Alyson Muldrew

Identification of lesion components that influence visual function in age related macular degeneration

Aims: To explore the relation between lesion composition as assessed by fundus photography and fluorescein angiography with clinical measures of vision in eyes of patients with age related macular degeneration (AMD). Methods: A standardised visual function assessment along with colour stereo pair fundus photography was carried out in both eyes of 58 subjects with a confirmed clinical diagnosis of AMD. The size, location, and composition of the macular lesion (blood, exudate, subretinal fluid, pigment, membrane, atrophy, and fibrosis) were measured on the colour photographs using computer assisted image analysis. Of the 58 subjects, 44 also had concurrent fluorescein angiography. Classic and occult choroidal neovascularisation (CNV), blood, blocked fluorescence, fibrosis, geographic atrophy, and the total area of abnormal fluorescence were measured. Multiple linear regression was used to examine the relation between clinical measures of vision and the location and extent of lesion components identified by both colour and fluorescein image capture. Results: The composition of the macular lesion strongly influenced visual function, with atrophy (p=0.001) and fibrosis (p=0.002) accounting for most of the variation. When the location of the lesion with respect to the fovea was examined, fibrosis within the fovea significantly influenced all clinical measures of vision (p=0.008). The regression model selected the total area of abnormal fluorescence and a composite parameter (a semiquantitative measure of the following characteristics: atrophy, exudates, blood, and fibrosis ) from colour photography (r2 =0.52) as the variables that explained most of the variation in clinical measures of vision. Conclusions: The composition and extent of the macular lesion strongly influences visual function in eyes with AMD. Both colour photography and angiography yielded information, which together explained considerably more of the variation in the clinical measures of vision than either on its own.

Stereotactic radiotherapy for neovascular age-related macular degeneration: year 2 results of the INTREPID study.

PURPOSE To determine the safety and efficacy of low-voltage, external-beam, stereotactic radiotherapy (SRT) for patients with neovascular age-related macular degeneration (AMD). DESIGN Randomized, double-masked, sham-controlled, multicenter, clinical trial. PARTICIPANTS A total of 230 participants with neovascular AMD who received ≥ 3 ranibizumab or bevacizumab injections within the preceding year and requiring treatment at enrollment. METHODS Participants received 16 Gray, 24 Gray, or sham SRT. All arms received pro re nata (PRN) ranibizumab for 12 months, with PRN bevacizumab or ranibizumab thereafter. MAIN OUTCOME MEASURES Mean number of PRN injections; best-corrected visual acuity (BCVA); loss of <15 Early Treatment of Diabetic Retinopathy Study letters; change in optical coherence tomography central subfield thickness; and change in angiographic total lesion area and choroidal neovascularization (CNV) area. RESULTS At year 2, the 16 and 24 Gray arms received fewer PRN treatments compared with sham (mean 4.5, P = 0.008; mean 5.4, P = 0.09; and mean 6.6, respectively). Change in mean BCVA was -10.0, -7.5, and -6.7 letters for the 16 Gray, 24 Gray, and sham arms, respectively, with 46 (68%), 51 (75%), and 58 participants (79%), respectively, losing <15 letters. Mean central subfield thickness decreased by 67.0 μm, 55.4 μm, and 33.3 μm, respectively. Mean total active lesion area increased by 1.0, 4.2, and 2.7 mm(2), respectively. Mean CNV area decreased by 0.1 mm(2) in all groups. An independent reading center detected microvascular abnormalities in 6 control eyes and 29 SRT eyes, of which 18 were attributed to radiation; however, only 2 of these possibly affected vision. An exploratory subgroup analysis found that lesions with a greatest linear dimension ≤ 4 mm (the size of the treatment zone) and a macular volume greater than the median (7.4 mm(3)) were more responsive to SRT, with 3.9 PRN injections versus 7.1 in comparable sham-treated participants (P = 0.001) and mean BCVA 4.4 letters superior to sham (P = 0.24). CONCLUSIONS A single dose of SRT significantly reduces intravitreal injections over 2 years. Radiation can induce microvascular change, but in only 1% of eyes does this possibly affect vision. The best response occurs when AMD lesions fit within the treatment zone and they are actively leaking.

Functional and morphologic benefits in early detection of neovascular age-related macular degeneration using the preferential hyperacuity perimeter.

Purpose: To estimate the usefulness of preferential hyperacuity perimetry (PHP) in detecting conversion of early to late age-related macular degeneration in the Carotenoids and co-antioxidants in patients with Age-Related Maculopathy, a multicenter randomized controlled clinical trial. Methods: This was a nested case control study within the Carotenoids and co-antioxidants in patients with Age-Related Maculopathy (CARMA) clinical trial and included all participants enrolled in a single center (n = 200). Data are from participants who progressed to neovascular age-related macular degeneration (nvAMD) during time on study, Group 1 (n = 10) before the use of PHP and Group 2 (n = 10) during use of PHP. We also randomly selected 21 other participants (Group 3) who did not progress to nvAMD during time on study as a control group. Change in best-corrected visual acuity and contrast sensitivity and size of neovascular lesion at detection of conversion to nvAMD in Groups 1 and 2. Results: At detection of nvAMD, mean best-corrected visual acuity in Group 1 was 57.5 letters versus 67.4 in Group 2. In Group 1, the change in best-corrected visual acuity from baseline to detection of nvAMD was twice that of Group 2 (21.6 ± 9.0 versus 11.9 ± 10.7) with a mean difference of 9.7 letters (95% confidence interval, 0.41 to 19.0, P = 0.04, independent-samples t-test). The size of the neovascular lesion at detection was 3.06 mm2 in Group 1 versus 0.89 mm2 in Group 2 (P = 0.02). Two thirds of the participants in Group 2 were asymptomatic at detection of nvAMD compared with one fifth in Group 1. Preferential hyperacuity perimetry distortion maps were abnormal in 9 of 10 eyes in Group 2, which were confirmed by optical coherence tomography. Of the 21 eyes in Group 3, PHP maps were normal in 18 and abnormal in 3. Conclusion: Preferential hyperacuity perimetry detected abnormalities in central visual function with high reliability. Eyes with nvAMD lesions detected by PHP had smaller lesions and better function when compared with the group before the introduction of PHP. The false-negative rate was <10% on PHP. The PHP distortion map was helpful in alerting clinicians to the presence of subclinical nvAMD.

