Electrophysiological evidence of early functional damage in glaucoma and ocular hypertension

Purpose. The quantification of early retinal ganglion cell damage in ocular hypertension and glaucoma. Methods. Thirty subjects under treatment for open-angle glaucoma, 23 subjects with ocular hypertension, and 28 healthy subjects in a control group were investigated by monocular pattern electroretinogram (ERG), L&M (long and medium wavelength) cone ERG, and S (short wavelength)-cone ERG. The diagnosis of glaucoma was based on masked assessment of digital stereoscopic optic nerve head images by three glaucoma specialists. The optic nerve head and retinal nerve fiber layer was assessed by scanning laser ophthalmoscopy and optical coherence tomography. Results. All types of ERG had reduced mean amplitudes in ocular hypertension and open-angle glaucoma groups compared with the control group. In the ocular hypertension group, the N95 and the L&M-pathway photopic negative response (PhNR) were significantly attenuated (by 19% and 18% compared with the control group, respectively; by 30% and 22%, respectively, in the open-angle glaucoma group compared with the control group). In the subjects with open-angle glaucoma, the pattern ERG P50-N95 was found to be the most sensitive electrophysiological test, and the cup–disc area ratio, when examined by scanning laser ophthalmoscopy, was the most sensitive imaging parameter. Modest but not statistically significant correlations were found between the imaging and electrophysiologic parameters. Conclusions. With disc appearance used for the classification of open-angle glaucoma and ocular hypertension, significant electrophysiological losses were found in both conditions. The modest correlation between the structural and electrophysiological measures suggests that these assess different aspects of the pathologic process; electrophysiology can be used to quantify retinal ganglion cell dysfunction that occurs before cell death

Automated registration of multimodal optic disc images: clinical assessment of alignment accuracy

Purpose: To determine the accuracy of automated alignment algorithms for the registration of optic disc images obtained by 2 different modalities: fundus photography and scanning laser tomography. Materials and Methods: Images obtained with the Heidelberg Retina Tomograph II and paired photographic optic disc images of 135 eyes were analyzed. Three state-of-the-art automated registration techniques Regional Mutual Information, rigid Feature Neighbourhood Mutual Information (FNMI), and nonrigid FNMI (NRFNMI) were used to align these image pairs. Alignment of each composite picture was assessed on a 5-point grading scale: “Fail” (no alignment of vessels with no vessel contact), “Weak” (vessels have slight contact), “Good” (vessels with 50% contact), and “Excellent” (complete alignment). Custom software generated an image mosaic in which the modalities were interleaved as a series of alternate 5×5-pixel blocks. These were graded independently by 3 clinically experienced observers. Results: A total of 810 image pairs were assessed. All 3 registration techniques achieved a score of “Good” or better in >95% of the image sets. NRFNMI had the highest percentage of “Excellent” (mean: 99.6%; range, 95.2% to 99.6%), followed by Regional Mutual Information (mean: 81.6%; range, 86.3% to 78.5%) and FNMI (mean: 73.1%; range, 85.2% to 54.4%). Conclusions: Automated registration of optic disc images by different modalities is a feasible option for clinical application. All 3 methods provided useful levels of alignment, but the NRFNMI technique consistently outperformed the others and is recommended as a practical approach to the automated registration of multimodal disc images

The S-cone PhNR and pattern ERG in primary open angle glaucoma

PURPOSE. To compare the sensitivity of the photopic negative response (PhNR) from the shortwave (S)-sensitive and the long (L)- and medium (M)-wave–sensitive cone electroretinograms (ERGs), with the pattern electroretinogram (PERG) in the early stages of primary open-angle glaucoma (POAG). METHODS. Eighteen patients under treatment for diagnosed POAG and 19 normal control subjects were investigated. Scone ERGs were elicited using adaptation to 650-nm light to suppress L-cone activity, and substitution between 450 nm and 535 nm to silence M-cone response at luminances higher than rod saturation. PhNRs from the L&M-cone pathways were elicited by a 200-msec pulse of red light (650 nm) on a continuous blue (450 nm) background. PERGs were recorded in accordance with the International Society for Clinical Electrophysiology of Vision (ISCEV) standard. RESULTS. Each method showed a statistically significant difference in the two groups. The S-cone PhNR was the most sensitive test and provided the most statistically significant results, with the largest area enclosed by the receiver operating characteristic (ROC) curve. CONCLUSIONS. The findings indicate that all three types of ERG may be useful in glaucoma investigation. The L- and M-cone PhNRs may have a role in monitoring established glaucoma. The previously reported high sensitivity of the PERG was confirmed. Extensive diffuse damage to S-cone bipolar and bistratified ganglion cells appears to occur at a very early stage in POAG, owing to a pressure-related mechanism, and the S-cone PhNR was the most sensitive test. It may in future have an important role in diagnosis and monitoring of early glaucoma. Further investigation of this possibility is recommende

