Purpose
To assess retinal nerve fiber layer (RNFL) and macular thickness using optical coherence tomography (OCT) on HIV-infected patients without ocular manifestations and to correlate these findings with frequency-doubling technology perimetry (FDT).
Design
Cross-sectional study.
Methods
setting: Single center. study population: Seventy-three patients (146 eyes) with clinically normal examination classified in 3 groups: group A, HIV-infected patients with CD4 count <100 cells/mm 3 for at least 6 months; group B, HIV-infected patients with CD4 count >100 cells/mm 3 since diagnosis; and group C, HIV-negative control subjects. observation procedures: Fast RNFL and fast macula scan strategies on Stratus OCT and Humphrey Matrix 24-2 full-threshold program. main outcome measures: OCT RNFL and macular thicknesses and FDT indices (mean deviation [MD], pattern standard deviation [PSD], and glaucoma hemifield test [GHT]).
Results
Group A had a significantly thinner average RNFL, temporal outer macula, and inferior outer macula thicknesses when compared to groups B and C ( P < .05). Statistically significant differences were observed in the FDT MD between groups A and C ( P = .034) and in PSD in group A compared to groups B and C ( P = .011). Eyes of HIV patients with GHT and PSD results outside normal confidence limits had thinner average RNFL thickness measures than eyes with results within normal limits in the same group of patients ( P < .05).
Conclusions
HIV-infected patients with low CD4 count have a significant RNFL and macular thinning. Functional loss detected by FDT is related to RNFL thinning in HIV-infected patients.
The introduction of highly active antiretroviral therapy (HAART) in 1996 changed the clinical picture of human immunodeficiency virus (HIV)-associated disease with a marked decrease in the incidence of opportunistic infections, most notably cytomegalovirus retinitis. However, HIV-infected patients in the era before as well as after HAART have experienced loss of visual function even in the absence of infectious retinitis.
It is hypothesized that damage to the inner retina from retinovascular disease in HIV-positive patients, including retinal cotton-wool spots, areas of capillary dropout, and ischemia, leads to permanent damage to the ganglion cell layer and retinal nerve fiber layer (RNFL) with consequent visual function abnormalities. Previous studies have reported the presence of visual deficit in the absence of infectious retinopathy using different measurements of visual function, including visual field testing, contrast and color sensitivity, and electrophysiological tests. Recent studies have demonstrated thinning of the RNFL in eyes of HIV-infected patients without retinitis using laser scanning ophthalmoscopy (HRT; Heildelberg retinal tomograph), scanning laser polarimetry (GDx), and optical coherence tomography (OCT). However, we are unaware of previous studies that attempted to study the association between the anatomic changes and perimetric findings.
In recent years, perimetric tests that measure visual function with non-white-on-white thresholds have become available. These tests isolate specific retinal ganglion cell subtypes that represent small populations and possibly are more sensitive to early damage. Short-wavelength automated perimetry (SWAP) tests the function of blue-sensitive cells of the koniocellular pathway and, as in glaucoma, SWAP may reveal the extent of defects in the visual field of HIV-infected patients earlier than standard automated perimetry (SAP) does. Frequency-doubling technology (FDT) perimetry measures contrast-detection thresholds through a frequency-doubled stimulus and may be mediated by a group of retinal ganglion cells called My cells or by cortical mechanisms. In the same way that SWAP may predict SAP visual field loss, FDT perimetry may also detect field loss earlier than SAP. Second-generation FDT perimetry (Humphrey Matrix) uses a smaller stimulus size (5 degrees square stimulus) and a higher density of test locations than its previous version, with a stimulus pattern similar to the Humphrey field analyzer’s test (Carl Zeiss Meditec, Dublin, California, USA). Humphrey Matrix perimetry also has full-threshold tests using the zippy estimation by sequential testing (ZEST) strategy, as well as a more advanced statistical analysis of results, including the glaucoma hemifield test (GHT). In HIV-infected patients, evaluation of visual field has not yet been reported with FDT perimetry.
The purpose of this study is to evaluate RNFL and macular thickness measured by OCT on HIV-infected patients without ocular manifestations and to correlate these results with perimetric findings assessed by FDT perimetry.
Methods
The participants of this study were recruited between August 10, 2007 and July 3, 2008 from the Uveitis and AIDS Service of the Federal University of São Paulo (UNIFESP), whereas control subjects were recruited from normal volunteers.
