Table 1 were also associated with a higher corneal sensitivity.

The authors also assessed continuous variables. Variables that came out significantly correlated with lower corneal mechanical detection threshold (higher sensitivity) included a high depression score, a greater post-traumatic stress disorder score, worse dry eye symptoms and more severe eye pain. Other significantly correlated factors were a lesser quality of life, younger age and lower cholesterol and triglycerides levels.

Lower corneal mechanical detection threshold (higher sensitivity) may be associated with pain phenotypes, such as the presence of chronic pain involving the trigeminal system, five or more pain conditions and the presence of arthritis. Beyond pain phenotypes, additional factors that may play a role include a higher depression score, race, dyslipidaemia and continuous positive airway pressure use.

This article is based on Brandon Baksh’s presentation at the 2021 Association for Research in Vision and Ophthalmology virtual annual meeting. Mr Baksh has no financial disclosures.

Evidence shows that higher corneal sensitivity may be associated with pain phenotypes, such as the presence of chronic pain involving the trigeminal system. 

Corneal mechanical sensitivity in individuals with chronic pain

Allergan, an AbbVie company, announced FDA approval of pilocarpine HCl ophthalmic solution 1.25% (VUITY) for the treatment of presbyopia, commonly known as age-related blurry near vision, in adults.

According to the company, pilocarpine HCl ophthalmic solution 1.25% is the first and only FDA-approved eye drop to treat this common and progressive eye condition that affects 128 million Americans, nearly half of the US adult population.

Michael Severino, MD, vice chairman and president of AbbVie, noted that most adults cope with presbyopia, or difficulty with near vision, as they age.

“Beginning around the age of 40, many find themselves using reading glasses, holding text further away, or even increasing the font size and lighting on screens to try to see more clearly," he said in a statement. “We are proud to offer VUITY as a first-of-its-kind once-daily eye drop that we believe will change the way people and their eye doctors approach presbyopia. The FDA approval of VUITY exemplifies our continued pursuit of innovative new treatments that push the boundaries of what's possible in eye care.”

Pilocarpine HCl ophthalmic solution 1.25% is a daily, prescription eye drop that works in as early as 15 minutes and lasts up to 6 hours, as measured on day 30, to improve near and intermediate vision without impacting distance vision.

Specifically designed for presbyopia, pilocarpine HCl ophthalmic solution 1.25% is an optimized formulation of pilocarpine, an established eye care therapeutic, delivered with pHast technology. The proprietary pHast technology allows pilocarpine HCl ophthalmic solution 1.25%to rapidly adjust to the physiologic pH of the tear film. Pilocarpine HCl ophthalmic solution 1.25% uses the eye's own ability to reduce pupil size, improving near vision without affecting distance vision.

"As we age, the lenses of our eyes become less flexible, making it more difficult to focus on things up close. VUITY offers a novel, safe, well-tolerated and effective alternative to current options for managing age-related blurry near vision," said George O. Waring IV, MD, FACS, medical director, Waring Vision Institute, South Carolina, and GEMINI 1 and GEMINI 2 principal study investigator. "I am particularly encouraged by the rapid onset of action and duration of efficacy for VUITY to improve near and intermediate vision without impacting distance vision with one drop daily, particularly for those with mild to moderate presbyopia."

The FDA approval of VUITY is based on data from two pivotal phase 3 clinical studies, GEMINI 1 and GEMINI 2, which evaluated the efficacy, safety and tolerability of VUITY for the treatment of presbyopia. In both studies, the drops met the primary endpoint, reaching statistical significance in improvement in near vision in low light (mesopic) conditions without a loss of distance vision versus the vehicle (placebo) on day 30 at hour 3. Additionally, improvement was seen as early as 15 minutes and lasted through 6 hours. There were no serious adverse events observed in participants receiving VUITY in either the GEMINI 1 or GEMINI 2 study. The most common adverse events occurring at a frequency of >5% were headache and eye redness.

In the phase 3 GEMNI 1 and GEMINI 2 clinical studies, a total of 750 participants aged 40 to 55 years old with presbyopia were randomized in the two studies in a one-to-one ratio of placebo to pilocarpine HCl ophthalmic solution 1.25%.

According to the company, study participants were instructed to administer one drop of VUITY or placebo once daily in each eye.

Both studies met their primary endpoints with a statistically significant proportion of participants treated with VUITY gaining three lines (the ability to read three additional lines on a reading chart) or more in mesopic (in low light), high contrast, binocular distance corrected near visual acuity (DCNVA), without losing more than 1 line (5 letters) of corrected distance visual acuity (CDVA) at day 30, hour 3, versus placebo.

There were no serious adverse events observed in any participants treated with pilocarpine HCl ophthalmic solution 1.25% VUITY in either clinical study. The most common treatment emergent non-serious adverse events occurring at a frequency of >5% in participants treated with pilocarpine HCl ophthalmic solution 1.25% were headache and eye redness.

