Scanning laser entoptic perimetry for the detection of visual defects associated with diabetic retinopathy.

AIM: To determine the sensitivity and specificity of entoptic perimetry for diagnosing diabetic retinopathy at all levels of severity. METHODS: A prospective clinical study at the Shiley Eye Center, University of California, and San Diego. 30 patients with photographically documented diabetic retinopathy and 24 controls with a similar age distribution. Sensitivity and specificity of entoptic perimetry were computed for detecting clinically significant macular oedema within the central 120 degree radius of the fovea compared to fundus photographs. RESULTS: Entoptic perimetry can detect clinically significant diabetic retinopathy with a sensitivity of 0.88 and specificity of 1.00. Entoptic perimetry can detect the earliest stages of diabetic retinopathy with a sensitivity of 0.86. CONCLUSION: Scanning laser entoptic perimetry is an effective tool for detecting visual function loss caused by diabetic retinopathy.

Retinal nerve fiber layer evaluation in human immunodeficiency virus-positive patients.

PURPOSE: To determine the effect of human immunodeficiency virus (HIV) infection on topographic measures of the optic disk and the retinal nerve fiber layer. METHODS: A cross-sectional study at the Acquired Immunodeficiency Syndrome (AIDS) Ocular Research Unit at the University of California, San Diego. Retinal nerve fiber layer thickness at the optic nerve head was evaluated using the Heidelberg Retinal Tomograph, a confocal scanning laser tomograph in 38 HIV-positive and 24 age-matched HIV-negative subjects. RESULTS: HIV-positive patients without CMV retinitis showed significant differences from HIV-negative normal controls in a number of measures of the retinal nerve fiber layer. This indicated a loss of retinal ganglion cells in HIV-positive patients without retinitis. HIV-positive patients with CMV retinitis were worse in most measurements than both HIV-negative controls and HIV-positive patients without CMV. CONCLUSIONS: Significant thinning of the retinal nerve fiber layer occurs in HIV-positive patients without infectious retinopathy, and there are further changes in the optic disk associated with CMV retinitis. Confocal scanning laser tomography may be of use in the diagnosis of early HIV-associated visual function loss.

Immune recovery vitritis and uveitis in AIDS: clinical predictors, sequelae, and treatment outcomes.

PURPOSE: To determine 1) clinical predictors of an inflammatory syndrome associated with cytomegalovirus (CMV) retinitis (immune recovery vitritis or uveitis [IRV or IRU]); 2) clinical sequelae of IRV; and 3) the effect of corticosteroid treatment on visual acuity. METHODS: A cohort study from the AIDS Ocular Research Unit of the University of California, San Diego, and a case series from the Cleveland Clinic consisted of patients who had acquired immunodeficiency syndrome and inactive CMV retinitis who responded to highly active antiretroviral therapy (HAART) with CD4 T-lymphocyte levels >60 cells/mm3. The cohort was followed for a median of 13.5 months following increase in CD4 count. The authors studied the occurrence of IRV, defined as symptomatic (vision decrease and/or floaters) vitritis of 1+ or greater severity associated with inactive CMV retinitis. Macular edema or epiretinal membrane formation was determined by clinical examination and fluorescein angiography. Five eyes were treated with sub-Tenon corticosteroid injections. RESULTS: In the cohort study, 19 (63%) of 30 HAART responders developed IRV (26 eyes). The clinical spectrum of inflammation included vitritis, papillitis, macular edema, and epiretinal membranes. Eyes with CMV surface area >30% of the retina were at the highest risk (relative risk = 4.5) of developing IRV (P = 0.03). During follow-up, inflammation persisted without treatment for a median of 20 weeks and 14 patients (16 eyes) developed macular changes. Treatment resulted in vision improvement without reactivation of retinitis. Histology and immunohistochemistry of associated epiretinal membranes showed evidence of chronic inflammation with a predominant T-lymphocyte cell population. In the case series, 3 (38%) of 8 HAART responders developed IRV (4 eyes). All four eyes were treated and resulted in visual acuity improvement of one line. CONCLUSIONS: Symptomatic IRV or IRU develops in a significant number of patients with CMV retinitis following successful HAART. Eyes with CMV surface area >30% of the retina are at the greatest risk. Eyes with IRV respond favorably to antiinflammatory therapy without reactivation of retinitis. Immune recovery vitritis may be the result of an immunologic reaction to latent CMV antigens in the eye in which T-lymphocytes play a role.