Each participant underwent a complete ophthalmologic evaluation, including best-corrected visual acuity measurement, slit-lamp evaluation, indirect ophthalmoscopy, and intraocular pressure measurements. Within a 2-week period after clinical examination, the subjects performed OCT and FDT tests; if both exams were performed in the same day, the patients completed the perimetry tests before OCT examination.
General inclusion criteria were as follows: best-corrected visual acuity 20/25 or better, spherical refractive error of 0 ± 4.0 diopters (D) and astigmatism of 0 ± 2.5 D, and normal intraocular pressure (≤21 mm Hg). Patients with retinal diseases such as HIV-related infectious retinopathy, diabetes, age-related macular degeneration, and/or cataract or any visible media opacity were not enrolled in the study. Participants were also excluded from the study if they were found to have any risk factor for the development of glaucoma or other eye disease (such as positive family history of glaucoma, previous intraocular surgery, previous ocular trauma, and retinal or neurologic abnormalities) that may affect the visual field or OCT measurements.
The study included 146 eyes from 73 patients (40 male, 33 female) who were classified in 3 groups. Group A consisted of 52 eyes of 26 HIV-infected patients with CD4 cell count below 100 cells/mm 3 at some point of time in their medical history lasting for at least 6 months. Group B comprised 50 eyes of 25 HIV-infected patients whose CD4 cell counts were never below 100 cells/mm 3 in their medical records. Group C was made up of 44 eyes of 22 HIV-negative subjects (control group). All HIV-infected patients were treated with HAART prior to and at the time of the examination.
Procedures
Optical coherence tomography scanning
Third-generation OCT evaluation (Stratus OCT, Model 3000; Carl Zeiss Meditec, Dublin, California, USA) was used to measure RNFL thickness and macular thickness under pupillary dilation.
The fast RNFL algorithm was used to obtain RNFL thickness measurements. Three images per eye were obtained, with each image consisting of 256 A-scans along a 3.4-mm-diameter circular ring around the optic disc, and a mean image was automatically created by the Stratus OCT software. Retinal nerve fiber layer thickness parameters were automatically calculated by Stratus OCT built-in software (version 4.0.1). The following parameters were evaluated: average thickness (360-degree measure), and temporal, superior, nasal, and inferior quadrant thicknesses.
The fast macular thickness protocol was used to obtain macular thickness measurements generated from 6 6-mm linear scans in a radial configuration, centered on the fovea, with each line 30 degrees apart. Delineation of the inner and outer boundaries of the neurosensory retina and a topographic map of the macula were automatically generated by OCT built-in software (version 4.0.1). The macular thickness parameters evaluated were foveal minimum thickness; central macular thickness; superior, inferior, temporal, and nasal inner macular thicknesses; and superior, inferior, temporal, and nasal outer macular thicknesses.
Only good scans with signal strength >6, focused images, proper centering, and no evidence of algorithm failure were included in the analysis.
Frequency-doubling technology perimetry
FDT perimetry was performed with the FDT Humphrey Matrix (Carl Zeiss Meditec, Dublin, California, USA; and Welch-Allyn, Skaneateles, New York, USA) using the 24-2 full-threshold strategy. Patients had both eyes tested in randomized order. Most patients did not have prior experience with FDT Matrix; therefore, at least 2 reliable tests were performed to minimize the influence of the learning effect. Only reliable visual fields (fixation losses <25%, false positives <33%, and false negatives <33%) were included; these criteria helped to rule out fatigue or illness in patients. Patient’s refraction error was corrected when necessary for perimetry testing. The main outcome measures considered were: mean deviation (MD), pattern standard deviation (PSD), and glaucoma hemifield test (GHT).
Statistical Analysis
The statistical package SPSS 16.0 for Windows (SPSS, Inc, Chicago, Illinois, USA) was used in the analysis of the data. The age and gender of patients in the 3 groups were compared by analysis of variance (ANOVA) and the χ 2 test, respectively. Duration of diagnosis of HIV infection, duration of HAART, and current and previous lowest CD4 cell counts in the 2 groups of HIV-infected patients were compared by Student t test. For each subject, both eyes were enrolled in the study; generalized estimating equations (GEE) models were performed to account for the correlation between eyes of the same patient. As researchers have consistently reported gender differences in macular thickness, gender was included as a covariate in the GEE models. Bonferroni correction for multiple comparisons was performed to analyze pairwise differences. Continuous variables were expressed as mean ± standard error (SE) and categorical variables were expressed as absolute and relative frequencies. P values of less than .05 were taken to indicate statistical significance.