Three-Dimensional 1060-nm OCT: Choroidal thickness maps in normal subjects and improved posterior segment visualization in cataract patients

Purpose. To evaluate the performance and potential clinical role of three-dimensional (3D) 1060-nm OCT by generating choroidal thickness (ChT) maps in patients of different ages with different degrees of ametropia and axial lengths and to investigate the effect of cataract grade on OCT retinal imaging quality. Methods. Axial lengths (ALs) and 45° fundus photographs were acquired from 64 eyes (34 healthy subjects, 19 to 80 years, ametropia +3 to −10 D). 3D 1060-nm OCT was performed over a 36° × 36° field of view with ∼7-μm axial resolution and up to 70 frames/s (512 A-scans/frame). ChT maps between retinal pigment epithelium and the choroidal–scleral interface, were generated and statistically analyzed. A further 30 eyes (19 subjects), with cataracts assessed with the LOCS III scale, were imaged with 3D 1060-nm OCT and 800-nm OCT, and visualization of the posterior segment was compared qualitatively. Results. In 64 eyes, ChT maps displayed a thickness decrease with increasing AL. Subfoveal ChT was 315 ± 106 μm (mean ± SD), negatively correlated with AL (R2 = −0.47, P 24.5 mm showed a larger variation and a thicker ChT superiorly than inferiorly. Reduced signal strength in cataractous eyes was found in 65% of the 800-nm OCT images, but in only 10% of the 1060-nm OCT images. Conclusions. The imaging performance of 3D 1060-nm OCT is unique, producing maps that show the variation in ChT over the entire field of view, in relation to axial length. This imaging system has the potential of visualizing a novel clinical diagnostic biomarker. Compared with 800-nm OCT, it provides superior visualization of the posterior pole in cataractous eyes

Mapping choroidal and retinal thickness variation in Type 2 diabetes using three-dimensional 1060-nm optical coherence tomography

Purpose. To map choroidal (ChT) and retinal thickness (RT) in healthy subjects and patients with diabetes with and without maculopathy using three dimensional 1060-nm optical coherence tomography (3D-1060nm-OCT). Methods. Sixty-three eyes from 42 diabetic subjects (41–82 years of age; 11 females) grouped according to a custom scheme using Early Treatment Diabetic Retinopathy Study definitions for pathology within 1 disc-diameter of fovea (without pathology [NDR], microaneurysms [M1], exudates [M2], clinically significant macular edema [CSME]) and 16 eyes from 16 healthy age matched subjects (38–79 years of age; 11 females) were imaged by 3D-1060nm-OCT performed over a 36° × 36° field of view. Axial length, 45° fundus photographs, body mass index, plasma glucose, and blood pressure measurements were recorded. The ChT at the subfoveal location and ChT maps between RPE and the choroidal–scleral interface were generated and statistically analyzed. Results. RT maps show thinning in the NDR group but an increase in thickness with increasing maculopathy in the temporal and central regions (unpaired t-test; P < 0.05). ChT mapping of all diabetic patients revealed central and inferior thinning compared to healthy eyes (unpaired t-test; P < 0.001). Subfoveal ChT (mean ± SD) for healthy eyes was 327 ± 74 μm, which was significantly thicker than all diabetic groups (214 ± 55 μm for NDR, 208 ± 49 μm for M1, 205 ± 54 μm for M2, and 211 ± 76 μm for CSME (ANOVA P < 0.001; Tukey P < 0.001)

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Ganglion Cell Loss and Dysfunction: Relationship to Perimetric Sensitivity

