P2X7-mediated alteration of membrane fluidity is associated with the late stages of age-related macular degeneration.

We have shown deficits in monocyte phagocytosis from patients with age-related macular degeneration (AMD). Cell membrane fluidity is known to affect phagocytic capacity and leucocyte functionality more generally. Therefore, we examined membrane fluidity of peripheral blood leucocytes in human patients with AMD and in the P2X7 null mouse model of AMD using flow cytometry with a fluorescent probe for fluidity, TMA-DPH. The results showed that membrane fluidity was decreased in all leucocyte types of late AMD relative to healthy controls (HC) including monocytes, neutrophils and lymphocytes but this was not apparent in earlier stages of AMD. Further analysis of factors contributing to membrane fluidity indicated that pre-treatment of monocytes and lymphocytes with ATP greatly increased membrane fluidity in humans and mice. Evidence from P2X7 null mice and P2X7 antagonists confirmed that these ATP-driven increases in membrane fluidity were mediated by P2X7 but were not associated with the classic P2X7 functions of pore formation or phagocytosis. Analysis of P2X7 expression indicated that receptor levels were elevated in classic monocytes of late AMD patients, further suggesting the P2X7 may contribute to altered plasma membrane properties. Our findings identified a novel biological function of P2X7 in modulating membrane fluidity of leucocytes and demonstrated reduced membrane fluidity in cellular changes associated with the late stage of AMD.

Effect of subthreshold nanosecond laser on retinal structure and function in intermediate age-related macular degeneration.

BACKGROUND: Subthreshold nanosecond laser (SNL) treatment has been studied as a potential intervention in intermediate age-related macular degeneration (iAMD). This study investigated the effect of 100 SNL treatment spots on retinal structure and function. METHODS: A prospective single-arm interventional pilot study. SNL treatment was delivered as 100 spots around the retinal vascular arcades of the study eye (worst visual acuity) in a single session in subjects with iAMD. Multimodal retinal imaging and dark-adapted chromatic perimetry were performed at baseline and at 0.5, 3, 6 and 12 months post treatment. Post treatment changes in best corrected visual acuity (BCVA), retinal thickness, relative ellipsoid zone reflectivity (rEZR) and rod-mediated functional parameters were compared to baseline. RESULTS: Twenty-one subjects with iAMD were recruited. SNL treatment was associated with an increase in retinal thickness (p = 0.008) and decrease in rEZR (p < 0.001) at 2 weeks post laser. Recovery of retinal thickness and rEZR was observed at the 3-month post laser visit. A gradual improvement in BCVA was observed after laser treatment. The mean change in BCVA between baseline and 12-month visit was +1.9 ± 3.3 letters for the SNL treated eyes, compared to -0.4 ± 3.0 letters for the fellow eyes (p = 0.027). Rod-mediated function improved at 3 months post laser (p < 0.001) and returned to the baseline levels at 12 months post treatment. CONCLUSIONS: A single treatment with 100 SNL spots causes a short-term change in retinal structure and improvement in retinal function that are apparent at 3 months post treatment.

Which plants matter? A comparison of academic and community assessments of plant value and conservation status in the Moroccan High Atlas.

As interest in including local communities and their knowledge in biodiversity conservation increases, challenges to do so become clear. One of them is to harmonize local and academic assessments of conservation status. Here, we document the culturally valuable flora of two Amazigh communities in the Moroccan High Atlas Mountains and contrast local conservation observations with IUCN and other red-listing assessments. Our study reveals two levels of mismatch. Unsurprisingly, the species of interest of these two knowledge systems differ considerably. Moreover, species' availability and populations' trends of change and the conservation evaluations often diverge between local and academic assessments. Locally valuable species are rarely threatened, but a focus on locally prioritized species is essential to ensure the active participation of local communities in conservation initiatives. Given the salient role of IUCN Red Lists in guiding conservation action, a better understanding of the differences in plant value and conservation assessments between the two knowledge systems can help harmonize biodiversity conservation and community wellbeing goals.