Scanning laser entoptic perimetry for the screening of macular and peripheral retinal disease.

OBJECTIVE: To determine the effectiveness of scanning laser entoptic perimetry as a noninvasive platform for screening for retinal damage in visually asymptomatic patients within the central 120 degrees (diameter) of vision. DESIGN: A masked study comparing entoptic perimetry with fundus photographs. SETTING: The Shiley Eye Center and the AIDS Ocular Research Unit at the University of California, San Diego. PATIENTS: Fifty-eight patients recruited during ophthalmologic visits for treatment or follow-up of ocular disease. MEASUREMENTS: For each testing session, we compared the presence of a disturbance in the entoptic stimulus with the presence of retinal disease within the central 120 degrees of vision, centered on the fovea. RESULTS: Scanning laser entoptic perimetry has a sensitivity and specificity of more than 90%, a positive predictive value of 100%, and a negative predictive value of 89% for screening retinal lesions within the central 120 degrees diameter of vision. CONCLUSION: Scanning laser entoptic perimetry may be an effective and inexpensive screening test for diagnosing retinal disease in hospitals and community clinics. Arch Ophthalmol. 2000;118:1205-1210

Correlation between static automated and scanning laser entoptic perimetry in normal subjects and glaucoma patients.

OBJECTIVE: To compare the effectiveness of scanning laser entoptic perimetry with static automated perimetry as a noninvasive instrument for screening for glaucomatous damage in visually asymptomatic subjects within the central 60 degrees (diameter) of vision. DESIGN: A masked cross-sectional study comparing entoptic perimetry to achromatic threshold perimetry. PARTICIPANTS: Twenty-three subjects and controls from the Sharp Rees-Stealy Hospital and the Shiley Eye Center at the University of California, San Diego. TESTING: Virtual reality-based entoptic perimetry was compared with achromatic threshold perimetry. MAIN OUTCOME MEASURES: For each testing session, we compared the presence of a disturbance in the entoptic perimetry stimulus with the presence of defects in visual function as measured by Humphrey automated visual field perimetry. RESULTS: Scanning laser entoptic perimetry reasonably estimates the overall visual field loss for moderate-to-severe scotomas as measured by the pattern deviation in standard visual field perimetry. Scanning laser entoptic perimetry has a sensitivity from 27% to 90% and a specificity from 50% to 100% for screening moderate-to-severe visual field defects caused by glaucoma within the central 60 degrees diameter of vision. CONCLUSIONS: Scanning laser entoptic perimetry may be an effective and inexpensive screening test in hospitals and community clinics for diagnosing visual field loss caused by glaucoma.

Characterization of reactivation of cytomegalovirus retinitis in patients healed after treatment with highly active antiretroviral therapy.

PURPOSE: To delineate the immune parameters associated with reactivation of cytomegalovirus (CMV) retinitis in patients for whom highly active antiretroviral therapy (HAART) was not successful. METHODS: Prospective, longitudinal observational study of a cohort of 102 patients with CMV retinitis treated with HAART and being followed up at the AIDS Ocular Research Unit of the University of California, San Diego from November 1995 to November 1998. The study included serial clinical and fundus photographic examinations with CD4 T-lymphocyte counts and HIV viral load measurements. RESULTS: Forty-seven of the 102 patients with CMV retinitis responded to HAART. Thirty-five of the patients were successfully withdrawn from anti-CMV therapy. During a median follow-up of 74.71 weeks (range, 4.86-144 weeks) after discontinuation of anti-CMV therapy, four patients experienced a reactivation of CMV retinitis. In each case, the CD4 count decreased before reactivation to a median of 31.5 cells/mm3 (mean, 31.25 cells/mm3; range, 23-39 cells/mm3). The association between the CD4 count decreasing to less than 50 cells/mm3 and reactivation of CMV retinitis was statistically significant (P < 0.0003). CONCLUSION: Four patients treated with HAART experienced reactivation of CMV retinitis as their CD4 count decreased. The threshold CD4 count below which reactivation of CMV retinitis occurred in patients for whom HAART was not successful appeared to be 50 cells/mm3. Despite an initial response to HAART, patients are still at risk for reactivation of CMV retinitis if their CD4 count decreases to less than 50 cells/mm3. The HIV viral load did not appear to predict CMV reactivation.

