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Biomedical subjects

W R Freeman

Publications and source records attributed to W R Freeman.

At least 127 records · Page 7Linked to original sources
PubMed1995

AIDS-related optic neuropathy: a histological, virological and ultrastructural study.

BACKGROUND: Clinical and histopathological evidence of optic nerve axonal loss has been reported in AIDS patients without retinitis. The study was carried out to investigate the possible involvement of HIV-infected cells in the development of optic nerve degeneration. METHODS: Optic nerves were obtained from eight AIDS patients and four normal controls. These nerves were morphologically and immunohistochemically analyzed. Additionally, using PCR amplification techniques, the retina and optic nerve samples obtained from three HIV-seropositive patients and one control were examined for the presence of HIV and cytomegalovirus antigens. RESULTS: We noted various stages of axonal degeneration in the optic nerves obtained from AIDS patients in whom there was an absence of retinal findings. Characteristic glial changes involving hypertrophic astrocytes, vacuolated oligodendrocytes, and mononuclear phagocyte series cells were also seen in the AIDS optic nerves. HIV DNA was present in at least four of five optic nerves but in only one of five retinas. Control specimens were each negative for all cytomegalovirus and HIV antigens. CONCLUSIONS: Degeneration in the optic nerve may be mediated by HIV-infected macrophages rather than by direct viral infection of neurons. Axonal degeneration due to AIDS at the level of the optic nerve can occur independently of retinal infection.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Phase I/II study of intravitreal cidofovir for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome.

PURPOSE: In this study we evaluated the safety and efficacy of the nucleoside phosphonate analogue intravitreal cidofovir to treat cytomegalovirus retinitis in humans. METHODS: We conducted a phase I/II unmasked consecutive case series in a single-center institutional referral practice. Eligible patients with the acquired immunodeficiency syndrome had active cytomegalovirus retinitis in at least one eye, despite adequate intravenous therapy with ganciclovir or foscarnet, were intolerant to intravenous therapy, were noncompliant with intravenous therapy, or refused intravenous therapy. In a preliminary safety study (Group 1), ten eyes of nine patients received 14 injections of cidofovir while being treated concurrently with intravenous ganciclovir. In a dose-escalating efficacy study (Group 2), eight eyes of seven patients received 11 injections of cidofovir as sole treatment for cytomegalovirus retinitis. The primary outcome was time to retinitis progression. RESULTS: In the Group 1 eyes receiving 20 micrograms of cidofovir, the median time to retinitis progression was between 49 and 92 days (mean, 78 days). In Group 2 eyes treated with 20 micrograms cidofovir, the median time to retinitis progression was 64 days (mean, 63 days). Hypotony occurred in the two eyes treated with a 100-micrograms dose of cidofovir and in one of three eyes receiving a 40-micrograms dose. No adverse effects resulted from the remaining 20 cidofovir injections. CONCLUSIONS: Cidofovir (also known as HPMPC) appears to be safe and effective for the local treatment of cytomegalovirus retinitis, providing a long duration of antiviral effect. These preliminary results indicate that additional studies should be performed to investigate more fully this promising medication.

AIDS-Related Opportunistic Infections↗
PubMed1995

Confocal scanning infrared laser ophthalmoscopy for indocyanine green angiography.

PURPOSE: We used indocyanine green to study wavelength-optimized confocal scanning infrared laser angiography in patients with retinal and choroidal disease. METHODS: A confocal scanning laser ophthalmoscope with an excitation wavelength of 795 nm was operated both in tight and wide confocal imaging modes. We examined 77 subjects with and without retinal and choroidal disease (including diabetic retinopathy, age-related macular degeneration, and subretinal neovascularization). RESULTS: The scanning laser ophthalmoscope allowed acquisition of images, in the wide confocal imaging mode, of the retinal circulation and late leakage sites without late injections of dye to outline the retinal vasculature. In the tight confocal imaging mode, optical subtraction of the light contribution of the retinal circulation allowed examination of the choroidal circulation, and vice versa. The wide confocal mode appears equivalent to other scanning laser ophthalmoscopes in recording images from retinal and choroidal layers. CONCLUSIONS: There are three differences between the confocal scanning laser ophthalmoscope and conventional instruments. First, the late images allow excellent visualization of the retinal circulation without a landmark injection. Second, confocal imaging allows optical subtraction of retinal circulation when focusing on the choroid and vice versa. Third, the instrument acquires and processes all data digitally, is personal computer-based, is compact, operates with a mouse-driven graphical user interface, and allows easy data exchange with conventional software. With further modifications in software and hardware, this device offers the possibility of producing a three-dimensional map of the retinal and choroidal vasculature.