Dose Response in the Subthreshold Nanosecond Laser Trial in Early Stages of AMD: A LEAD Study Report.

BACKGROUND AND OBJECTIVE: To examine the association between treatment parameters and the progression to late age-related macular degeneration (AMD) in the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study, a randomized, controlled trial of a subthreshold nanosecond laser (SNL) for slowing disease progression in the early stages of AMD. PATIENTS AND METHODS: The association between treatment parameters early in the trial period for participants in the SNL arm of the LEAD study and time to develop late AMD during the 3-year trial duration was examined. Parameters included treatment energy at the baseline and 6-month visits and the number of laser spots visible on fundus autofluorescence (FAF) imaging taken at 6 and 12 months (taken as a proxy measure of early, adequate delivery of the laser treatment at the baseline and 6-month visits, respectively). RESULTS: A multivariable analysis revealed there were no significant associations between time to develop late AMD and number of FAF-visible laser spots at 6-months (adjusted P = .537) nor laser energy used at baseline (adjusted P = .910). No significant associations were also observed when evaluating FAF-visible spots at 12-months (adjusted P = .107) and the average laser energy used at baseline and 6 months (adjusted P = .558). CONCLUSIONS: This study did not find any evidence to suggest that there was a dose response for the effect of laser treatment using these treatment parameters on the progression of AMD. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:380-386.].

Deficits in Monocyte Function in Age Related Macular Degeneration: A Novel Systemic Change Associated With the Disease.

Age-related macular degeneration (AMD) is characterized by the accumulation of debris in the posterior eye. In this study we evaluated peripheral blood monocyte phagocytic function at various stages of AMD and in aged matched control participants. Real-time tri-color flow cytometry was used to quantify phagocytic function of peripheral blood monocyte subsets (non-classic, intermediate and classic) isolated from subjects with intermediate or late AMD and compared with age matched healthy controls. Assessment of phagocytic function of monocytes isolated from those with and without reticular pseudodrusen was also made, and the effect of glatiramer acetate on phagocytic function assessed. Phagocytic function was reduced in all subjects with AMD, irrespective of stage of disease. However, there was no correlation between phagocytic function and drusen load, nor any difference between the level of phagocytosis in those with or without reticular pseudodrusen. Treatment with glatiramer acetate increased phagocytosis of classical and non-classical monocytes, normalizing the reduction in phagocytosis observed in those with AMD. These findings suggest that defective systemic phagocytosis is associated with both intermediate and late stages of AMD, highlighting a potential role in the accumulation of debris that occurs early in the disease process. Assessing peripheral monocyte phagocytic function provides further insights into the etiology of this disease and offer a novel therapeutic target.

Subthreshold Nanosecond Laser in Age-Related Macular Degeneration: Observational Extension Study of the LEAD Clinical Trial.