Results
Table 1 describes the baseline characteristics for each of the 3 groups. The groups were matched for age ( P = .946) and the groups composed by HIV-infected patients (groups A and B) were matched for duration of laboratory diagnosis of HIV infection and duration of HAART ( P = .428 and P = .749, respectively).
| Characteristics | Group A (n=26) | Group B (n=25) | Group C (n=22) | P Value a |
|---|---|---|---|---|
| Age (years), mean ± SE | 43.54 ± 1.51 | 42.68 ± 1.61 | 43.27 ± 2.59 | .946 |
| Male/female, n (%) | 18(69.2%)/8(30.8%) | 10(40.0%)/15(60.0%) | 12(54.5%)/10(45.5%) | .111 |
| Duration of laboratory diagnosis of HIV infection (months), mean ± SE | 100.73 ± 15.45 | 85.88 ± 10.03 | NA | .428 |
| Duration of HAART (months), mean ± SE | 70.96 ± 13.81 | 76.96 ± 10.34 | NA | .731 |
| Current CD4 count (cells/mm 3 ), mean ± SE | 219.96 ± 49.18 | 502.29 ± 41.36 | NA | <.001 |
| Previous lowest CD4 count (cells/mm 3 ), mean ± SE | 28.31 ± 4.67 | 301.08 ± 31.11 | NA | <.001 |
Average RNFL thickness was significantly thinner in patients from group A when compared to groups B and C ( P = .002). Analysis of RNFL thickness by quadrants revealed statistically significant differences for group A compared with groups B and C in the inferior quadrant ( P = .006), between groups A and C in the nasal quadrant ( P = .026), and between groups A and B in the superior quadrant ( P = .028). No statistical difference was found in RNFL thickness average and in the quadrant measurements between groups B and C. Peripapillary OCT RNFL measures estimates are presented in Table 2 .
| Peripapillary Area | Group A (n=52) | Group B (n=50) | Group C (n=44) | P Value |
|---|---|---|---|---|
| Average | 96.06 ± 2.95 | 107.31 ± 1.55 b | 107.16 ± 1.91 b | .002 |
| Temporal | 65.67 ± 1.77 | 69.74 ± 1.84 | 71.42 ± 1.87 | .070 |
| Superior | 119.38 ± 4.52 | 133.87 ± 2.99 b | 129.36 ± 2.51 | .028 |
| Nasal | 76.70 ± 3.82 | 87.42 ± 2.40 | 89.42 ± 3.37 b | .026 |
| Inferior | 122.92 ± 4.47 | 138.02 ± 2.33 b | 138.57 ± 2.65 b | .006 |
a Values are expressed in micrometers as mean ± standard error (estimated by GEE models).
Table 3 shows macular thickness measurements estimates in eyes of patients from the 3 study groups. The measurements in the temporal outer and inferior outer areas were significantly decreased in eyes of group A compared with groups B and C (respectively, P = .012 and P = .011). There were no differences in the macular thickness measurements between groups B and C.
| Macular Area | Group A (n=52) | Group B (n=50) | Group C (n=44) | P Value |
|---|---|---|---|---|
| Fovea minimum | 162.26 ± 4.92 | 159.97 ± 2.99 | 165.12 ± 3.82 | .567 |
| Central macula | 197.97 ± 5.60 | 194.25 ± 2.97 | 200.64 ± 5.03 | .520 |
| Temporal inner | 255.48 ± 3.16 | 259.22 ± 2.42 | 265.27 ± 4.47 | .200 |
| Superior inner | 267.81 ± 3.13 | 272.38 ± 2.60 | 278.74 ± 4.64 | .142 |
| Nasal inner | 268.71 ± 3.50 | 270.09 ± 2.71 | 277.39 ± 4.66 | .298 |
| Inferior inner | 267.01 ± 3.29 | 269.43 ± 2.69 | 279.16 ± 4.71 | .098 |
| Temporal outer | 215.04 ± 2.30 | 223.08 ± 2.37 b | 226.56 ± 4.14 b | .012 |
| Superior outer | 230.93 ± 2.84 | 237.74 ± 2.43 | 240.81 ± 3.35 | .057 |
| Nasal outer | 251.82 ± 3.01 | 258.25 ± 3.03 | 260.92 ± 4.42 | .157 |
| Inferior outer | 222.35 ± 3.91 | 234.78 ± 2.50 b | 238.38 ± 4.85 b | .011 |
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