Adult↗
PubMed1995

Baseline characteristics, natural history, and risk factors to progression in eyes with stage 2 macular holes. Results from a prospective randomized clinical trial. Vitrectomy for Macular Hole Study Group.

PURPOSE: The purpose of this study is (1) to determine baseline characteristics and natural history of immature full-thickness macular holes, (2) to describe progression and resolution, and (3) to present new aspects of pathogenesis of idiopathic macular hole. METHODS: The authors analyzed 41 eyes with stage 2 macular holes (37 patients) in a multicentered prospective randomized trial; 19 eyes were randomized to observation (versus surgery) and had more than 12 months of follow-up, allowing determination of the natural course. Baseline and subsequent examinations included best-refracted visual acuity (Early Treatment of Diabetic Retinopathy Study, potential acuity meter, Pelli-Robson contrast sensitivity, and Bailey-Lovie reading vision), of clinical examinations, photography, and fluorescein angiography. RESULT: Mean Snellen visual acuity was 20/66 at baseline. Centric holes usually had a small break (201 microns average mean diameter) with a dark yellow ring and without significant retinal elevation. Eccentric holes had a high maximum/minimum diameter ratio (mean, 1.88 +/- 0.7) and an incomplete cuff of subretinal fluid or yellow ring. Posterior vitreous detachment prevalence was 32% (8/25) in the centric hole group and 0% (0/ 16) in the eccentric hole group (P < 0.05). For the 19 eyes with 12 months of followup, progression rate to stage 3 (or 4) was 74% (n = 14). The diameter of the stage 2 holes increased significantly between baseline and 12 months (P < 0.001). Progression rate to stage 3 was 100% (8/8) in the eyes with pericentral hyperfluorescence (PCH) and 55% (6/11) in eyes without PCH (P < 0.05). Enlargement occurred in 100% of eccentric holes and 60% of centric holes (P = 0.09). Different progression patterns in eccentric and centric holes suggest different mechanisms of pathogenesis. CONCLUSION: Eccentric and centric stage 2 macular holes may have a different pathogenesis. Most stage 2 macular holes, especially with PCH (P < 0.05) or eccentric holes, progressed to stage 3 or 4. In addition to purely tangential traction, some component of obliquely oriented anteroposterior vitreous traction component may be important for pathogenesis of senile macular holes, particularly eccentric stage 2 macular holes.

Aged↗
PubMed1995

Intravitreal cidofovir (HPMPC) treatment of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome.

PURPOSE: The authors previously conducted a pilot, dose-escalating study which suggested that a 20-micrograms dose of intravitreal cidofovir (HPMPC) may be safe and effective in treating cytomegalovirus (CMV) retinitis in humans. The purpose of this series is to expand the authors' prior experience with the 20-micrograms dose of cidofovir as the sole treatment for CMV retinitis in patients with acquired immune deficiency syndrome. METHODS: The study design was an unmasked consecutive case series trial in a single-center institutional retina referral practice. Eligible patients with acquired immune deficiency syndrome had active CMV retinitis in at least one eye and no evidence of extraocular CMV disease. Patients received a 20-micrograms cidofovir trans pars plana injection and were treated with concomitant oral probenecid. Retreatments were performed for progression of retinitis as determined by serial fundus photographs judged independently by three observers. The primary outcome was time to retinitis progression determined by Kaplan-Meier analysis. Both globes of one patient who had unilateral retinitis were examined pathologically. RESULTS: There were 37 cidofovir injections in 24 eyes of 17 patients. The median time to retinitis progression after the initial 24 injections was 55 days. The median time to retinitis progression after 8 repeat cidofovir injections was 63 days. There was a significant decrease in intraocular pressure from baseline to both 2 and 4 weeks after injection. A mild to moderate iritis developed in five (20.8%) eyes that responded well to topical medications. Results of histopathologic examination of one treated globe did not show any significant toxic effects. CONCLUSIONS: This study demonstrates that prolonged arrest of the progression of CMV retinitis may be obtained with a single 20-micrograms cidofovir intravitreal injection. In addition, the effect of the drug appears to be maintained after a second injection. The effects of cidofovir in causing uveitis and a slight lowering of the intraocular pressure require further study.