PURPOSE: To evaluate the long-term effect of subthreshold nanosecond laser (SNL) treatment on progression to late age-related macular degeneration (AMD). DESIGN: Observational extension study of a randomized, sham-controlled trial. PARTICIPANTS: Two hundred twelve participants with bilateral large drusen. METHODS: The Laser Intervention in the Early Stages of AMD (LEAD) study was a 36-month trial where participants were randomized to receive SNL or sham treatment in 1 eye at 6-monthly intervals up to 30 months. After the completion of the LEAD study, the 2 largest recruiting sites offered remaining participants an opportunity to enroll in a 24-month observational extension study. This study thus examined all participants from these 2 sites who were enrolled in the LEAD study at baseline, including the additional observational data. MAIN OUTCOME MEASURES: Time to develop late AMD, defined on multimodal imaging, between those randomized the SNL or sham treatment. RESULTS: Overall, no significant difference was found in the rate of progression over a 60-month period in those randomized to the SNL compared with the sham group (adjusted hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.36-1.09; P = 0.098), similar to the findings at 36 months in the LEAD Study. However, evidence of treatment effect modification continued to emerge based on the coexistence of reticular pseudodrusen (RPD; P = 0.007, adjusted interaction). Namely, progression was slowed significantly with SNL treatment for those without coexistent RPD (adjusted HR, 0.34; 95% CI, 0.16-0.71; P = 0.004), but it was not significantly different for those with RPD (adjusted HR, 1.81; 95% CI, 0.67-4.88; P = 0.239). CONCLUSIONS: A 24-month observational extension study to the LEAD Study confirmed that SNL treatment did not significantly reduce the overall rate of progression to late AMD in a cohort with intermediate AMD. However, the persistence of a potential beneficial treatment effect in those without coexistent RPD over a longer follow-up duration of an additional 24 months without additional treatment is encouraging. These findings provide further justification for future trials to examine the potential value of SNL treatment for slowing progression in intermediate AMD.

USING MICROPERIMETRY AND LOW-LUMINANCE VISUAL ACUITY TO DETECT THE ONSET OF LATE AGE-RELATED MACULAR DEGENERATION: A LEAD Study Report.

PURPOSE: To evaluate the performance of microperimetry and low-luminance visual acuity for detecting late age-related macular degeneration (AMD) onset. METHODS: Two hundred ninety-two individuals with bilateral large drusen in the Laser Intervention in the Early Stages of AMD study underwent best-corrected visual acuity, low-luminance visual acuity, and microperimetry testing as well as multimodal imaging to detect late (neovascular or atrophic) AMD onset. The performance of the change in the measurement from baseline of each of visual function test for detecting late AMD onset was compared. RESULTS: The area under the receiver operating characteristic curve for detecting neovascular and atrophic AMD onset was not significantly different for low-luminance visual acuity (area under the receiver operating characteristic curve = 0.71 and 0.56, respectively) and microperimetry (area under the receiver operating characteristic curve = 0.82 and 0.62, respectively) compared with best-corrected visual acuity (area under the receiver operating characteristic curve = 0.57 and 0.56, respectively; P ≥ 0.126 for all). There was also only a fair degree of agreement between the three visual function measures for detecting the onset of neovascular and atrophic AMD (κ ≥ 0.24). CONCLUSION: Microperimetry, low-luminance visual acuity, and best-corrected visual acuity demonstrate limited performance for detecting the earliest onset of late AMD. It remains to be established whether they perform better than current methods designed to enable self-detection of neovascular AMD onset, such as Amsler grid testing.

NATURAL HISTORY OF QUANTITATIVE AUTOFLUORESCENCE IN INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate differences in quantitative autofluorescence (qAF) imaging measurements between eyes with and without large drusen, and whether qAF measurements change over time in the eyes with large drusen. METHODS: Eighty-five eyes from participants with bilateral large drusen and 51 eyes from healthy participants underwent qAF imaging at least once, and the age-related macular degeneration participants were reviewed 6-monthly. Normalized grey values at 9° to 11° eccentricity from the fovea were averaged to provide a summary measure of qAF values (termed qAF8). RESULTS: In a multivariable model, qAF8 measurements were not significantly different between age-related macular degeneration eyes with large drusen and healthy eyes (P = 0.130), and qAF8 measurements showed a decline over time in the age-related macular degeneration eyes (P = 0.013). CONCLUSION: These findings add to the body of evidence that qAF levels are not increased in eyes with large drusen compared with healthy eyes, and qAF levels show a significant decline over time in the age-related macular degeneration eyes. These findings highlight how the relationship between qAF levels and retinal pigment epithelium health does not seem to be straightforward. Further investigation is required to better understand this relationship, especially if qAF levels are to be used as an outcome measure in intervention trials.

Examining the added value of microperimetry and low luminance deficit for predicting progression in age-related macular degeneration.

