Abstract
Mystification—explaining away what otherwise might be evident—seems rampant in our society. I hope this ability to ignore evidence, or to a lesser degree to misinterpret it, would have no role in “modern” medicine.
Sadly, this ability to “explain away” factual data is broadly seen at the podium, where data are oftentimes parsed and presented in a manner predetermined to define an outcome. This approach to presentations does retina specialists a disservice.
As important as presentations are to disseminate information, we must continue to focus on critical review—both as clinicians and as a retina specialty.
Critical review requires an understanding of research design and potential bias, both implicit and explicit. In a perfect world, data would be without bias and presented to address both its limitations and broader concerns inherent in the study design and the clinician’s role would be to integrate those data into their practice.
Much-needed attention is now being focused on inclusivity and diversity in clinical trials—but there is little emphasis on the broader impact of these studies for our patients and families, our communities, and ourselves. Think back to your last meeting and focus on a presentation that may have “explained away” the obvious evidence.
I am always concerned about the terms safe and effective in the context of a treatment with a known, unique complication profile. A recent turn of phrase is no new safety concerns—but without any discussion of prior known adverse treatment events, this phrase understates existing and known concerns.
As we evolve novel therapies, we understand the concern for safety. Case in point: Pegcetacoplan is a first-in-class molecule delivered by intravitreal injection to reduce geographic atrophy progression. This therapy obtained US Food and Drug Administration (FDA) approval in 2023. Known concerns for pegcetacoplan included increased neovascular complex formation and ischemic optic neuropathy with a frequency-of-use-dependent increase in complications.
Remarkably, no difference in visual acuity (VA) or function was noted for this treatment at 2 years. With the broad launch of pegcetacoplan in the retina community, severe visually compromising complications were reported to the ASRS Research and Safety in Therapeutics (ReST) Committee. The major concern was severe occlusive vasculitis not previously recognized during the 2 pivotal clinical trials.
Photo courtesy of Kevin Caldwell Photography.
The ReST Committee, now chaired by Andre Witkin, MD, FASRS, is an integral safety committee for our ASRS members and their patients. This committee has played a major role in recognizing and addressing safety concerns—particularly in newly released pharmacologic agents. A cluster of eyes with increased inflammation associated with intravitreal aflibercept was noted soon after it became commercially available, but subsequent studies assured the retina community of its safety. Intraocular inflammation with intravitreal brolucizumab was another excellent example. These are just 2 of the numerous potential concerns the ReST Committee has evaluated, highlighting the impact and importance of the committee.
The ReST Committee reports its analysis of pegcetacoplan safety issues in this issue of JVRD. The evaluation, presentation, and ultimately peer-reviewed JVRD publication of this investigation are unique in many ways. For the first time in ASRS history, threats of physical harm were levied against the ReST Committee chair. I applaud the fortitude of Immediate Past Chair Peter Kaiser, MD, FASRS, and the entire ReST Committee and the ASRS Board for maintaining the ReST Committee’s focus on the broad mandate of patient protection—along with rapid dissemination of this information to the ASRS membership and the broader retina community.
Publication of this report addresses the issues of concern and documents cases that underwent multiple-step review by a broad group of experts, both on the ReST Committee and in the ASRS specialty community. Once again, this article’s publication highlights the impact of JVRD for the ASRS and even more broadly, for our colleagues and our patients.
Peer-reviewed publication remains the gold standard for dissemination of research, enabling a known review process but also providing the reader with direct data access. This enhanced delivery of data—and the opportunity to have time to peruse and understand—is one major area that distinguishes peer-reviewed publications from podium presentations (often the first delivery of clinical trials data, clinical research, or translational research). We recognize the ReST Committee for its work and its further presentation of that investigation through both podium talks at the ASRS Annual Meeting and its publication of these results.
JVRD will continue to provide a platform for major ASRS committee releases including practice guidelines and therapeutic effects of treatment, along with reports from the ReST Committee and other high-impact committees. These manuscripts undergo an enhanced peer review prior to submission to JVRD and then go through independent JVRD peer and editorial review before acceptance for publication.
In This Issue
Witkin et al 1 present the ASRS ReST Committee’s aforementioned report on 14 cases of confirmed retinal vasculitis after intravitreal pegcetacoplan. All cases reported occurred after the first pegcetacoplan injection. Occlusive vasculitis was confirmed in 11 eyes. Six of 14 eyes in this series lost more than 6 lines of vision, and 2 eyes required enucleation. As of this reporting, no known etiology for the vasculitis was identified.
