The 48th Annual Aspen Retinal Detachment Society meeting, held in Snowmass, Colorado from February 29 to March 5, 2020, was an informative and highly interactive conference. Directed by Donald D’Amico, MD, and Timothy Murray, MD, MBA, the conference provided attendees the opportunity for interaction in a relaxed setting.

The Taylor Smith and Victor Curtin Lecture this year, “Intraocular Tumors-A Footprint Into the Future,” was delivered by Carol Shields, MD. The Founders Lecture, “Intraocular Drug Delivery- A Winding Journey,” was given by Glenn Jaffe, MD. Other guest faculty included R. V. Paul Chan, MD, MSc, Jay Duker, MD, Phil Ferrone, MD, Baruch Kuppermann, MD, PhD, Carl Regillo, MD, Giovanni Staurenghi, MD, Christina Weng, MD, MBA, and George Williams, MD. Conference topics included surgical retina pearls, retinal imaging, current and future retinal pharmacological therapy, intraocular tumors, pediatric retina, and artificial intelligence.

The following are highlights of the many subjects covered, as well as a few clinical pearls.

ASRS ReST Committee

The American Society of Retina Specialists Research in Safety and Therapeutics (ReST) Committee is important for reporting adverse events of drugs and is an integral part of the postmarketing experience. In this regard, brolucizumab (Beovu; Novartis) was discussed a great deal during the meeting, and reports of vasculitis with irreversible vision loss were disclosed upon analysis of postmarketing experience. The trials leading to FDA approval of brolucizumab showed a 4% rate of intraocular inflammation and a 1% rate of retinal artery occlusion. Postmarketing experience was released during the 2020 ARDS meeting, which highlighted brolucizumab-associated vasculitis. At the time of the meeting, 14 cases had been identified out of the 57,000 doses sold. It has been found that this can occur in the first or subsequent injections and can even occur after switching away from brolucizumab. Eleven out of the 14 cases were occlusive vasculitis resulting in irreversible vision loss. We await further data regarding these rare but serious issues. Novartis and the American Society of Retina Specialists are continuing to investigate this issue.

Intraocular Tumors

The Taylor Smith and Victor Curtain lecture was delivered on intraocular tumors by Dr. Shields. Highlights included the important mnemonic predictive of choroidal nevus transformation into melanoma: “To Find Small Ocular Melanoma Doing Imaging representing Thickness greater than 2 mm, Fluid in the subretinal space by OCT or ultrasound, Symptoms of vision loss, Orange pigment, Melanoma hollowness by ultrasound, DIameter greater than 5 mm by photography.” The 5-year rate of growth was 1% for those with no risk factors to greater than 50% with 4, 5, or 6 risk factors.

Genetic markers, including TCGA (the cancer genome atlas) and BAP1 (BRCA-associated protein-1) tumor predisposition, were discussed. TCGA established clinical outcome prognosis with a comprehensive genetic analysis of genes frequently seen mutated in choroidal melanoma: 4 groups were identified, ranging from a 5-year metastatic risk of 4% in the lowest risk group to 63% in the highest risk group. Genetic analysis also demonstrated the decreased prognosis in uveal melanoma patients with melanomas showing chromosome 3 loss, chromosome 8p loss or chromosome 8q gain; melanoma chromosome 6p gain was correlated with improved prognosis in terms of risk for metastasis.

Maculopathy was also discussed, including intravitreal bevacuzumab for prevention of macular edema and the possibility of intravitreal silicone oil to attenuate radiation retinopathy.

The AU-011 (Aura Biosciences) viral-like particle therapy study included choroidal melanomas which were 2 mm to 3.4 mm in thickness and less than 16 mm base. The treatment involves intravitreal injection of the synthetic viral-like particles conjugated to infrared-activated small molecules which bind selectively to uveal melanoma cells. These small molecules are then activated with 689 nm light (the same diode laser used in photodynamic therapy), generating singlet oxygen, destroying the melanoma cell membranes, leading to tumor necrosis. There was a 67% involutional rate at 2 years in the phase 1b/2 study. Phase 3 studies are planned.