PURPOSE: To examine the added predictive value of microperimetric sensitivity and low luminance deficit (LLD; difference between photopic and low luminance visual acuity (VA)) to information from colour fundus photography (CFP) for progression to late age-related macular degeneration (AMD) in individuals with bilateral large drusen. METHODS: 140 participants with bilateral large drusen underwent baseline microperimetry testing, VA measurements and CFP. They were then reviewed at 6-monthly intervals to 36 months, to determine late AMD progression. Microperimetry pointwise sensitivity SD (PSD), LLD and the presence of pigmentary abnormalities on CFPs were determined. Predictive models based on these parameters were developed and examined. RESULTS: Baseline microperimetry PSD and presence of pigmentary abnormalities were both significantly associated with time to develop late AMD (p≤0.004), but LLD was not (p=0.471). The area under the receiver operating characteristic curve (AUC) for discriminating between eyes that progressed to late AMD based on models using microperimetry PSD (AUC=0.68) and LLD (AUC=0.58) alone was significantly lower than that based on CFP grading for the presence of pigmentary abnormalities (AUC=0.80; both p<0.005). Addition of microperimetry and/or LLD information to a model that included CFP grading did not result in any improvement in its predictive performance (AUC=0.80 for all; all p≥0.66). CONCLUSIONS: While microperimetry, but not LLD, was significantly and independently associated with AMD progression at the population level, this study observed that both measures were suboptimal at predicting progression at the individual level when compared to conventional CFP grading and their addition to the latter did not improve predictive performance.

Multi-focal electro-retinogram response following sub-threshold nano-second laser intervention in age-related macular degeneration.

IMPORTANCE: The effect of sub-threshold nano-second laser (SNL) treatment on retinal function remains unknown. BACKGROUND: SNL treatment has been studied as a potential intervention in intermediate age-related macular degeneration (iAMD). This study investigated the longitudinal effect of SNL treatment on retinal function. DESIGN: This was a sub-study of the LEAD trial; a 36-month, multi-centre, randomized and sham-controlled trial. PARTICIPANTS: Subjects with iAMD. METHODS: Eligible participants were assigned randomly to receive SNL or sham treatment to the study eye at 6-monthly visits. Multi-focal electro-retinography (mfERG) was performed at each study visit from a study site. The mfERG responses were grouped into three regions (central, middle and outer rings) and compared between the SNL and sham group. MAIN OUTCOME MEASURES: mfERG P1 response amplitude and implicit time. RESULTS: Data were collected from 50 subjects (26 in the SNL group, 24 in the sham group). At baseline, the P1 amplitudes of both the study eyes and the fellow eyes were similar between the groups at all rings. In the sham group, the P1 amplitude gradually decreased over time (P < .05). In the SNL group, there was an improvement in P1 amplitude which became statistically significant at the 36-month visit, detected in both the treated and fellow eyes at the central (P = .005) and middle ring (P = .007) but not at the outer ring (P = .070). No difference in P1 implicit time detected between the groups (P > .05). CONCLUSIONS AND RELEVANCE: SNL treatment improved electro-physiological function. mfERG could be useful for monitoring AMD progression and evaluating the efficacy of SNL treatment.

Prospective Longitudinal Evaluation of Nascent Geographic Atrophy in Age-Related Macular Degeneration.