AIDS-Related Opportunistic Infections↗
PubMed1995

Results of rhegmatogenous retinal detachment repair in cytomegalovirus retinitis with and without scleral buckling.

PURPOSE: To determine if scleral buckling is of any benefit in surgical repair of cytomegalovirus (CMV)-associated retinal detachment if combined with vitrectomy, silicone oil, and inferior midperipheral endolaser. MATERIALS AND METHODS: Twenty-two consecutive eyes with CMV-associated retinal detachments were repaired with vitrectomy and endolaser to all breaks and to the inferior midperipheral retina using silicone oil without scleral buckling (group 1, control group) between July 1987 and May 1992. Results were compared with another series of 56 consecutive eyes undergoing vitrectomy, silicone oil injection, endolaser to all breaks, and 360 degrees encircling scleral buckling (group 2, study group) between June 1992 and July 1993. RESULTS: Total retinal reattachment rates were 84% for group 1 and 86% for group 2. Rates of macular reattachment were 91% for group 1 and 91% for group 2. Mean best postoperative refracted visual acuity was 20/66 for group 1 and 20/67 for group 2. Median best postoperative refracted visual acuity was 20/74 for group 1 and 20/80 for group 2. These differences in results between the two groups were not statistically significant. Mean postoperative refractive error was +3.95 for group 1 and +4.92 for group 2. Patients who underwent surgery with the macula attached had a better postoperative visual outcome. CONCLUSION: Scleral buckling may not be necessary in CMV-related retinal detachment if repaired with vitrectomy, silicone oil, and inferior midperipheral endolaser. Elimination of scleral buckling may reduce intraoperative time, patient morbidity, and the risk of an accidental needle stick. Patients with macula-on retinal detachments also should be considered for surgery before macular detachment.

AIDS-Related Opportunistic Infections↗
PubMed1995

Intravitreous and plasma concentrations of ganciclovir and foscarnet after intravenous therapy in patients with AIDS and cytomegalovirus retinitis.

This study evaluated intravitreous and plasma ganciclovir and foscarnet concentrations after intravenous administration in AIDS patients with cytomegalovirus (CMV) retinitis and retinal detachment. Undiluted vitreous samples were prospectively obtained from 60 eyes (52 patients) at the time of pars plana vitrectomy. Thirty-three plasma samples (from 27 patients in the initial group of 52) were obtained simultaneously during surgery on 33 eyes. High-pressure liquid chromatography showed the mean vitreous ganciclovir concentrations in patients on induction and maintenance therapy were, respectively, 4.74 +/- 1.49 microM (n = 24) and 3.29 +/- 1.84 microM (n = 30; P = .005). Simultaneous plasma ganciclovir concentrations were less than the vitreous concentrations in 78% of the patients. The mean intravitreous foscarnet concentrations in patients receiving induction dosages were 189 +/- 177 microM (n = 5) versus 163 +/- 167 microM (n = 4; P > .20) for those receiving maintenance therapy. The foscarnet vitreous plasma concentration ratio averaged 1.43. Current drugs and doses for CMV retinitis result in borderline or progressively subtherapeutic concentrations.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Evaluation of retinal toxicity of acetylcholine in rabbit eyes.

PURPOSE: In vitreoretinal surgery, pupillary constriction may be required at the termination of a procedure especially if mechanical pupillary dilation was used in eyes filled with gas or silicone oil. A miotic agent instilled into the anterior chamber will sink and come into direct contact with retina in the aphakic or pseudophakic vitrectomized eye. Therefore, the retinal toxicity of acetylcholine, a miotic used for pupillary constriction, was studied. METHODS: Eight Dutch pigmented rabbit eyes were vitrectomized, had air-fluid exchange, and were injected with a 20% mixture of SF6. Subsequently eyes were randomly selected to have injections of 0.75 ml of 10 mg/ml acetylcholine (Miochol, Iolab Corp., Claremont CA) versus 0.75 ml of lactated Ringer's solution. Short-term (2 weeks) and long-term (6 weeks) retinal toxicity was assessed by ophthalmoscopy, electroretinogram, and histology by light and electron microscopy at both times. RESULTS: Ophthalmoscopy, electroretinographic tracings, histology, and electron microscopy disclosed no significant abnormalities. CONCLUSIONS: Acetylcholine does not appear to have significant retinal toxicity even when undiluted solutions are in direct contact with the retina. We therefore postulate that intraoperative use of acetylcholine in previously vitrectomized eyes filled with gas or silicone is safe.