Pattern of early visual field loss in HIV-infected patients.

OBJECTIVE: To determine the topographic pattern of visual field loss, if any, and its relationship to the stage of disease in human immunodeficiency virus-positive patients without infectious retinopathy. METHODS: A total of 151 eyes from 81 alert and cooperative patients with human immunodeficiency virus were evaluated with visual field testing. Results were analyzed relative to the associated underlying nerve fiber layer patterns associated with retinal ganglion cell axons as they traverse the retina to the optic nerve. The stage of visual field loss was analyzed relative to the length of survival using Kaplan-Meier survival analysis. RESULTS: No correlation of CD4 cell count with visual field mean defect (r2 = 0.23) or corrected pattern standard deviation (r2 = 0.00) was found. A pattern of visual field loss, consistent with sparing of the papillomacular bundles and associated with damage primarily to the inferior retina external to the posterior pole, was found. Survival analysis indicated a significant difference in time of survival between individuals with normal visual fields and those with a diffuse visual field loss, with a trend to less survival with increasing field loss severity. CONCLUSIONS: These results are consistent with disease at the level of the optic nerve. The relationship of stage of visual field loss to survival has important implications for early detection of field loss and appropriate therapeutic intervention to maintain function and quality of life.

The utility of entoptic perimetry as a screening test for cytomegalovirus retinitis.

OBJECTIVE: To determine the sensitivity and specificity of entoptic perimetry as a noninvasive test for detecting retinal damage due to peripheral cytomegalovirus (CMV) retinitis. DESIGN: A masked study comparing entoptic perimetry with fundus photography under 4 experimental conditions (determined by increasing pixel sizes) on 2 separate testing sessions. SETTING: Acquired immunodeficiency syndrome Ocular Research Unit at the University of California, San Diego. PATIENTS: Twenty-four human immunodeficiency virus-positive and 8 human immunodeficiency virus-negative subjects; 21 eyes with documented CMV retinitis, and 26 eyes that were retinitis free. MEASUREMENTS: For each testing session, screening method, and condition, the presence of CMV retinitis was determined for each meridian (i.e., clock hour), each quadrant (consisting of 3 meridians), and each eye (consisting of all meridians); the amount of retinitis was defined as the percentage of meridians or quadrants with CMV retinitis. RESULTS: Entoptic perimetry was as sensitive and specific as fundus photography in determining the presence of CMV retinitis. Determination of the amount of CMV retinitis tended to be underestimated by perimetry for larger pixel sizes. CONCLUSION: Entoptic perimetry may be an effective and inexpensive alternative to fundus photography for CMV retinitis in hospitals and community clinics.

Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy.

This study was conducted to determine the likelihood of the development of a new ocular inflammatory syndrome (immune recovery vitritis, IRV), which causes vision loss in AIDS patients with cytomegalovirus (CMV) retinitis, who respond to highly active antiretroviral therapy (HAART). We followed 30 HAART-responders with CD4 cell counts of >/=60 cells/mm3. Patients were diagnosed with IRV if they developed symptomatic vitritis of >/=1+ severity associated with inactive CMV retinitis. Symptomatic IRV developed in 19 (63%) of 30 patients and in 26 (59%) of 44 eyes over a median follow-up from HAART response of 13.5 months. The annual incidence of IRV was 83/100 person-years. Excluding patients with previous cidofovir therapy did not significantly alter the time course of IRV (P=.79). These data suggest that IRV develops in a significant number of HAART-responders with CMV retinitis and is unrelated to previous cidofovir therapy.

Neuropsychological impairment-associated visual field deficits in HIV infection. HNRC Group. HIV Neurobehavioral Research Center.

