Lynda Charters

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Dr Richard B. Rosen reported that clinical optical coherence tomography (OCT) can image and measure macular surface macrophage cells.

“This OCT capability provides a new clinical biomarker for tracking the initiation and progression of retinal vascular disease and response to therapy,” Dr Rosen said. He is Professor of Ophthalmology at the Ican School of Medicine at Mount Sinai and Visiting Professor in Applied Optics at the University of Kent, Canterbury, UK.

These cells at the retinal surface can provide physicians with an early warning system because they act as sensors and regulators of vascular and neuronal tissue and can signal disease onset and severity, he explained further.

The investigators used spectral-domain OCT (Avanti RTVue-XR, Optovue) to assess patients with diabetic retinopathy (49 eyes), serous chorioretinopathy (12 eyes), and retinal vascular occlusion (RVO) (10 eyes) and 14 controls. Ten scans (3 x 3 mm) of each eye were obtained and averaged.

Dr Rosen explained that the the borders of the foveal avascular zone (FAZ) were manually outlined on the OCT-A scans. Using a novel MATLAB application, the automated cell density measurements of the macrophages in the FAZ were performed on the 3-micron OCT-reflectance slab above the surface of the internal limiting membrane. Surface macrophage cell density map were generated for each participant. The capillary density was measured using the OCT-A full vascular slab; the measurement included the internal limiting membrane to 9 microns below the posterior boundary of the outer plexiform layer.

The investigators reported finding surface macrophage cells in the FAZ in 80%, 86%, and 90% of patients, respectively, with diabetes, serous chorioretinopathy, and retinal vein occlusion compared with 31% of controls; the respective mean ± standard deviations in cells/mm2 were 5 ± 5, 6 ± 7, 13 ± 10, and 1±1. The differences in the densities of the surface macrophage cells between patients and controls reached significance (p=0.0005), Dr. Rosen reported.

He also reported an inverse correlation between the surface macrophage cell densities in the FAZ and the perifoveal perfused capillary densities (R= -0.22, p = 0.037).

“Clinical OCT and offers a new clinical biomarker for tracking the onset and progression of retinal vascular disease and the response to therapy. The higher densities of surface macrophage cells in the FAZ seem to correlate with the progressive reduction of the surrounding perfused capillary density as the ischemic burden worsens,” Dr Rosen concluded.

Articles

At ASRS 2021 in San Antonio, TX, Dr Richard B. Rosen reported that clinical optical coherence tomography (OCT) can image and measure macular surface macrophage cells.

Using commercial OCT to track macrophages in the macular circulation

With the onset of the COVID-19 pandemic, glaucoma specialists had to make marked changes to their well-established clinical practice routines on the fly to ensure patient follow-up. “We had to make changes to several aspects of clinical flow and patient interaction, especially regarding diagnostic testing and disease monitoring, with the emphasis on visual field (VF) testing,” said Dr Oluwatosin U. Smith, Glaucoma Associates of Texas, Dallas, United States.

Before the pandemic, long clinic waiting times for patients were commonplace for routine follow-up visits. Because of the pandemic, Dr Smith pointed out, testing and visits were separated and testing centres were designated in some facilities.

Regarding VF testing, new requirements for cleaning equipment and ensuring adequate time between patients after each VF test resulted in prolonged delays in the clinic. In an effort to reduce the waiting times, virtual VF testing and home VF tests were implemented.

“When considering perimetry needs,” Dr Smith said, “a number of factors are considered that include the reliability, reproducibility and quantitativeness of the test; the efficiency and safety for physicians and patients; affordability; comfort; and ease of both use and cleaning. Virtual reality and home VF tests meet some of those criteria.”

Available virtual reality and home technology

Various devices are available commercially. They include head-mounted devices, referred to as virtual reality perimetry, such as the VisuALL S for clinic use and the VisuALL H for home use (both from Olleyes), IMO (Crewt Medical Systems) and the C3 Field Analyzer (Remidio).

The visual acuity assessment is usually included in most available VF testing systems, as is threshold/suprathresold testing. However, the size V stimulus test is not currently available. Specific devices can administer both adult and paediatric tests, depending on requirements.

The VisuALL system, a head-mounted device that can be bought or rented, has the advantages of being lightweight and portable; it offers goggle technology, with each eye stimulated by an individual flat screen, and threshold and suprathreshold strategies. The web-based test included with the system is similar to the in-clinic test. Patient instruction and training are required.

Dr Smith referred to a recent study that compared this system with standard automated perimetry.

 The study included 102 eyes of 25 healthy patients and 26 patients with mild-to-moderate glaucoma. All participants were evaluated with both tests.

The authors reported that the test time was longer than with the Humphrey Field Analyzer (HFA) for both the normal subjects (6.13 minutes) and the patients (9.28 minutes) (P = 0.02 and P < 0.001, respectively). The investigators found a significant correlation in the global mean sensitivity of the HFA and VisuALL in normal subjects (P = 0.001) and patients (P < 0.001). The VisuALL mean sensitivity had a greater receiver operating characteristic curve than the HFA mean sensitivity for discriminating normal eyes from glaucomatous eyes (P = 0.06).