PURPOSE: Nascent geographic atrophy (nGA) describes features on OCT imaging previously observed to precede the development of atrophy. This study sought to prospectively evaluate the predictive ability of nGA for the conventional clinical endpoint of geographic atrophy (GA) as defined on color fundus photography (CFP). DESIGN: Prospective, longitudinal, observational study. PARTICIPANTS: A total of 284 eyes from 142 participants with bilateral large drusen and without nGA nor late age-related macular degeneration (AMD) at baseline were included. METHODS: OCT volume scans and CFP images were obtained from all participants at baseline and then at 6-month intervals for up to 36 months. OCT and CFP images were graded independently for the presence of nGA and GA, respectively. Eyes that developed neovascular AMD were censored at the day of its detection. MAIN OUTCOME MEASURES: Time to development of GA. RESULTS: A total 12 eyes from 10 participants progressed to GA over 36 months of follow-up, and nGA was detected in 10 of these eyes (83%) at a preceding visit (median, 13 months prior; interquartile range, 6-25 months). A total of 40 eyes from 28 participants developed nGA or GA over 36 months of follow-up, and the probability of progression to nGA and GA after 36 months was 20% (95% confidence interval [CI], 14%-28%) and 9% (95% CI, 6%-13%), respectively. After the detection of nGA, the probability of progression to GA was 38% (95% CI, 15%-55%) after 24 months. The development of nGA was associated with a markedly increased risk of progression to GA compared with when it did not develop (adjusted hazard ratio, 78.1; 95% CI, 13.6-448.0; P < 0.001), and the development of nGA explained 91% of the variance in the time to GA development. CONCLUSIONS: This study prospectively demonstrated that nGA was a strong predictor for the development of GA, providing supportive evidence of the potential value of nGA as a surrogate endpoint in future intervention trials for the early stages of AMD to improve their feasibility substantially.

Structural OCT Signs Suggestive of Subclinical Nonexudative Macular Neovascularization in Eyes with Large Drusen.

PURPOSE: To further define the structural OCT features described as the "double-layer sign" suggestive of subclinical, nonexudative macular neovascularization (NE-MNV) in asymptomatic eyes with age-related macular degeneration (AMD). DESIGN: Cross-sectional observational study. PARTICIPANTS: Participants with large drusen (>125 µm) secondary to AMD in at least 1 eye. METHODS: Participants in a "discovery" cohort, with known NE-MNV identified on swept-source (SS) OCT angiography (OCTA) and the "double-layer sign" on structural spectral-domain OCT (SD-OCT) imaging, were used to identify characteristic features of this sign. These features were then assessed by masked grading in an "evaluation" cohort of AMD eyes with large drusen to determine the predictive values for NE-MNV. MAIN OUTCOME MEASURES: Description of OCT features associated with an increased risk of NE-MNV and their diagnostic and predictive performance. RESULTS: The discovery cohort of 4 eyes revealed that in retinal pigment epithelium (RPE) elevations with a greatest transverse linear dimension of 1000 µm or more, an irregular RPE layer with a height of predominantly less than 100 µm, and a nonhomogenous internal reflectivity as characteristic features of the double-layer sign when NE-MNV was present. We term these collective features as a shallow, irregular RPE elevation (SIRE). Features on OCT images from 233 eyes in the evaluation cohort that were associated significantly with NE-MNV when the RPE elevation was more than 1000 µm in length were: height of the RPE elevation, overall flat or variable morphologic features, RPE layer irregularity, and nonhomogeneous reflectivity (all P ≥ 0.032). Twenty-four eyes (10.3%) were identified with a SIRE. On SS-OCTA imaging, 6 of the 233 eyes were found to have definite NE-MNV, and all 6 graded positively for SIRE (sensitivity, 100%). The absence of SIRE was identified in 209 of 227 eyes without NE-MNV (specificity, 92.1%). The positive predictive value for SIRE was 25% and the negative predictive value was 100%. CONCLUSIONS: Eyes whose OCT images display a SIRE sign are at higher risk of having subclinical NE-MNV. SIRE can be used as a screening tool on routine structural OCT imaging. More frequent follow-up and diligent home monitoring is recommended for those with SIRE.

Evaluation of an emergency department buprenorphine induction and medication-assisted treatment referral program.