Sunitinib was given systemically to patients with TCGA class C and D, demonstrating improved survival. Although “checkpoint inhibitors” show promise for treatment of patients with metastatic skin melanoma, they did not demonstrate the same promise for patients with choroidal melanoma. A potential treatment currently being investigated for metastatic uveal melanoma is immune mobilizing monoclonal T cell receptors against cancer (ImmTAC) T cell weekly infusions, which directs CD4+ and CD8+ T cells against tumor cells.

Uveal metastasis was also discussed. In approximately 33% of patients with uveal metastasis, there is no prior diagnosis of cancer. The most common primary cancer sites are breast (37%) and lung (26%). Thyroid cancer is the metastatic source with the longest duration between primary diagnosis and metastatic diagnosis (more than a decade may pass between the diagnosis of thyroid cancer and the discovery of thyroid cancer uveal metastasis). There is a 57% 1-year survival rate and a 25% 5-year survival rate in patients with uveal metastasis. Lung carcinoid uveal metastasis demonstrates the best survival rate. Photodynamic therapy treatment provides good local control of uveal metastasis less than 4 mm thickness, with regression in 78% and visual preservation in 66%.

Dr. Shields highlighted the tremendous accomplishments that have occurred in saving lives in eyes using intravenous intra-arterial and intravitreal chemotherapy in the treatment of retinoblastoma. There are approximately 300 cases of retinoblastoma per year in the United States. The death rate has decreased to 2% and the enucleation rate has decreased to 5%. There is a 4% incidence of metastasis at 5 years. The possibility of routine germline testing for retinoblastoma at birth is currently being investigated.

Surgical Retina

Adult surgical retina was covered by Drs. Regillo, Jaffe, D’Amico, Duker, and Kupperman; pediatric surgical retina was covered by Drs. Ferrone and Chan.
Perfluorocarbon Liquids

Perfluoro-octane (PFO) liquids are a useful retinal surgical tool (and, in some cases, temporary tamponade). However, one potential issue is inadvertent PFO retention and subretinal migration. Valved cannulas avoid “bubbling“ of PFO liquids, which can be associated with retention and subretinal migration of the perfluorocarbon liquid. It was emphasized that the use of PFO liquid should be an “all or none” phenomenon. If used, the PFO liquid fill should occur to the ora serrata. Amputation of the flap of a horseshoe retinal tear to release vitreoretinal traction and enlarge and anteriorize the break will also reduce the chances of subretinal migration of perfluorocarbon liquid and enhance chances of surgical success during repair of a rhegmatogenous retinal detachment.

It was advised to fill and remove the PFO liquid slowly and instill initially away from the macula. The globe should be tilted away from the break when instilling perfluorocarbon liquid. When removing the PFO liquid, the retained balanced salt solution anterior to the perfluorocarbon liquid should be removed initially during an air-fluid exchange. Following this removal, “rinsing” by adding balance salt solution over the posterior pole under air and then extruding the fluid and venting after the air-fluid exchange effectively removes remaining perfluorocarbon liquid droplets. It’s effective to aspirate over the break first during the air fluid exchange to remove anterior subretinal fluid. It’s best to try to keep the PFO liquid as one bubble. Perfluorocarbon liquid maybe used for primary retinal detachment repair, but it may be more cost-effective to only use PFO for cases of proliferative vitreoretinopathy.

If subretinal perfluorocarbon liquid does occur, direct removal with a 41-gauge penetrating cannula after increased intraocular pressure tamponade may be effective. Alternatively, the silicone-tipped aspirator can be used following an internal limiting membrane peel to remove the subretinal silicone oil.