PURPOSE: To examine the relationship between loss in peripheral visual sensitivity and neuropsychological functioning in seropositive patients with human immunodeficiency virus (HIV) without infectious retinopathy. METHODS: Subjects carefully screened for retinal disease and well-matched across demographic and medical variables were grouped according to normal (perimetry-nl) versus abnormal (perimetry-abnl) performance on achromatic automated perimetry and short-wavelength automated perimetry, standard clinical ophthalmologic measures of visual function. All subjects completed a detailed neuropsychological test battery and were classified as impaired or unimpaired, globally and across eight neurocognitive domains. Subjects were also classified according to whether they met diagnostic criteria for minor cognitive/motor disorder (MCMD) or HIV-associated dementia (HAD). RESULTS: Visual field loss was associated with lower performance in the abstraction, perceptual-motor, learning, and motor domains. Significant group differences were also found on numerous individual neuropsychological tests. Based on clinical ratings, we found deficits in learning and motor functioning. No perimetry-nl subjects met criteria for MCMD or HAD, whereas 32% of perimetry-abnl subjects met diagnostic criteria for syndromic cognitive disorders (five MCMD and one HAD). In a subset of subjects who underwent a lumbar puncture, there was a trend for the perimetry-abnl group to have a higher concentration of beta2 microglobulin, a marker for central nervous system immune activation. CONCLUSIONS: These results suggest that in some HIV-infected people reduced visual function may be caused by nonretinal disease, and perimetry may present a sensitive measure of HIV-related brain dysfunction.

Color from invisible flicker: a failure of the Talbot-Plateau law caused by an early 'hard' saturating nonlinearity used to partition the human short-wave cone pathway.

The Talbot-Plateau law fails for flicker detected by the short-wavelength-sensitive (S) cones: a 30-40 Hz target, flickering too fast for the flicker to be resolved, looks more yellow than a steady target of the same average intensity. The color change, which is produced by distortion at an early compressive nonlinearity, was used to reveal a slightly bandpass S-cone temporal response before the distortion site and a lowpass response after it. The nonlinearity is probably a 'hard' nonlinearity that arises because the S-cone signal is limited by a response ceiling, which the mean signal level approaches and exceeds as the S-cone adaptation level increases. The nonlinearity precedes the combination of flicker signals from all three cone types.

Visual dysfunction in HIV-positive patients without infectious retinopathy.

Persons with HIV disease are susceptible to various manifestations of retinal damage, such as infectious retinopathies (e.g., cytomegalovirus [CMV] retinitis and toxoplasmosis) and noninfectious complications (microangiopathic infarctions or cotton-wool spots [CWS]); CWS being quite common in AIDS patients. Until recently, little research focused on noninfectious ocular pathology in HIV disease. These disorders may all affect normal functioning of the visual system while funduscopic examination results appear normal. A review of the psychophysical changes, color and contrast sensitivity, peripheral visual function, electrophysiologic and morphologic changes, the relationship of vision loss and neuropsychological changes, postretinal damage, and imaging capabilities cast important new light on quality of life issues and vision function for all HIV/AIDS patients regardless of CD4 count, other measures of wellness, or treatment protocols. Entopic perimetry, a low-cost psychophysical technique screening test, allows sensitive and specific identification of very peripheral areas of visual field loss. The authors recommend its implementation and use by primary care providers, particularly for early detection of retinal damage when funduscopic examination results may appear normal.

Analysis of visual dysfunctions in HIV-positive patients without retinitis.

