Visual Function Abnormalities and Prognosis in Eyes with Age-related Geographic Atrophy of the Macula and Good Visual Acuity

doi:10.1016/S0161-6420(97)30079-7

Ophthalmology

Volume 104, Issue 10, October 1997, Pages 1677-1691

https://doi.org/10.1016/S0161-6420(97)30079-7 Get rights and content

Purpose: Geographic atrophy (GA) may cause significant compromise of visual function, even when there still is good visual acuity (VA), because of parafoveal scotomas and foveal function abnormalities antedating visible atrophy. This study evaluates the visual function abnormalities at baseline and the 2-year worsening of VA and reading rate for eyes with GA compared with a group of eyes with drusen only.

Methods: Seventy-four eyes with GA and VA greater than or equal to 20/50 from a prospective natural history study of GA were included, as were 13 eyes with only drusen. Baseline visual function testing and 2-year VA and maximum reading rate are reported.

Results: The worsening of VA in decreased luminance and foveal dark-adapted sensitivity showed severe abnormalities for the GA group. Contrast sensitivity was significantly reduced for the eyes with GA. Half the eyes with GA, but none of the drusen eyes, had maximum reading rates below 100 words per minute. A scanning laser ophthalmoscope (SLO) measure of the scotoma near fixation combined with a measure of residual foveal function accounted for 54% of the variability in maximum reading rate in the eyes with GA.

Of 40 eyes with GA observed for 2 years, half lost greater than or equal to 3 lines of VA and one quarter lost greater than or equal to 6 lines. The nine eyes with drusen with follow-up had no significant change in VA. Low foveal dark-adapted sensitivity, SLO measures of the scotoma within 1° of fixation, and low maximum reading rate were statistically significant risk factors for doubling of the visual angle. Significant reduction in maximum reading rates at 2 years was present for the eyes with GA.

Conclusions: The eyes with GA with good VA have profound decreases in visual function, particularly in dim lighting and in reading. Half the eyes with GA had doubling in visual angle at 2 years after the baseline examination, whereas the drusen eyes remained essentially unchanged. Impaired visual function at baseline was predictive of an adverse outcome for the eyes with GA.

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Cited by (233)