Acetylcholine↗
PubMed1995

Effect of partial retinal destruction and gliosis on the intravitreal pharmacokinetics of HPMPC.

PURPOSE: Intravitreal HPMPC ([S]-1-[3-hydroxy-2 phosphonylmethoxypropyl cytosine) has a long antiviral effect in patients with cytomegalovirus retinitis. The authors evaluated the pharmacokinetics of intravitreal injections of HPMPC to understand major route of HPMPC elimination in a pigmented rabbit that had undergone scatter laser photocoagulation over half of the retinal surface. METHODS: The authors treated the inferior half of the retina, receiving an average of 605 grade 3 or 4 (gray-white or white) diode laser burns in a scatter fashion in the left eyes of 13 rabbits. After 4 weeks, 13 rabbits received intravitreal injection of HPMPC (100 micrograms in 0.1 mL) in both eyes. Forty-eight hours after injection, unfixed vitreous samples were obtained for high-pressure liquid chromatography analysis. Two rabbits were used for light microscopic examination of diode laser photocoagulated retina with the perfusion fixation. RESULTS: The HPMPC concentration in the vitreous was 5.93 +/- 1.75 micrograms/mL in the laser-treated group and 4.76 +/- 1.2 micrograms/mL in the control group 48 hours after intravitreal HPMPC injection. The difference was statistically different (P = 0.037). CONCLUSIONS: Results showed a higher concentration of intravitreal HPMPC in the eye that had approximately 25% of the retina destroyed by the laser photocoagulation. The higher concentration is likely the result of reduced elimination and a concomitant increase in half-life. This suggests that HPMPC may be eliminated via the retinal route. Eyes with more extensive retinal involvement with human cytomegalovirus may have an even longer duration of action of intravitreal HPMPC. This may lead to modification of dosing regimens.

Animals↗
PubMed1995

Antiviral effect in human cytomegalovirus-infected cells, pharmacokinetics, and intravitreal toxicology in rabbits of acyclovir diphosphate dimyristoylglycerol.

Acyclovir diphosphate dimyristoylglycerol (ACVDP-DG) is a lipid prodrug which is active against ACV-resistant strains of herpes simplex virus because of its intracellular metabolism to ACV monophosphate. In human cytomegalovirus (HCMV)-infected MRC-5 cells, ACVDP-DG was ninefold more active than ACV. When liposomal [8-3H]ACVDP-DG was injected intravitreally at the maximum nontoxic dose of 1 mumol in rabbits, the drug remained above its estimated 90% HCMV-inhibitory concentration for 18 days. Intravitreal ganciclovir persists above its 90% inhibitory concentration for only 1 to 2 days. ACVDP-DG may be useful as a local treatment for HCMV retinitis.

Acyclovir↗
PubMed1995

Mutations in human cytomegalovirus UL97 gene confer clinical resistance to ganciclovir and can be detected directly in patient plasma.

Specific mutations in the UL97 region of human cytomegalovirus (HCMV) have been found to confer resistance to laboratory-adapted strains subjected to ganciclovir selection. In this study, mutations in the UL97 region of HCMV isolates obtained from patients receiving ganciclovir therapy were examined to determine whether they would confer ganciclovir resistance, and if these mutations could be detected directly in the plasma of AIDS patients with progressive HCMV disease despite ganciclovir treatment. A single nucleotide change within a conserved region of UL97 was found in five resistant isolates, resulting in an amino acid substitution in residue 595: from leucine to phenylalanine in one, and from leucine to serine in four resistant isolates. A sixth resistant isolate demonstrated a single nucleotide change, leading to a threonine to isoleucine substitution in residue 659. The role of the 595 amino acid substitution in conferring ganciclovir resistance was confirmed by marker transfer experiments. In further studies, direct sequencing of HCMV DNA present in plasma obtained from persons with resistant viruses revealed the identical amino acid substitutions in plasma as those present in the cultured viruses. These findings indicate that clinical resistance to ganciclovir can result from specific point mutations in the UL97 gene, and that the emergence of the resistant genotype can be detected directly in patient plasma.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Immune predispositions for cytomegalovirus retinitis in AIDS. The HNRC Group.