PURPOSE: To investigate visual dysfunctions in ophthalmoscopically normal human immunodeficiency virus (HIV)-positive patients and to correlate the results to the stage of HIV disease and neuropsychological status. METHODS: Fifty-one randomly selected eyes (26 right, 25 left) of 51 HIV-positive patients with visual acuity measurements of 20/20 or better and no ophthalmoscopically detectable disorders were prospectively examined using achromatic and short-wavelength automated perimetry, color vision testing, and contrast sensitivity testing. CD4+ T-lymphocyte count, presence of systemic infection, hemoglobin, hematocrit, serum beta 2-microglobulin levels, and results of neuropsychological testing were also analyzed. RESULTS: On achromatic automated perimetry, 21.6% (11/51) of patients performed abnormally according to the mean defect and 27.5% (14/51) according to the Glaucoma Hemifield Test; 29.4% (15/51) performed abnormally on short-wave-length automated perimetry according to the mean defect and 23.5% (12/51) according to the Glaucoma Hemifield Test. On contrast sensitivity, 5.9% (3/51) of patients performed abnormally in the 1.5-cycles per degree (cpd) line, 2.0% (2/51) in the 3-cpd line, 23.5% (12/51) in the 6-cpd line, 25.5% (13/51) in the 12-cpd line, and 33.3% (17/51) in the 18-cpd line. On the Farnsworth-Munsell 100-hue test, 29.4% (15/51) of patients performed abnormally. After correction for multiple correlations, two statistically significant correlations were found: sum of log contrast sensitivity with achromatic automated perimetry and sum of log contrast sensitivity with the Farnsworth-Munsell 100-hue test. CONCLUSIONS: A significant percentage of HIV-positive patients with visual acuity of 20/20 or better and no ophthalmologic evidence of retinitis performed abnormally on visual psychophysical tests. The severity of visual dysfunction was not correlated with the stage of HIV infection or the degree of neuropsychological dysfunction.

Pattern electroretinograms and visual evoked potentials in HIV infection: evidence of asymptomatic retinal and postretinal impairment in the absence of infectious retinopathy.

Retinal microangiopathy associated with HIV infection is usually asymptomatic and escapes detection unless funduscopic examination is performed when evanescent cotton-wool spots are present. The aim of this study was to assess retinal and optic nerve/retrochiasmal function in HIV infection by means of electrophysiologic techniques that are sensitive to the detection of subclinical visual impairment. We studied transient and steady state pattern electroretinograms grams (PERGs) and pattern-reversal visual evoked potentials (PVEPs) in 21 HIV-negative controls and 33 HIV-positive subjects (16 with CD4 > or = 200/mL and 17 with CD4 < 200/mL) without visual symptoms or infectious retinopathy. HIV-positive subjects with CD4 > or = 200/mL had reduced amplitude of the transient PERG P1 potential, but no other latency or amplitude abnormalities. The HIV-positive group with CD4 < 200/mL had reduced P1 transient PERG amplitude, as well as latency delay of the transient PVEP. These findings suggest that HIV infection is associated with subclinical retinopathy and that, when severe immunosuppression occurs, both retinopathy and optic nerve/retrochiasmal dysfunction are present. Transient PERGs are more sensitive measures of visual system disease in HIV infection than are steady state responses.

Visual field loss in HIV-positive patients without infectious retinopathy.

PURPOSE: To determine the extent of vision loss in a cross-sectional study of HIV-positive individuals who had no infectious retinopathy. METHODS: Visual field loss was determined by computerized achromatic automated perimetry and short-wavelength automated perimetry in both eyes in 65 HIV-positive individuals without infectious retinopathy and in one randomly selected eye each in 57 age-matched normal controls. Results were analyzed using the global index of mean defect and the Glaucoma Hemifield Test, and significance was determined through analysis of variance, chi-square, and Tukey-Kramer tests. RESULTS: We found that HIV-positive patients, compared with age-matched HIV-negative controls, demonstrated significant (at least P < .01) localized defects as well as an increased mean defect. The HIV-positive patients also had a significantly greater number of defective points, especially on short-wavelength automated perimetry, even while ophthalmoscopic examination and fundus photographs suggested that the retinas were normal. CONCLUSIONS: There is a significant loss of visual function in HIV-positive individuals that is not the result of infectious retinopathies. The finding by short-wavelength perimetry of more severe defects suggests that the vision defects are not caused by attentional or other suprachiasmatic problems because the neurologic difficulty of both achromatic and short-wavelength perimetry is similar. The effects of this vision loss on the daily living and occupational tasks of this population require further study.

Effectiveness of entoptic perimetry for locating peripheral scotomas caused by cytomegalovirus retinitis.