Surgical Advances

Cutter designs and vitrectomy instrumentation gauge as well as cutter speeds are all advancing. Illumination and viewing advances were discussed, including the heads-up viewing system with high-resolution macular imaging, especially with the use of the chandelier. Preoperative anti-VEGF therapy given 2 to 4 days in advance of diabetic vitrectomy surgery is helpful to decrease vascularity in the fibrovascular proliferations seen in these cases. Chromovitrectomy staining techniques for visualizing intraocular tissues during vitrectomy surgery was discussed. Pars plana vitrectomy for proliferative diabetic retinopathy and epiretinal membrane (especially associated with a dome retinal appearance) may be performed relatively early in the course of the process to enhance patient outcomes. Importantly, interactive patient discussions are important during consideration of this approach.

Retinal Imaging

Retinal imaging was covered by Drs. Staurenghi, Duker, and Chan.

Optical Coherence Tomography Angiography

Optical coherence tomography angiography (OCTA) was highlighted. It was emphasized that, at this time, OCTA is a diagnostic platform with no definitive treatment implications. OCTA depends on a red blood cell decorrelation signal. The superficial capillary plexus is identified in the nerve fiber layer, ganglion, and inner plexiform layers, whereas the deep retinal capillary plexus is seen in the inner nuclear and outer plexiform layers.

When no flow is noted, it simply means that the flow is below threshold detection. This could indicate true nonperfusion or, alternatively, a “false negative” flow deficiency. For instance, polyps in idiopathic polypoidal choroidal vasculopathy and microaneurysms are low-flow structures, therefore, are often not seen. Branched vascular networks may be seen in idiopathic polypoidal choroidal vasculopathy. It was also noted that different OCT-A instrument platforms can give different automated readings, which may affect artificial intelligence interpretation.

Spectral-Domain OCT and Swept-Source OCT

Spectral-domain OCT (SD-OCT) uses wavelengths of approximately 800 nm (in the near infrared region), whereas swept-source OCT uses light sources slightly longer than 1,000 nm. The longer wavelengths penetrate tissue and media opacities better with the trade-off of lower achievable axial resolution; an increased number of images acquired with swept-source may compensate for this. SD-OCT has an increased roll-off of sensitivity with depth as compared with swept-source, which limits the ability of SD-OCT to image the choroid; however, the use of SD-OCT enhanced depth imaging mode can compensate for this. Grayscale images show improved detail versus color images. One can also invert black and white with the grayscale images to perhaps further improve detail.

Pediatric Retinal Imaging

Pediatric retinal imaging was covered by Dr. Chan. Multimodal imaging, including that which can be obtained with examination under anesthesia, was highlighted. Ultra-widefield fluorescein angiography and photography can demonstrate peripheral telangiectasias in Coats disease, which clinically exhibits xanthocoria (vs the leukocoria seen with retinoblastoma). The differential diagnosis can be difficult, however, and MRI examination may yield enhancement of the solid tumor in cases of retinoblastoma. It was emphasized that the ionizing radiation associated with CT scanning theoretically can promote second tumors in patients with retinoblastoma, so CT scans in this scenario are no longer recommended. Optical coherence tomography can demonstrate outer retinal folds and cystoid macular edema in patients with rhegmatogenous retinal detachment; these features are not seen in patients with exudative retinal detachment.

Current and Future Retinal Pharmacologic Therapy

Exciting advances in retinal pharmacologic therapy were highlighted by Drs. Regillo, Jaffe, and Kuppermann.

Second-Generation Anti-VEGF Treatments

Second-generation anti-VEGF agents are characterized by longer duration compared with currently available treatments. At ARDS, several were highlighted, including brolucizumab (Beovu; Novartis); abicipar pegol (Allergan; a DARPin molecule pegylated to extend durability), conbercept (Chengdu Kanghong Pharmaceutical), KSI-301 (Kodiak Sciences), faricimab (Roche/Genentech), aflibercept 8-mg dosage (4 times the usual dose; being studied to evaluate for extended durability in wet AMD and DME), OPT-302 (Opthea), The Port Delivery System (PDS, containing ranibizumab; Genentech), sunitinib malate (GB-102; Graybug Vision), and gene therapies such as RGX-314 (Regenxbio), ADVM-022 (Adverum Biotechnologies), and voretigene neparvovec-ryzl (Luxturna; Spark Therapeutics).