BACKGROUND: Emergency departments are struggling to manage the increasing number of patients seen for opioid use disorders and opioid overdose. With opioid overdose deaths rising at alarming rates, emergency physicians are beginning to induce patients with long-acting opioids such as buprenorphine and referring patients to outpatient medication-assisted treatment facilities. The objective of this study was to describe a pragmatic approach to buprenorphine induction, referral to treatment, and assess follow-up rates. METHODS: Single center, retrospective analysis of emergency department patients undergoing buprenorphine induction and referral to outpatient medication-assisted treatment. Patients were identified by an ongoing log of induced patients, between May 2017 and October 2018. The data is analyzed using descriptive statistics, with means and associated standard deviations, medians and interquartile ranges for continuous variables, and frequencies as percentages for categorical data. RESULTS: Overall, 219 patients were seen and induced with buprenorphine in the emergency department. Mean age was 35 years old (SD 10.3) and 56% were male. Intravenous opioids were most commonly abused at 75%. Our primary outcome of interest was the percentage of patients enrolled in MAT at 30 days, which occurred in 49.3% of our population. Patients were in moderate withdrawal based on initial COWS scores of 13.1(SD 5.8), and received mean total doses of 7.7 mg (SD 3.3). Median ED length of stay decreased by 40% between May 2017 and October 2018. CONCLUSION: Emergency department initiated buprenorphine induction using a structured pragmatic approach is effective at maintaining patients in medication-assisted therapy.

Presymptomatic Retinal Sensitivity Changes in Intermediate Age-Related Macular Degeneration Associated With New Retinal Fluid.

PURPOSE: To determine whether change in retinal sensitivity in areas with subretinal or intraretinal fluid secondary to age-related macular degeneration (AMD) precedes visual symptoms. If confirmed, retinal sensitivity testing could be used for home monitoring in AMD. METHODS: Individuals with intermediate AMD enrolled in a longitudinal study were seen every 6 months and underwent best-corrected visual acuity testing (BCVA), spectral domain-optical coherence tomography (SD-OCT), and microperimetry. Asymptomatic individuals who developed incidental, reading center-determined retinal fluid detected on SD-OCT were identified. The point-wise sensitivity (PWS) at the time of fluid detection was compared with 6 and 12 months prior. RESULTS: Fourteen of 161 individuals developed fluid without symptoms. PWS over fluid areas at detection was reduced compared with 6 (difference -2.04 dB, P < 0.001) and 12 months (-2.27 dB, P < 0.001) prior. PWS over fluid areas was reduced compared with perifluid areas (difference -1.02 dB, P = 0.03), peripheral areas (-1.51 dB, P < 0.001), nonprogressed fellow eyes (-1.49 dB, P = 0.006), and nonprogressed age-matched intermediate AMD eyes (-2.29 dB, P = 0.001). No difference in BCVA was observed in eyes developing fluid compared to eyes that do not develop fluid (P = 0.76). CONCLUSIONS: Retinal areas with fluid on SD-OCT had a corresponding reduction in retinal sensitivity at the time of fluid detection compared with 6 and 12 months prior, in asymptomatic intermediate AMD without change in BCVA. TRANSLATIONAL RELEVANCE: Development of self-monitoring tools to detect changes in retinal sensitivity may be helpful for early detection of retinal fluid suggestive of progression to neovascular AMD before acuity is affected.

Secondary and Exploratory Outcomes of the Subthreshold Nanosecond Laser Intervention Randomized Trial in Age-Related Macular Degeneration: A LEAD Study Report.

