Daniel J. Plummer

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.

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.

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.

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.

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.

Spectrally opponent inputs to the human luminance pathway: slow +M and −L cone inputs revealed by intense long‐wavelength adaptation

The nature of the inputs to achromatic luminance flicker perception was explored psychophysically by measuring middle‐ (M‐) and long‐wavelength‐sensitive (L‐) cone modulation sensitivities, M‐ and L‐cone phase delays, and spectral sensitivities as a function of temporal frequency. Under intense long‐wavelength adaptation, the existence of multiple luminance inputs was revealed by substantial frequency‐dependent changes in all three types of measure. Fast (f) and slow (s) M‐cone input signals of the same polarity (+sM and +fM) sum at low frequencies, but then destructively interfere near 16 Hz because of the delay between them. In contrast, fast and slow L‐cone input signals of opposite polarity (−sL and +fL) cancel at low frequencies, but then constructively interfere near 16 Hz. Although these slow, spectrally opponent luminance inputs (+sM and −sL) would usually be characterized as chromatic, and the fast, non‐opponent inputs (+fM and +fL) as achromatic, both contribute to flicker photometric nulls without producing visible colour variation. Although its output produces an achromatic percept, the luminance channel has slow, spectrally opponent inputs in addition to the expected non‐opponent ones. Consequently, it is not possible in general to silence this channel with pairs of ‘equiluminant’ alternating stimuli, since stimuli equated for the non‐opponent luminance mechanism (+fM and +fL) may still generate spectrally opponent signals (+sM and +sL).

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 cytomeg‐alovirus (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‐lympho‐cyte 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.

Spectrally opponent inputs to the human luminance pathway : slow +L and -M cone inputs revealed by low to moderate long-wavelength adaptation

The luminance pathway has slow (s), spectrally opponent cone inputs in addition to the expected fast (f), non‐opponent inputs. The nature of these inputs to luminance flicker perception was further explored psychophysically by measuring middle‐ (M‐) and long‐wavelength‐sensitive (L‐) cone modulation sensitivities, M‐ and L‐cone phase delays, and flicker spectral sensitivities under three conditions of low to moderate long‐wavelength adaptation. Under these conditions we find that the luminance channel has fast M‐ and L‐cone input signals (+fM and +fL), and slow, spectrally opponent cone input signals (+sL and −sM). The slow signals found under these conditions are therefore of the opposite polarity to those (+sM and −sL) found under more intense long‐wavelength adaptation. At these less intense levels, fast and slow M‐cone signals of opposite polarity (−sM and +fM) cancel at low frequencies, but then constructively interfere at intermediate frequencies (ca 12.5–22.5 Hz, depending on adapting level) because of the delay between them. In contrast, fast and slow L‐cone signals of the same polarity (+sL and +fL) sum at low frequencies, but then destructively interfere at intermediate frequencies. Importantly, the spectrally opponent signals (+sL and −sM) contribute to flicker nulls without producing visible colour variation. Although its output generates an achromatic percept, the luminance channel has slow spectrally opponent as well as fast non‐opponent inputs.

Long-wavelength adaptation reveals slow, spectrally opponent inputs to the human luminance pathway

In addition to its expected fast, additive L- and M-cone inputs (L + M), the luminance pathway has slow, spectrally opponent inputs. We have previously shown that on long-wavelength fields, the dominant slow signals change from L-M at moderate intensity levels to M-L signals at high. Here, we focus on the transition between them, which we find is marked by substantial changes in temporal phase delay, and by large and unexpected shifts in flicker spectral sensitivity. At moderate temporal frequencies, counter to the selective adaptation caused by the field, spectral sensitivity changes from being M-cone-like to more L-cone-like. These changes can be accounted for by a change in the relative strengths of the slow spectrally opponent cone signals from L-M exceeding M-L below the transition to M-L exceeding L-M above it, and by the resulting changes in constructive and destructive interference between the dominant signal components. We speculate that the transition is caused by the deep-red field becoming equivalent, postreceptorally, to a green field at high bleaching levels. These results further challenge the dogma that there are separable psychophysical channels for the transmission and processing of color and luminance information. Although its output generates an achromatic percept, the luminance channel has spectrally opponent inputs.

Paradoxical activity of CMV retinitis in patients receiving highly active antiretroviral therapy.

Purpose To report two types of atypical behaviors of cytomegalovirus (CMV) retinitis in the highly active antiretroviral therapy (HAART) era, including active CMV retinitis in the presence of persistently high CD4 cell counts during HAART and CMV retinitis that has not reactivated despite persistently low CD4 cell counts. Methods Prospective, longitudinal, observational study of a cohort of 116 patients with acquired immunodeficiency syndrome who had a history of CMV retinitis during the HAART era. Results Sixty (52%) of the 116 patients with acquired immunodeficiency syndrome and CMV retinitis were HAART responders. Subsequently, HAART failed for 9 of the 60 patients with low CD4 cell counts. Of these 9 patients, 5 developed reactivation of CMV retinitis, and 4 remained free of CMV retinitis despite CD4 cell counts of <50/&mgr;L and lack of anti-CMV therapy. Paradoxically, there was a patient with a documented median CD4 cell count of 204/&mgr;L for 19 months who had newly diagnosed active CMV retinitis. Conclusion In the HAART era, CMV retinitis may remain quiescent despite extremely low CD4 cell counts, and rarely, CMV retinitis may become active in the setting of persistently high CD4 cell counts in a subset of HAART responders.