Dr Smith said the VisuALL system had lower peak brightness and background illumination than the HFA and an eye tracker that was similar in technology to the Octopus 600 (Haag-Streit). It provided full threshold testing versus standard automated perimetry testing but required more time than the HFA because of the absence of a normal database and a frequency-of-seeing curve.

The print-out of the VisuALL system is formatted like that of the HFA print-outs. Using the system, either one eye alone or both eyes simultaneously can be tested. The system provides a full threshold test, which the IMO does not; the IMO has a special algorithm that helps improve the accuracy and speed of testing.

The important advantages of virtual reality field tests are efficiency (the devices are easy to clean after each use and multiple devices can be used at the same time), safety and the ability for devices to be worn over glasses. Ease of use is another draw since it facilitates more frequent testing, which can rapidly detect VF progression.

In addition, it is not necessary for a technician to monitor use of the devices, although someone can be available if needed. The testing can be performed in any position and location.

The major disadvantages include the potential for patient disorientation when wearing the goggle headset, preference for standard perimetry, possible high cost and the fact that further clinical studies are needed to test the device with advanced glaucoma and with size V test objects. Studies to determine patient preferences with the tests, repeat test performance, clinical utility and normal database are under way.

The Melbourne Rapid Fields (MRF) device (M&S Technologies) provides portable tablet-based perimetry. When using the MRF, patients can wear their own glasses. The software includes fixation and fast thresholding using Bayes logic. This perimetry device is available for use in the clinic and for home VF testing.

The MRF provides a printout in a similar way to the HFA, and one or both eyes can be tested at the same time. The stimulus size, ranging from the equivalent of size III to size IV depending on the degree of eccentricity, is adjustable during testing to allow for the tangent effect of a planar screen. The test requires that the patient maintains a certain distance from the screen.

 that included 12 normal eyes and 78 eyes with glaucoma and compared the MRF with the HFA in glaucoma patients, found a high correlation between the two devices and comparable test-retest reliability. Another study3 that compared the MRF and the HFA in 60 patients with stable glaucoma or ocular hypertension over 6 months reported that the two were strongly correlated with each other over four visits and had good test-retest reliability.

The home-testing MRF sends a link to the patients and allows testing to be performed on the patients’ own devices. Some calibration is required, and testing is performed at a specific distance from the screen. There is a slight learning curve associated with this test.

The greatest advantage of portable tablet VF testing is that the home test can be performed on the patient’s own tablet or computer. The disadvantages are that the size V stimulus test is not available, there is some patient discomfort with the positioning required and a home test is technically more challenging to perform because of the required calibration.

Dr Smith explained that the virtual reality fields and home VFs are valuable additions to the future of office perimetry, telemedicine, remote patient monitoring and screening. “The devices have been correlated with the established perimetry method, the Humphrey VF test,” she concluded.

“There is need for improvement in the diagnostic and disease progression monitoring capabilities, and validation of use for more advanced disease is ongoing for the devices commercially in the US. Home monitoring VF devices may identify rapid VF progression.”

This article is adapted from Dr Smith’s presentation at the American Glaucoma Society’s 2021 virtual annual meeting. Dr Smith has no financial interest in this subject matter.

Razeghinejad R, Gonzalez-Garcia A, Myers JS, Katz LJ. Preliminary report on a novel virtual reality perimeter compared with standard automated perimetry. J Glaucoma. 2021;30:17-23.

Kong YXG, He M, Crowston JG, Vingrys AJ. A comparison of perimetric results from a table perimeter and Humphrey Field Analyzer in glaucoma patients. Transl Vis Sci Technol. 2016;5:2.

Prea SM, Kong XYG, Mehta A, et al. Six-month longitudinal comparison of a portable tablet perimeter with the Humphrey Field Analyzer. Am J Ophthalmol. 2018;190:9-16.

Home testing technology is proving to be a key advancement in monitoring and screening glaucoma patients.

Taking a step forward in diagnostic testing and disease monitoring

Dr David Boyer reported that pegcetacoplan (APL2-103, Apellis Pharmaceuticals, Inc.), an investigational product to treat geographic atrophy (GA) administered in monthly or every-other-month regimens, was well tolerated by patients in the phase 3 DERBY and OAKS studies compared with sham treatment. He is adjunct clinical professor of ophthalmology, University of Southern California Keck School of Medicine, Los Angeles.

Ocular adverse events were rare in the study groups and were mostly related to the injection procedure.

The most concerning adverse event was intraocular inflammation (IOI). After the initial enrollment in the trials in 2018, 4 cases of IOI (3 of intraocular inflammation and 1 of noninfectious endophthalmitis) developed. The trials were suspended as a result and restarted in 2019 when the impurity was removed from the pegcetacoplan formulation.

No cases of vasculitis or occlusive vasculitis developed.