PURPOSE: To evaluate the secondary and exploratory outcomes of the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study, a 36-month trial of a subthreshold nanosecond laser (SNL) treatment for slowing the progression to late age-related macular degeneration (AMD) in its early stages. DESIGN: Multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two-hundred ninety-two patients with bilateral large drusen. METHODS: Participants were randomly assigned to receive SNL or sham treatment to the study eye at 6-month intervals. MAIN OUTCOME MEASURES: The secondary outcome measure of the LEAD study was the time to development of late AMD, defined by multimodal imaging in the non-study eye. The exploratory outcome measures were the rate of change in best-corrected visual acuity (BCVA), low-luminance visual acuity, microperimetric mean sensitivity, drusen volume in the study and non-study eyes, and participant-reported outcomes based on the Night Vision Questionnaire and Impact of Vision Impairment questionnaire. RESULTS: Progression to late AMD in the non-study eye was not significantly delayed with SNL treatment (hazard ratio, 0.83; 95% confidence interval, 0.40-1.71; P = 0.611). There was no evidence of effect modification based on the coexistence of reticular pseudodrusen; interaction P = 0.065). There was no significant difference between study groups in the rate of change of low-luminance visual acuity, microperimetric mean sensitivity, and drusen volume in the study or non-study eyes, and Night Vision Questionnaire and Impact of Vision Impairment questionnaire scores (all P ≥ 0.167). The rate of BCVA decline was slightly higher for participants in the SNL group compared with the sham treatment group in the study eye (-0.54 and 0.23 letters/year, respectively; P < 0.001) but not the non-study eye (-0.48 and -0.56 letters/year, respectively; P = 0.628). CONCLUSIONS: Subthreshold nanosecond laser treatment of one eye did not have an effect on delaying progression to late AMD in the fellow eye and did not, in general, have an impact on the exploratory structural, functional, and participant-reported outcomes.

Performance of a Defect-Mapping Microperimetry Approach for Characterizing Progressive Changes in Deep Scotomas.

PURPOSE: To examine whether a microperimetry testing strategy based on quantifying the spatial extent of functional abnormalities (termed "defect-mapping" strategy) could improve the detection of progressive changes in deep scotomas compared to the conventional thresholding strategy. METHODS: A total of 30 healthy participants underwent two microperimetry examinations, each using the defect-mapping and thresholding strategies at the first visit to examine the test-retest variability of each method. Testing was performed using an isotropic stimulus pattern centered on the optic nerve head (ONH), which acted as a model of a deep scotoma. These tests were repeated at a second visit, except using a smaller stimulus pattern and thereby increasing the proportion of test locations falling within the ONH (to simulate the progressive enlargement of a deep scotoma). The extent of change detected between visits relative to measurement variability was compared between the two strategies. RESULTS: Relative to their effective dynamic ranges, the test-retest variability of the defect-mapping strategy (1.8%) was significantly lower compared to the thresholding strategy (3.3%; P < 0.001). The defect-mapping strategy also captured a significantly greater extent of change between visits relative to variability (-4.70 t-1) compared to the thresholding strategy (2.74 t-1; P < 0.001). CONCLUSIONS: A defect-mapping microperimetry testing strategy shows promise for capturing the progressive enlargement of deep scotomas more effectively than the conventional thresholding strategy. TRANSLATIONAL RELEVANCE: Microperimetry testing with the defect-mapping strategy could provide a more accurate clinical trial outcome measure for capturing progressive changes in deep scotomas in eyes with atrophic retinal diseases, warranting further investigations.

Head and Gaze Behavior in Retinitis Pigmentosa.

Purpose: Peripheral visual field loss (PVFL) due to retinitis pigmentosa (RP) decreases saccades to areas of visual defect, leading to a habitually confined range of eye movement. We investigated the relative contributions of head and eye movement in RP patients and normal-sighted controls to determine whether this reduced eye movement is offset by increased head movement. Methods: Eye-head coordination was examined in 18 early-moderate RP patients, 4 late-stage RP patients, and 19 normal-sighted controls. Three metrics were extracted: the extent of eye, head, and total gaze (eye+head) movement while viewing a naturalistic scene; head gain, the ratio of head movement to total gaze movement during smooth pursuit; and the customary oculomotor range (COMR), the orbital range within which the eye is preferentially maintained during a pro-saccade task. Results: The late-stage RP group had minimal gaze movement and could not discern the naturalistic scene. Variance in head position in early-moderate RP was significantly greater than in controls, whereas variance in total gaze was similar. Head gain was greater in early-moderate RP than in controls, whereas COMR was smaller. Across groups, visual field extent was negatively correlated with head gain and positively correlated with COMR. Accounting for age effects, these results demonstrate increased head movement at the expense of eye movement in participants with PVFL. Conclusions: RP is associated with an increased propensity for head movement during gaze shifts, and the magnitude of this effect is dependent on the severity of visual field loss.