Macular Sensitivity Endpoints in Geographic Atrophy: Exploratory Analysis of Chroma and Spectri Clinical Trials
2024, Ophthalmology Science
To assess different microperimetry (MP) macular sensitivity outcome measures capturing functional deterioration in eyes with geographic atrophy (GA) secondary to age-related macular degeneration (AMD).
Patients were included from 2 identically designed, phase III, double-masked, randomized controlled clinical trials, Chroma (NCT02247479) and Spectri (NCT02247531).
Patients enrolled were aged ≥ 50 years with bilateral GA and no evidence of previous or active neovascular AMD.
Patients were randomized 2:1:2:1 to receive through 96 weeks intravitreal lampalizumab 10 mg every 4 weeks (LQ4W), every 6 weeks (LQ6W), or corresponding sham procedures. For this study, mesopic macular sensitivity of the central 20° was assessed using MP-1 microperimeter at selected sites.
Two exploratory endpoints were developed, namely perilesional sensitivity (average of points adjacent to absolute scotomatous points) and responding sensitivity (average of all nonscotomatous points; > 0 dB at baseline) by using customized masks for each patient. These were compared with conventional MP endpoints (mean macular sensitivity and number of absolute scotomatous points).
Of 1881 Chroma and Spectri participants, 277 agreed to participate in the present study. Of these, 197 (LQ4W, n = 63; LQ6W, n = 68; pooled sham, n = 66) had reliable MP results. Enlargement of GA lesion area by approximately 2 mm²/year across treatment groups was accompanied by deterioration in all MP parameters. There was no difference in worsening of macular sensitivity or absolute scotomatous points among treatment groups. Perilesional and responding sensitivities showed greater decline over time than mean macular sensitivity. Change in GA lesion area at week 48 showed better correlation with perilesional sensitivity (r = −0.17) and responding sensitivity (r = −0.20) than mean macular sensitivity (r = −0.03), while the correlation was highest with the number of absolute scotomatous points (r = 0.37).
Perilesional or responding macular sensitivity measured by MP should be considered more sensitive endpoints than mean macular sensitivity for monitoring functional decline over time in GA. Although perilesional, responding, and mean macular sensitivity had weak correlation with GA lesion area, the number of absolute scotomatous points may provide additional information on the anatomic/functional correlation.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
The Role of the Complement Pathway in Clinical Progression of Geographic Atrophy: Analysis of the Phase III Chroma and Spectri Trials
2023, Ophthalmology Science
To investigate the relationship between complement pathway activities and progression of geographic atrophy (GA) secondary to age-related macular degeneration in samples collected from patients enrolled in the Chroma and Spectri trials.
Chroma and Spectri were phase III, double-masked, and sham-controlled, 96-week trials.
Aqueous humor (AH) samples collected at baseline and week 24 visits from 81 patients with bilateral GA across all 3 treatment groups (intravitreal lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested, along with patient-matched plasma samples collected at baseline.
Antibody capture assays using the Simoa platform were used to measure the levels of complement factor B, the Bb fragment of complement factor B, intact complement component 3 (C3), processed C3, intact complement C4, and processed C4. Complement factor D levels were measured using enzyme-linked immunosorbent assay.
Correlations of complement levels and activities (i.e., processed:intact ratio of complement component) in AH and plasma with baseline GA lesion size and growth rate.
In baseline AH, there were strong correlations (Spearman’s rho ≥ 0.80) between intact complement proteins, between processed complement proteins, and between linked processed and intact complement proteins; weak correlations (rho ≤ 0.24) were found between complement pathway activities. There were no strong correlations between complement protein levels and activities measured in AH and plasma at baseline (rho ≤ 0.37). Baseline complement levels and activities in AH and plasma did not correlate with baseline GA lesion size or change from baseline in GA lesion area at week 48 (i.e., annualized growth rate). There were no strong correlations between changes in complement levels/activities in the AH from baseline to week 24 and annualized GA lesion growth rate. Genotype analysis did not reveal a meaningful correlation between complement-related, age-related macular degeneration risk single-nucleotide polymorphisms and complement levels and activities.
Complement levels or activities in AH and plasma did not correlate with GA lesion size or growth rate. This suggests that local complement activation as measured in AH does not appear to be related to GA lesion progression.
Proprietary or commercial disclosure may be found after the references.
Decreased Central Macular Choriocapillaris Perfusion Correlates With Increased Low Luminance Visual Acuity Deficits
2023, American Journal of Ophthalmology
Correlations between low luminance visual acuity deficits (LLVADs) and central choriocapillaris perfusion deficits were investigated to help explain how increases in LLVAD scores at baseline predict annual growth rates of geographic atrophy (GA).
Prospective cross-sectional study.
Photopic luminance best-corrected visual acuity (PL-BCVA) and low luminance BCVA (LL-BCVA) were measured using the Early Treatment Diabetic Retinopathy Study chart. LL-BCVA was measured using a 2.0-log unit neutral density filter. LLVADs were calculated as the difference between PL-BCVA and LL-BCVA. Within a fovea-centered 1-mm circle, the percentage of choriocapillaris flow deficits (CC FD%), drusen volume, optical attenuation coefficient (OAC) elevation volume, and outer retinal layer (ORL) thickness were assessed.
In all 90 eyes (30 normal eyes; 31 drusen-only eyes; 29 non-foveal GA eyes), significant correlations were found between the central CC FD% and PL-BCVA (r = −0.393, P < .001), LL-BCVA (r = −0.534, P < .001), and the LLVAD (r = 0.439, P < .001). Central cube root (cubrt) drusen volume, cubrt OAC elevation volume, and ORL thickness were correlated with PL-BCVA, LL-BCVA, and LLVADs (all P < .05). Stepwise regression models showed that central cubrt OAC elevation volume and ORL thickness were associated with PL-BCVA (R² = 0.24, P < .05); central CC FD%, cubrt OAC elevation volume, and ORL thickness were associated with LL-BCVA (R² = 0.44, P < .01); and central CC FD% and ORL thickness were associated with LLVAD (R² = 0.24, P < .01).
The significant correlations between central CC FD% and LLVAD support the hypothesis that the ability of LLVAD to predict the growth of GA is mediated through a decrease in macular choriocapillaris perfusion.
Alternative Complement Pathway Inhibition by Lampalizumab: Analysis of Data From Chroma and Spectri Phase III Clinical Trials
2023, Ophthalmology Science
Lampalizumab, an antigen-binding fragment of a humanized monoclonal antibody directed against complement factor D (CFD), is designed to treat geographic atrophy (GA) secondary to age-related macular degeneration. Given the lack of clinical efficacy observed in patients with GA in the phase III Chroma/Spectri trials, we investigated the impact of lampalizumab on the complement system in vivo. We developed 6 novel assays to measure changes in complement pathway activities in aqueous humor samples collected from patients enrolled in these trials.
Chroma/Spectri were double-masked, sham-controlled, 96-week trials.
Aqueous humor samples from 97 patients with bilateral GA across all groups (i.e., intravitreous lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested.
Novel antibody capture assays were developed on the Simoa platform for complement factor B (CFB), the Bb fragment of CFB, intact complement component 3 (C3), processed C3, intact complement component 4 (C4), and processed C4.
The ratio of processed vs. intact complement factors (i.e., complement activity) in aqueous humor were assessed.
Patients treated with either of the lampalizumab regimens demonstrated an increase in CFD level at week 24 compared with baseline, along with a corresponding median reduction in the Bb:CFB ratio of 41% to 43%. There were no strong correlations between lampalizumab concentrations in aqueous humor and change in CFD levels or Bb:CFB ratio over time. No change in downstream C3 processing was observed with lampalizumab treatment. Additionally, there was no change in C4 processing.
The collection of aqueous humor samples from patients in Chroma and Spectri trials provided key insights on the effects of lampalizumab, a novel complement inhibitor, on local ocular complement activation. Lampalizumab inhibited the alternative complement pathway in the eyes of patients with GA; however, this did not translate into a measurable reduction in either classical or total complement activity, based on absence of changes in C4 and C3 processing, respectively.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
The Underreporting of Age-related Geographic Atrophy of the Macula See Editorial on page 287.
2023, Ophthalmology Retina
Microperimetry in Retinal Diseases
2023, Asia-Pacific Journal of Ophthalmology
Retinal microperimetry (MP) is a procedure that assesses the retinal sensitivity while the fundus is directly observed, and an eye tracker system is active to compensate for involuntary eye movements during testing. With this system, the sensitivity of a small locus can be accurately determined, and it has become an established ophthalmic test for retinal specialists. Macular diseases are characterized by chorioretinal changes; therefore, the condition of the retina and choroid requires careful and detailed evaluations to perform effective therapy. Age-related macular degeneration is a representative retinal disease in which the macular function has been evaluated by the visual acuity throughout the course of the disease process. However, the visual acuity represents the physiological function of only the central fovea, and the function of the surrounding macular area has not been sufficiently evaluated throughout the different stages of the macula disease process. The new technique of MP can compensate for such limitations by being able to test the same sites of the macular area repeatedly. This is especially useful in the recent management of age-related macular degeneration or diabetic macular edema during anti-vascular endothelial growth factor treatments because MP can assess the effectiveness of the treatment. MP examinations are also valuable in diagnosing Stargardt disease as they can detect visual impairments before any abnormalities are found in the retinal images. The visual function needs to be carefully assessed along with morphologic observations by optical coherence tomography. In addition, the assessment of retinal sensitivity is useful in the presurgical or postsurgical evaluations.