Allergan developed VUITY, which it noted is the first and only FDA-approved eye drop to treat presbyopia.

Eye drops for treatment of presbyopia approved by US FDA

On October 11, 2021, Dr Nathan Steinle presented his talk entitled, “

Efficacy of Intravitreal Pegcetacoplan in Geographic Atrophy: Results from the Phase 3 DERBY and OAKS Trials,” 

at the American Society of Retina Specialists 39th Annual Scientific Meeting in San Antonio, Texas.

Dr Steinle practices at California Retina Consultants in Santa Barbara, California.

 So my name is Nathan Steinle, and I'm of California and consultants in Santa Barbara, California.

So it's exciting to be here in San Antonio for ASRS and presenting top-line data for both OAKS and DERBY. These are the two very large registration trials for Apellis, looking at their molecule, pegcetacoplan, and the treatment of geographic atrophy. And the top-line results get kind of interesting.

You have OAKS, and you have DERBY. Both of them have about 600 patients in each trial, looking at either monthly dosing of pegcetacoplan, or every-other-month dosing of pegcetacoplan compared to monthly and every-other-month sham, so the monthly, every-other-month versus sham in both OAKS and DERBY.

These are identical trials. They are, you know, everything you want: multicentred, sham-controlled, and they should hopefully lead eventually to the possible approval of this drug pegcetacoplan for the treatment of geographic atrophy.

As far as the results go, it gets kind of complicated. In OAKS, both monthly as well as the every-other-month dosing met its primary endpoint of being significant reduction in GA progression at the one-year mark. Whereas in DERBY, both the monthly and the every-other-month dosing just barely missed, from a statistical standpoint, the primary endpoint at the one-year mark. In fact, the monthly dosing just missed the significant p-value as this p-value was .0528. So just missed it at the one-year mark.

What we showed here then is a pooled analysis, which is a pre-specified outcome. And it showed at the one-year mark, if you pooled both OAKS and DERBY, it is highly statistically significant when you pool all those patients together at the one-year mark, both the monthly and every-other-month dosing of pegcetacoplan.

And the final analysis we showed here, which is new and never been shown before, was the fellow eye effect. If you think about it, in both OAKS and DERBY, we’re comparing it to a sham pool of patients. But what better control than your own internal eye? And so we went back and looked at patients who had qualified with both eyes for OAKS and DERBY and said, hey, one eye got treatment, one eye did not get treatment—how did the non-treated eye do versus the treated eye internally in these same patients?

And we showed the results here, but there's a robust separation of the curve, especially in the monthly dose patients with pegcetacoplan. So if the patient got monthly therapy and one eye and no therapy in the other eye, there was robust separation of the curve that was highly statistically significant at the one-year mark, which gives further evidence this drug really does work.

Dr Nathan Steinle discusses top-line results of the OAKS and DERBY trials, testing the efficacy of pegcetacoplan for the treatment of geographic atrophy.

Efficacy of pegcetacoplan in geographic atrophy: OAKS and DERBY phase 3 results

Researchers at the University of Michigan, Ann Arbor, described a new potential recipe for counteracting the extremely deleterious effects that COVID-19 has on patients with underlying disease processes such as type 2 diabetes. Macrophages may be key to controlling that excess inflammation in response to infection.

This hyperinflammatory response, a so-called cytokine storm, in patients with severe COVID-19, results in increased morbidity and mortality in this patient population.

The researchers led by first author Dr William J. Melvin from the Section of Vascular Surgery, Department of Surgery, theorised that targeting the key players in the inflammatory response in patients with diabetes may result in less inflammation. They reported their results in 

Proceedings of the National Academy of Science

“Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in type 2 diabetes, to promote excess inflammation in response to infection,” the investigators commented.

They found that in both patients with type 2 diabetes infected with severe COVID-19 and an established murine model of SARS that the coronavirus induces an increased macrophage-mediated inflammatory response resulting from the viral-induced decrease in the enzyme SETDB2 in the macrophages. This in turn leads to increased transcription of inflammatory cytokines.

The investigators also found that interferon beta IFNβ regulates SETDB2 in the macrophages through the JaK1/STAT3 signaling pathway and that administration of IFNβ reverses the inflammation, particularly in the diabetic macrophages via increased levels of SETDB2.

These observations suggested to the research team “a potential mechanism for the increased macrophage-mediated cytokine storm in patients with type 2 diabetes in response to COVID-19 and suggests that therapeutic targeting of the IFNβ/SETDB2 axis … may decrease pathologic inflammation associated with COVID-19.”

Melvin WJ, Audu CO, Davis FM, et al. Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2. Proc Natl Acad Sci 2021;118:e2101071118; 

A team of investigators from the University of Michigan may have unlocked a potential new recipe for counteracting the impact that COVID-19 has on patients with underlying disease processes such as type 2 diabetes.