Purpose. To describe two methods of neural damage quantification from perimetric data, and to discuss their theoretical implications. Methods. A recently published model of retinal ganglion cell (GC) receptive field density is used to obtain best estimates of the receptive fields per solid degree at each stimulus point in the 24-2 test pattern array. A method of age related change compensation is proposed and a functional relationship between perimetric sensitivity and GC survival is used for loss quantification. Results. Data for the 24-2 test pattern array for the right eye are presented. These can be adjusted for age related loss, but are also expressed as percentages which are considered to be age invariant. Simple models relating receptive field density to sensitivity are proposed for quantification. Conclusions. Equations relating GC receptive field densities at points in the visual field to normative data on sensitivity are proposed to estimate GC loss in glaucoma. If 1/Lambert sensitivity is <800, (29 dB), a linear relationship applies and a loss factor of 1-10(TD/10), where TD is the signed total deviation in decibels, may be applied to values in a percentage chart which are provided to give the percentage loss for each stimulus. Higher sensitivities are non-linearly related. Two equations are proposed to cover the range corresponding to thresholds from 0 dB to 33 dB. Hypothetical examples are given and the relationship between visual field defects and pattern electroretinograms is discussed in quantitative terms

Effect of a proparacaine 0.50%-sodium fluorescein 0.25% mix and contact ultrasound pachymetry on central and midperipheral corneal thickness measured by noncontact optical pachymetry

Purpose To assess the effect of a combination of proparacaine 0.50%–sodium fluorescein 0.25% and ultrasound (US) pachymetry on central and midperipheral corneal thickness. Setting School of Optometry and Vision Sciences, Cardiff University, Cardiff, Wales, United Kingdom. Design Case series. Method Topographic measurements of corneal thickness in healthy right eyes were obtained using a scanning-slit device (Orbscan IIz) and a Scheimpflug device (Pentacam) before and after application of proparacaine 0.50%–sodium fluorescein 0.25% and US pachymetry. Changes in corneal thickness in the center and 2.5 mm from the center in the temporal, nasal, inferior, and superior locations were assessed. Results The study evaluated 35 eyes. The scanning-slit and Scheimpflug devices recorded a small but statistically significant increase in corneal thickness at all locations (mean 4.9 ± 14.3 [SD] to 9.1 ± 11.7 μm; P.05, t test). The 95% limits of agreement were broad (−10 to +30 μm), suggesting a large degree of interindividual variability. Conclusions Ultrasound pachymetry combined with proparacaine 0.50%–sodium fluorescein 0.25% caused a small (<10 μm) but significant amount of corneal swelling on average. Because the effect on corneal thickness may be greater than −10 to +30 μm in individual cases, clinicians should avoid contact procedures before obtaining topographic maps of corneal thickness using scanning-slit and Scheimpflug devices

Tear ferning in contact lens wearers

Tear ferning (TF) has shown good sensitivity and specificity in the diagnosis of dry eye, but is a relatively uncommon test, especially in contact lens wearers. The aim of this study was to investigate the relationship between TF, ocular comfort and tear film stability amongst contact lens (CL) wearers and non-contact lens (NCL) wearers. Subjects (36 NCL, 24 CL; mean age 23.2 ± 4.8 years) underwent assessment of non-invasive tear break up time (NIBUT), fluorescein tear break up time (FBUT) and completed the Ocular Comfort Index (OCI) questionnaire. Non-stimulated tears were collected from the inferior tear meniscus with a glass capillary. Samples of 1.5 μL were air dried, observed by light microscopy and the TF pattern quantified according to Rolando’s grading scale. Significantly higher grades of TF pattern and discomfort (higher OCI scores) were observed in CL wearers compared to NCL wearers (Mann–Whitney U-test; p < 0.005 and p < 0.05 respectively). Differences in tear film stability were not significant between groups. Even when asymptomatic (low OCI scores) CL and NCL subjects were compared, TF remained significantly different (p < 0.005). In both CL and NCL subjects, TF displayed poor correlation with tear film stability tests and OCI scores. Higher TF grades in CL wearers, even if asymptomatic, indicate an unfavourable ratio of salt to macromolecule concentration within the tear film of such subjects. The lack of significant difference in TF between symptomatic CL and NCL wearers could suggest similar aetiology (tear film hyperosmolarity) in each cohort. The TF technique demonstrates limited sensitivity and specificity for the prediction of ocular surface comfort in both CL and NCL wearers