Grading of age-related maculopathy: slit-lamp biomicroscopy versus an accredited grading center.

Purpose: To compare clinical age-related maculopathy (ARM) grading using slit-lamp biomicroscopy (SLB) versus photographic grading of stereoscopically captured fundus photographs (FP) using a high-resolution fundus camera. Methods: A subset (129) of participants in the Carotenoids in ARM study were clinically graded for ARM signs and the corresponding FPs were graded in an accredited reading center. Results: Drusen were said to be present in 192 (94.5%) eyes graded by FP, and in 165 (82.5%) eyes examined by SLB (agreement = 84%, k = 0.23). A good and modest degree of agreement was observed between SLB and FP for quantification of total drusen number (agreement = 81%, k = 0.33) and for classification of drusen subtypes (agreement = 60%, k = 0.33), respectively. Localization of drusen to either the inner zone or the outer zone was comparable for both techniques of ARM grading (inner zone: agreement = 89%; outer zone: agreement = 88%, k = 0.39). Agreement between SLB and FP was 76% (k = 0.46) for identification of any pigment abnormality; however, agreement was less for hypo-pigmentation abnormalities (agreement = 64%, k = 0.21). Conclusions: From the statistical perspective, SLB grading of ARM is generally comparable with findings from standardized grading of FP. However, the lower levels of agreement for classification of drusen subtypes and detection of hypo-pigmentation suggest these features may go unrecorded in a study which relies on SLB for grading ARM.

The design and implementation of a study to investigate the effectiveness of community vs hospital eye service follow-up for patients with neovascular age-related macular degeneration with quiescent disease

IntroductionStandard treatment for neovascular age-related macular degeneration (nAMD) is intravitreal injections of anti-VEGF drugs. Following multiple injections, nAMD lesions often become quiescent but there is a high risk of reactivation, and regular review by hospital ophthalmologists is the norm. The present trial examines the feasibility of community optometrists making lesion reactivation decisions.MethodsThe Effectiveness of Community vs Hospital Eye Service (ECHoES) trial is a virtual trial; lesion reactivation decisions were made about vignettes that comprised clinical data, colour fundus photographs, and optical coherence tomograms displayed on a web-based platform. Participants were either hospital ophthalmologists or community optometrists. All participants were provided with webinar training on the disease, its management, and assessment of the retinal imaging outputs. In a balanced design, 96 participants each assessed 42 vignettes; a total of 288 vignettes were assessed seven times by each professional group.The primary outcome is a participant’s judgement of lesion reactivation compared with a reference standard. Secondary outcomes are the frequency of sight threatening errors; judgements about specific lesion components; participant-rated confidence in their decisions about the primary outcome; cost effectiveness of follow-up by optometrists rather than ophthalmologists.DiscussionThis trial addresses an important question for the NHS, namely whether, with appropriate training, community optometrists can make retreatment decisions for patients with nAMD to the same standard as hospital ophthalmologists. The trial employed a novel approach as participation was entirely through a web-based application; the trial required very few resources compared with those that would have been needed for a conventional randomised controlled clinical trial.

Microvascular abnormalities secondary to radiation therapy in neovascular age-related macular degeneration: findings from the INTREPID clinical trial

Purpose To report the incidence and features of retinal microvascular abnormalities (MVAs) occurring secondary to stereotactic radiotherapy (SRT) in a randomised double-masked sham-controlled clinical trial at 21 European sites. Methods Two hundred and thirty participants with neovascular age-related macular degeneration (AMD) treated with at least three intravitreal antivascular endothelial growth factor (anti-VEGF) injections prior to enrolment, and demonstrating a continuing need for re-treatment. Interventions: 16 Gy, 24 Gy or sham SRT. All three groups received pro re nata anti-VEGF injections if the lesion was judged to be active at review visits. Colour fundus images from baseline and 6 months and fluorescein angiograms from baseline and annual visits were graded for measures of morphological outcome and safety using a prespecified protocol with accompanying definitions to distinguish RT-related MVA from non-specific retinal vessel abnormalities that are known to occur in neovascular AMD. The main outcome measure was MVA detected by months 12, 24 and 36 after enrolment. Results The frequency of MVAs in the combined SRT arms was 0% in year 1, 13.1% in year 2 and 30.3% in year 3. The area of MVA was small and the mean change in visual acuity in year 2 was similar in a subset of SRT eyes with MVAs, versus those without MVAs. MVA was considered to have possibly contributed to vision loss in 2 of 18 cases with MVA in year 2, and 5 of 37 cases in year 3. Conclusion Treatment with SRT is associated with development of subtle MVAs that have little or no impact on visual outcome. These findings can help clinicians recognise the retinal MVAs that occur in response to SRT.