View all citing articles on Scopus

: The baseline visual function abnormalities were presented at the 1995 meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida. The natural history aspect of this article is being submitted as an abstract for presentation at the 1997 American Academy of Ophthalmology Meeting, San Francisco, California.

: Supported by NEI grants R01EY08552 (JS, CA, NB, BH, MM, DH) and RO1EY06380 (GR, JS).

: The work with the scanning laser ophthalmoscope has been supported in part by the Harry and Jeanette Weinberg Foundation, Baltimore, Maryland; the Morris Rodman Philanthropic Foundation, Rockville, Maryland; the Altsheler-Durell Foundation, Louisville, Kentucky; the Grousbeck Family Foundation, Boston, Massachusetts; and the Macula Foundation, New York, New York.

: The authors have no proprietary interest in the development or marketing of instruments used in this study or in competing instruments.

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Visual Function Abnormalities and Prognosis in Eyes with Age-related Geographic Atrophy of the Macula and Good Visual Acuity

Am J Ophthalmol

Ophthalmology

Ophthalmology

Am J Ophthalmol

Age-related macular degeneration and blindness due to neovascular maculopathy

Arch Ophthalmol

The relationship of age-related maculopathy, cataract, and glaucoma to visual acuity

Invest Ophthalmol Vis Sci

Evolution of geographic atrophy of the retinal pigment epithelium

Eye

Retinal sensitivity over drusen and nondrusen areas. A study using fundus perimetry

Arch Ophthalmol

Landmark-driven fundus perimetry using the scanning laser ophthalmoscope

Invest Ophthalmol Vis Sci

Dark adaptation and the acuity/luminance response in senile macular degeneration (SMD)

Am J Optom Physiol Optics

Reliability and sensitivity of clinical contrast sensitivity tests

Clin Vis Sci