Neuroprotection and Neuroenhancement

Neuroprotection refers to cytoprotection, which may apply to the retinal pigment epithelium and neural retina. Neuroenhancement refers to interventions that may actually improve function. These concepts may have particular usage in preventing progression of the dry form of age-related macular degeneration. Apoptosis, programmed cell death without inflammation, is a homeostatic function, but not always desirable — especially in the macula region. Therefore, cytoprotection may be important.

Brimonidine is cytoprotective in cell culture and appears to preserve visual field in glaucoma patients to a better degree than would be expected given its relatively mild decrease in intraocular pressure — therefore may be a neuroprotective agent that may be useful in dry AMD. Complement 3 inhibition (APL-2; Apellis) and complement 5 inhibition (Zimura; Iveric bio) may decrease growth of geographic atrophy by greater than 20% each. Risuteganib (Allegro Ophthalmics), which is an anti-integrin, reduces oxidative stress and has been shown to improve visual acuity in preliminary studies. Mitochondrial membrane stabilizers such as elamipretide may also be protective. Human retinal progenitor cells (allogeneic stem cells) have been attempted in both intravitreal and subretinal delivery systems. These have the potential for improving visual acuity.

Ciliary neurotrophic factor encapsulated cell therapy, which failed in dry AMD protection studies, is recruiting for treatment of macular telangiectasia in a phase 3 study.

Uveitis

In uveitis, the sustained-release 0.18-mg fluocinolone acetonide implant (Yutiq; Eyepoint Pharmaceuticals) demonstrated efficacy in 2 randomized, controlled, double-masked phase 3 clinical trials with a median time to uveitis recurrence of 1,051 days. Only 6% of treated patients needed glaucoma filtration surgery in that study.

Pediatric Retina

Surgical pediatric retina was covered by Drs. Ferrone and Chan. The incidence of rhegmatogenous retinal detachment in the pediatric population is approximately 1 in 200,000 (vs the adult incidence annually of 12 per 100,000). Frequently, a retinal detachment in a child presents late; examination under anesthesia may be critical for detecting pathology. Pediatric retinal detachment is usually treated with a scleral buckle alone. Challenging cases may also include Stickler syndrome, Coats disease, optic nerve pit, a combined coloboma and retinal detachment, and the issues that may be associated with amblyopia following treatment.

Pediatric macular holes are usually due to blunt trauma. Approximately 40% of pediatric macular holes may undergo spontaneous closure. A trial of topical nonsteroidal anti-inflammatory agents may allow for pediatric macular hole closure if there is associated cystoid macular edema. Because the incidence of spontaneous closure of macular holes in the pediatric population is so high, it is frequently helpful to have a 3-month period of observation to see whether the pediatric macular hole will undergo spontaneous closure. If surgery is necessary, there is a high percentage of primary success (81% in a recent series). Ten-percent C3F, a gas with an attempted face-down positioning, has been shown to be associated with good success. If the first attempt was not successful, a second surgical attempt could be made with an internal limiting membrane flap or platelet-rich plasma.

Artificial intelligence and telemedicine in pediatric retina were covered by Drs. Chan and Weng. Artificial intelligence has been demonstrated to be effective in ophthalmology. The first autonomous AI system, IDxDR, was FDA approved in 2018 for detecting diabetic retinopathy. Addition of OCT to this type of system would improve diabetic macular edema detection, but cost will be an issue. Artificial intelligence for retinopathy of prematurity has received breakthrough approval by the FDA and has shown promise that it may even perform better than expert human examiners in detecting plus disease.

A Wealth of Information

As usual, the ARDS meeting provided a wealth of information. Especially at this time, we look forward to having the opportunity to engage in future similar gatherings.