Ponugoti et al 2 evaluate the impact of e-cigarette use on macular perfusion employing optical coherence tomography angiography (OCTA) and note no differences in the foveal avascular zone in the studied 25 patients; however, they report decreased inner macular thicknesses and suggest a potential early chronic effect of e-cigarette inhalation.
Garg et al 3 review the spontaneous development of a full-thickness macular hole arising from lamellar macular holes and note that this progression, although rare, can be surgically managed with a reviewed closure rate of approximately 85.6%. This review highlights the difficulty with literature reviews, even in our age of electronic medical records (EMRs).
The authors’ MEDLINE search strategy identified 329 peer-reviewed publications through June 2022, but removal of duplicates decreased the identified manuscripts to 198 and with screening review, only 16 studies were included. In this context, only 76 eyes were identified to include in the study, in which 40 eyes were treated with internal limiting membrane (ILM) peeling, and 32 eyes were treated with an ILM flap approach.
No significant difference in surgical approach was noted; the authors report an 85% closure rate with ILM peeling and an 88% closure rate for ILM flap. Such data can be reassuring for the vitreoretinal surgeon dealing with this type of complex macular hole.
Capellan et al 4 (including JVRD Immediate Past Editor-in-Chief Donald D’Amico, MD, FASRS) report on teleophthalmology experience in New York City, including a review of 300 consecutive diabetic patients screened for retinopathy and a web-based survey of 36 participating physicians and staff.
Teleophthalmology experienced a marked increase during the COVID-19 pandemic, but concerns have remained regarding implementation, standardization, and program-associated costs. The study of 300 patients established a diabetic retinopathy diagnosis in 57 patients, with 31 patients referred for in-person evaluation. Only 22 patients were seen in person (38.5%), and ultimately 6 patients were treated (5 with antivascular endothelial growth factor and 1 with panretinal photocoagulation).
The web-based survey noted barriers to implementation, including extended screening time, delayed interpretation times, the need for fundus camera support, and better integration of teleophthalmology into patient scheduling. Of note, 71% of the surveyed participants continued to want an inpatient ophthalmology examination for their patients.
Christensen et al 5 compare 25-gauge and 27-gauge vitrectomy for macular surgery using a systematic approach to wound closure; 25-gauge surgery was performed from 2013 to 2015, while 27-gauge surgery was overlapped from 2014 to 2017.
The authors report a higher incident rate of potential complications and note a transition from nonvalved to valved cannulas; 7 (5.6%) of 125 patients undergoing 25-gauge vitrectomy had an intraoperative identified retinal tear.
Counterintuitively, hypotony was noted at 4.8% for the 25-gauge cohort and 7.2% for the 27-gauge cohort. (Expected hypotony rates for the authors’ 23-gauge and 25-gauge practice are less than 1% in over 5000 cases.) Sutured wound closure was extremely rare, with only 1 patient in the 25-gauge cohort undergoing suture placement.
My recent JVRD “From the Editor-in-Chief” column series has focused on aspects of retina specialty care that define our possible futures in retina. From leadership to civil discourse, we have noted the uniqueness of our field. This study describes a moment in time and highlights the importance of evaluating the transitional use of advanced technology. Near-real-time outcome assessments can be obtained in the era of enhanced EMRs—something that should be a mainstay in all surgical practices.
Kundu et al 6 present the Duke Eye Center experience of branch retinal vein occlusion (BRVO) in patients younger than 50 years. Of the 302 patients, 23 were followed in the younger cohort and 279 in the older cohort. Their review suggested that BRVO risk factors were similar irrespective of patient age but that final visual outcomes were better in the younger cohort. Interestingly, the younger cohort included a greater proportion of Asians (23), while the older cohort had a greater proportion of Whites. No difference was seen for the other classified racial groups.
Cheng et al 7 discuss disease awareness among patients with age-related macular degeneration (AMD) using the 2005–2008 National Health and Nutrition Examination Survey (NHANES). AMD was determined by retinal images and disease awareness by self-reporting for this group of 5553 adults older than 50 years.
Within this cohort, 425 patients (6.5%) were noted to have AMD. Only 34 patients had late AMD, and in this small group, 59.2% were aware of their diagnosis. If bilateral disease was present, the patient had a 5-fold increased likelihood of AMD awareness. Nonetheless, these data suggest the ongoing need for patient education at a public health level to potentially improve early diagnosis and enhanced treatment.
Joseph et al 8 report microvascular differences in the choroid and retina between patients with Lewy body dementia (clinical diagnosis, 18 patients) and the relatively matched “normal” cognition control group (48 patients). OCTA documented an increase in capillary perfusion density in patients with clinical Lewy body dementia.