Longitudinal Assessment of Rod Function in Intermediate Age-Related Macular Degeneration With and Without Reticular Pseudodrusen.

Purpose: To evaluate rod function longitudinally in intermediate age-related macular degeneration subjects with reticular pseudodrusen (RPD) and without RPD (AMD). Methods: Retinal sensitivities (505 and 625 nm) during dark adaptation, at 14 locations within the central 12° macula were obtained after photobleaching at baseline and 12-month visits. Pointwise sensitivity differences between both stimuli were used to assess static rod function, while rod intercept time (RIT) and rod recovery rate (RRR) were used to evaluate dynamic function. Changes in function over time were compared between groups. Results: A total of 23 controls, 12 AMD, and 13 RPD cases were followed-up. At baseline, the RPD group had significantly worst static and dynamic rod function compared to AMD and control groups. Static function in AMD was similar to controls. Static and dynamic function across the central 12° was consistent in controls; however, it was most impaired at 4° compared to 12° eccentricity in disease groups. Over 12 months, no AMD cases progressed clinically and static function in AMD improved (P ≤ 0.04), but remained unchanged in control and RPD groups (P ≥ 0.17). The RRR for control and RPD groups remained stable, while the AMD group deteriorated, but only at 12° (P = 0.02). The RIT was stable in AMD (P = 0.75) and RPD (P = 0.71) groups but improved in the control group (P = 0.002). Conclusions: A decrease in RRR was detected over 12 months at 12° eccentricity in the AMD group. Evaluating changes in rod function requires testing at multiple locations including the peripheral macula.

Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration: The LEAD Randomized Controlled Clinical Trial.

PURPOSE: There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. DESIGN: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. METHODS: Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. MAIN OUTCOME MEASURES: The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. RESULTS: Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. CONCLUSIONS: In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.

Longitudinal Changes in Retinotopic Rod Function in Intermediate Age-Related Macular Degeneration.

Purpose: Although impairment of rod function in the early stages of age-related macular degeneration (AMD) has been well recognized, data on longitudinal changes in rod function at multiple retinal locations remain limited. This study investigated the longitudinal changes in retinotopic rod function in eyes with intermediate AMD (iAMD). Methods: Complete ophthalmic examination, multimodal imaging, and scotopic perimetry were performed at baseline and at 12-month follow-up. Perimetric scotopic retinal sensitivities for the 505-nm stimulus were repeatedly measured for 20 minutes after exposing to a single photobleach (∼30%). The rod intercept time (RIT) and retinal sensitivity at seven retinal loci within the central 12° were ascertained. Using the 95% limit of measurement variability derived from the control eyes as a reference, the proportion of test points with a significant change in retinal sensitivity or RIT at follow-up was determined. Results: Twenty iAMD and 6 control eyes were included. Decline in rod function was detected at 12-month follow-up in eyes with iAMD, but not in control eyes. Approximately 25% of test points in iAMD eyes showed a significant increase in RIT compared to 6% of test points with a decrease in RIT over the 12-month period (P < 0.001). Similarly, 40% of test points demonstrated a reduction in retinal sensitivity compared to the 7% of test points with an increase in retinal sensitivity at follow-up (P < 0.001). Conclusions: There are detectable retinotopic changes in rod function over 12 months in iAMD eyes, indicating an ongoing disease progression in rod impairment or loss with time.