OBJECTIVE: To determine the the effectiveness of random particle motion, presented on a computer monitor, as a noninvasive test for detecting cytomegalovirus retinitis. DESIGN: A prospective masked study in which patients were asked to trace out any disturbances on a transparency placed over a computer monitor that displayed continuous random particle motion, while the patient fixated on a central spot (entoptic perimetry). SETTING: The Acquired Immunodeficiency Syndrome Ocular Research Unit at the University of California, San Diego, in La Jolla. PATIENTS: Twenty-two men with cytomegalovirus retinitis who were positive for human immunodeficiency virus, 11 men without cytomegalovirus retinitis who were positive for human immunodeficiency virus, and eight men who were negative for human immunodeficiency virus. INTERVENTION: None. MEASUREMENTS: Sensitivities and specificities were used to compare the results of entoptic perimetry with fundus photographs. RESULTS: Entoptic perimetry demonstrated a 95% sensitivity and a 95% specificity in detection of cytomegalovirus retinitis. CONCLUSION: Entoptic perimetry may be an effective and inexpensive screening test for cytomegalovirus retinitis in hospitals and community clinics.

Perception of transparency in stationary and moving images.

If two neutral density (ND) filters overlap partially, the luminance of the overlapping region is given by a multiplicative relationship (e.g., if the filters have 50% transmittance then on a 100 cd m-2 background, the luminance of each filter would be 50 cd m-2 but the luminance of the overlapping region would be 50% of 50 cd m-2, i.e. 25 cd m-2). Does the visual system respect this relationship? Two grey rectangles were overlapped to form a 'cross' and the luminance of the intersection was randomly varied. Naive subjects' ratings of transparency showed a surprising consistency with physics. A similar relationship is seen if two moving square-wave gratings are superimposed. When the intersection luminances were close to the multiplicative (25 cd m-2) case, component motion was seen, and values less than 25 cd m-2 and higher than 50 cd m-2 caused a decline in perceived component motion. Two interpretations are offered. (a) The visual system has access to 'tacit knowledge' of transparency and shadows. (b) If you assume a log signal compression in the retina, then by multiplying the luminances you would null the Fourier energy from the 'blobs' (i.e. regions of overlap between the two gratings). This would prevent 'blob tracking' and lead to the perception of coherent motion. Since most researchers in the field had simply added the gratings linearly they would have inadvertently introduced extra Fourier energy in the blobs and this might account for all previous instances of coherent motion observed in such displays. Whatever the ultimate interpretation, the present results provide the first clear evidence that even the processing of certain primitive visual dimensions--such as motion--can be powerfully constrained by the perception of transparency (Ramachandran V. S. (1990) in: AI and the Eye, Wiley, Chichester; Stoner, G., Albright, T. and Ramachandran, V. S. (1990) Nature 344, 153-155). This is well in line with other recent results demonstrating that transparency can also constrain the processing of stereopsis (Nakayama, K., Shimojo, S. and Ramachandran, V. S. (1991) Perception 19, 497-513) and perceptual grouping (Ramachandran, V. S. (1990) in: AI and the Eye, Wiley, Chichester).

Giant axonal neuropathy: a conditional mutation affecting cytoskeletal organization.

Giant axonal neuropathy (GAN) results from autosomal recessive mutations (gan-) that affect cytoskeletal organization; specifically, intermediate filaments (IFs) are found collapsed into massive bundles in a variety of different cell types. We studied the gan- fibroblast lines WG321 and WG139 derived from different GAN patients. Although previous studies implied that the gan- IF phenotype was constitutive, we find that it is conditional. That is, when cells were grown under the permissive condition of medium containing over 2% fetal calf serum, most cells had normal IF organization. IF bundles formed when gan- cells were transferred to the nonpermissive condition of low (0.1%) serum. Microtubule organization appeared normal in the presence or absence of serum. The effect of serum starvation was largely blocked or reversed by the addition of BSA to the culture media. We found no evidence that the gan- phenotype depends upon progress through the cell cycle. We discuss the possible role of serum effects in the etiology of GAN and speculate as to the molecular nature of the gan- defect.