The capillary flux index and the ganglion cell–inner plexiform layer were both decreased in this analysis. This study highlights the continued linkage between dementia and ocular anatomy. The absence of an easily accessible biomarker continues to hamper ongoing research, and I commend authors for their focus.
Chawla et al 9 report the incidence of no light perception (NLP) after central retinal artery occlusion (CRAO) with ocular neovascularization. EMR review identified 345 patients with CRAO between 2012 and 2022. Of these, 34 patients had ocular neovascularization secondary to CRAO with a mean age of 72 years.
Kaplan-Meier analysis noted an NLP presentation of 25.1% at 4 months, increasing to 49.4% at 24 months. These data suggest that early CRAO management may be critical in limiting complications, including chronic pain and the need for enucleation.
Gupta and Lean 10 report the development of a full-thickness macular hole caused by acute subretinal hemorrhage in the setting of ongoing treatment for neovascular AMD. In this 84-year-old man, successful hole closure was obtained with ILM peeling and perfluoropropane gas tamponade performed 4 weeks after the hemorrhagic event and the VA recovered to 20/100.
Busquets 11 reports the use of an amniotic membrane graft for closure of an optic disc pit–associated maculopathy. In this 28-year-old woman, VA improved from 20/400 to 20/50; after 6 months with phacoemulsification and intraocular lens placement, the VA improved to 20/25 without recurrence of maculopathy.
Justin et al 12 report the use of transabdominal ultrasound at 32 weeks of age to document total retinal detachments in an infant with Norrie disease. The infant was delivered early at 37 weeks but was deemed inoperable at that time.
Aye et al 13 report a case of recurrent aggressive ciliochoroidal melanoma requiring enucleation after brachytherapy elsewhere for recurrence at the biopsy site. Uniquely, the tumor showed progression from gene expression profiling (GEP) class 1A, PRAME negative to GEP Class 1b. This study suggests the importance of post-treatment follow-up after globe-conserving therapies and/or biopsy in the setting of uveal melanoma.
Singh et al 14 report on a 75-year-old woman with relapsing-remitting multiple sclerosis who developed ponesimod-associated macular edema. Topical therapy with prednisolone acetate and bromfenac stabilized the macular edema. Tapering the topical therapy was associated with worsening of macular edema, and the neurology team recommended discontinuation of ponesimod.
At 1 month, using increased topical therapy, the authors noted total resolution of the macular edema. Topical therapy was discontinued without recurrence of macular edema. In this case, early clinical trial data had previously documented macular edema development associated with ponesimod use.
Mahmoudzadeh et al 15 describe a small case series of 4 eyes with macula-off tractional retinal detachments (3 with proliferative diabetic retinopathy, 1 with sickle cell trait) that improved without surgical intervention. The authors note the rarity of this event and the importance of OCT imaging.
Odden et al 16 present 7 cases of West Nile virus (WNV)–related chorioretinitis and note an increasing incidence over the past 4 years. The retina specialist’s recognition of this condition is critical as over 80% of neuroinvasive WNV will manifest a multifocal chorioretinitis.
Nguyen et al 17 describe 3 cases of ritonavir retinopathy in the setting of HIV treatment. Ritonavar-associated retinitis presented with macular atrophy in the absence of intraocular inflammation. Drug cessation did not stop progressive vision loss. Alterations in the prescribing usage of ritonavir may require earlier targeted evaluation, particularly of the macula, for potential toxicity.
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As retina specialists continue to employ novel therapies and as our medical colleagues deploy new approaches to managing malignancy, connective tissue disorders, and inflammatory disease, we will see new complications, often not previously recognized. Critical review of all study data leading to FDA approval of a novel agent will remain a mainstay of our clinical trials. Nonetheless, real-world surveillance after FDA approval has the opportunity to extend the clinical trial framework that goes beyond study inclusion and exclusion criteria. This opportunity to recognize early safety signals has been a major task of the ASRS ReST Committee.
The research presented in this issue of JVRD is focused on extending our abilities to diagnose and treat our patients. These data, and their preceding presentations, must take an unbiased approach to science and medicine.
As we listen or read within our specialty, we must maintain a high degree of focused, critical thinking. When uncertain, seek additional information from the author/presenter, look for independent confirmation from a second source, and maintain an open mind in your clinical care of your patients to the real-world impact.
Healthy skepticism is not a bad thing, nor is early adoption of novel diagnostic testing or treatment. As British writer Julian Barnes said, “Mystification is simple; clarity is the hardest thing of all.” Here’s to JVRD and the ASRS embracing clarity to help ourselves and our patients.