Overall, Dr Boyer reported, 13 cases of IOI developed that included the initial 4 cases. Most cases were mild and 10 of the 13 patients resumed treatment with intravitreal pegcetacoplan without a problem.

Infectious endophthalmitis developed in 3 patients. Two cases with culture positive for Gram-positive bacteria; no culture results were obtained in 1 case.

All patients were treated with intravitreal antibiotics; one case also underwent pars plana vitrectomy. All had favorable visual outcomes. The rates of infectious endophthalmitis per injection and per patient over 12 months were, respectively, 0.047% and 0.36%. These rates agreed with those reported by previous prospective clinical trials that evaluated intravitreal therapies.

Identifying exudative age-related macular degeneration (AMD)

In the phase 3 DERBY and OAKS studies, the design and approach were adapted based on what was learned from the phase 2 FILLY study.

The reading center (DARC) and grading methodology was the same across the FILLY, OAKS, and DERBY studies.

In the DERBY and OAKS trials, if exudative AMD was suspected, prespecified imaging was acquired and sent to the reading center; the responsibility to report exudative AMD-related adverse events and to start treatment with anti-vascular endothelial growth factor therapies, however, was solely left to the investigator, regardless of the reading center confirmation. In addition, cases of macular neovascularizion were detected by the reading center on fluorescein angiography at month 12, but not reported by investigators as adverse events, these are also reported.

In the phase 3 studies, no exclusion criteria pertained to the fellow eyes. Study eyes with a history or evidence of active exudative AMD were excluded; patients with subclinical macular neovascularization either based on the presence of a double layer sign (seen in 14% to 20% of patients at baseline) on optical coherence tomography (OCT) angiography were included. From 18% to 21% of patients had choroidal neovascularization in the fellow eye at baseline.

Dr Boyer, a consultant and investigator for Apellis, reported that the rates of exudative AMD were lower in OAKS and DERBY than in FILLY, as expected. Combined investigator-determined exudative AMD rates in the OAKS and DERBY studies were 6.0% in the monthly administration group, 4.1% in the every-other-month administration group, and 2.4% in the sham group. The respective results that included the reading center-detected cases not reported by investigators were 6.4%, 5.0%, and 3.8%.

The rate of fellow eye choroidal neovascularization was lower in OAKS and DERBY and closer to expected rates (~20%) compared to the FILLY study (35-42%).

There were no significant changes in best-corrected visual acuity.

These patients continued to be treated with intravitreal pegcetacoplan and also received anti-vascular endothelial growth factor therapy.

This article is based on Boyer’s presentation at the American Society of Retina Specialists 2021 annual meeting in San Antonio, Texas.

At ASRS 2021, Dr David Boyer reported that pegcetacoplan used to treat geographic atrophy and administered in monthly or every-other-month regimens was well tolerated in patients in the phase 3 DERBY and OAKS studies.

Intravitreal pegcetacoplan proves useful for geographic atrophy: Phase 3 results of OAKS and DERBY studies

Dr Arshad Khanani from the Sierra Eye Institute, Reno, NV, reported that the Port Delivery System with ranibizumab (PDS) (Lucentis, Genentech) (F. Hoffmann-La Roche Ltd.), an investigational product that continuously delivers ranibizumab intravitreally, achieved results similar to those in patients treated with monthly ranibizumab injections for neovascular age-related macular degeneration (nAMD).

Dr Khanani reported the primary study findings from the phase 3 study.

The PDS, which contains 100 mg/ml of ranibizumab, was non-inferior and equivalent to monthly 0.5-mg ranibizumab injections for changes in the best-corrected visual acuity compared with baseline at the average of weeks 36 and 40 and remained non-inferior through 2 refill-exchange intervals at the average of weeks 44 and 48.

The visual and anatomic results with the PDS were comparable to those with monthly ranibizumab through week 72 regardless of the presence or absence of subretinal or intraretinal fluid.

The presence of intraretinal fluid in the central 1 mm of the retina was associated with worse vision outcomes, which was consistent with the findings of other trials.

Continuous delivery of ranibizumab via the PDS every 24 weeks maintained the vision outcomes, regardless of the overall presence or absence of retinal fluid.

The vast majority of patients, i.e., over 90%, randomized to the PDS did not receive supplemental treatment before each refill-exchange procedure at 24-week intervals.

In addition, 93% of patients in this study population preferred PDS over monthly intravitreal injections of ranibizumab at week 40.

The adverse events associated with the PDS procedure were manageable and are continually being analyzed to optimize the patient outcomes with nAMD.

Dr Arshad Khanani reported at ASRS 2021 that the Port Delivery System with ranibizumab, an investigational product that continuously delivers ranibizumab intravitreally, achieved results similar to those in patients treated with monthly ranibizumab injections for nAMD.

Author | Lynda Charters

Articles

Taking a step forward in diagnostic testing and disease monitoring

Intravitreal pegcetacoplan proves useful for geographic atrophy: Phase 3 results of OAKS and DERBY studies

PDS with ranibizumab in nAMD offers similar results to ranibizumab monthly injections

Using commercial OCT to track macrophages in the macular circulation