CMV retinitis develops in approximately 28-35% of all AIDS patients at later stages of disease, often leading to blindness. To determine whether the subset of AIDS patients who developed CMV retinitis (CMV-R) were immunologically predisposed, T cell proliferation responses to CMV were examined prospectively in an HIV infected, HLA typed, longitudinal study population. Individuals who developed CMV-R had significantly lower T cell proliferation responses to CMV, both early and late in disease, compared to CD4 matched controls who have not developed CMV-R. Since HLA proteins influence T-cell recognition, phenotypes of 21 CMV-R patients were examined to determine whether certain HLA alleles were associated with low immune response and predisposed AIDS patients to CMV-R. HLA DR7 and B44 were at increased (nearly twice the expected) frequency in those with CMV-R. The combined association of either B44, 51 or DR7 with CMV-R was highly significant (P = .008, relative risk of CMV-R = 15) with correction for multiple comparisons. Low immune responses were twice as frequent in those with (61%) compared to those without (30%) predisposing alleles. Thus, AIDS patients with immunogenetically related hyporesponsiveness to CMV antigens may be at increased risk of retinitis.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Intraocular tolerance of perfluorooctylbromide (perflubron)

PURPOSE: To determine the intraocular tolerance of perfluorooctylbromide (perflubron) in vitrectomized rabbit and pig eyes and evaluated its use as a vitreous substitute in virteoretinal surgery. METHODS: Pars plana vitrectomy was performed on 33 Dutch pigmented rabbits and 11 micro mini pigs. After vitrectomy the eyes were filled with perflubron for 2 hours, 1 week, 2 weeks, 1 month, and up to 6 months. RESULTS: No clinical, electroretinographic, or light and electron microscopic evidence of adverse effects on the retina and lens were observed. Perflubron emulsified and dispersed into small bubbles after 2-3 weeks. The lens showed mild posterior subcapsular cataracts in pig eyes after long-term retention of perflubron. CONCLUSION: These findings indicate that perflubron is safe for intraoperative and for long-term use intravitreally. However, emulsification and the breakdown into small bubbles limits the view of the retina when perflubron is used as a long-term tamponade.

Animals↗
PubMed1994

Clinical and histopathologic study of varicella zoster virus retinitis in patients with the acquired immunodeficiency syndrome.

Varicella zoster virus retinitis in patients with the acquired immunodeficiency syndrome is known to be a devastating disease. We studied a series of six consecutive patients that sheds new light on the clinical manifestations and treatment options of this disorder. All patients had episodes of cutaneous zoster, long-term exposure to oral acyclovir, and CD4+ T lymphocyte counts less than 50 cells/mm3. Two of the six patients had simultaneous radiographically demonstrable and histologically proven varicella zoster virus encephalitis; this is an important association. Histologic examination of autopsy specimens disclosed that the retinal infection by varicella zoster virus involves the retinal pigment epithelium more heavily than the inner retina, which is consistent with the characteristic clinical impression of an outer retinal necrosis.

AIDS-Related Opportunistic Infections↗
PubMed1994

Macular serous exudation in patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis.

Central visual loss in cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome (AIDS) occurs in two forms: direct macular tissue destruction and secondary involvement as part of rhegmatogenous retinal detachment. We treated 32 patients (35 eyes) with macular exudation that caused reversible visual loss and initially manifested as neurosensory retinal detachment and lipid exudates. Of 35 eyes, 25 showed papillary or peripapillary active retinitis and ten showed retinitis 1,500 to 3,000 microns from the fovea. Of 23 eyes with reduced vision that were followed up until healing of the retinitis and resolution of subretinal fluid and lipid exudates, 22 (96%) showed visual improvement with anti-cytomegalovirus treatment. Our findings suggest that macular exudation is a reversible cause of visual loss in patients with cytomegalovirus retinitis.

AIDS-Related Opportunistic Infections↗
PubMed1994

Axial intensity distribution analysis of the human retina with a confocal scanning laser tomograph.

We have analysed the change of reflected light intensity along the optical axis or axial intensity distribution in images acquired with a confocal scanning laser tomographic system in human fundus examination. We hypothesized that confocal light detection units used in scanning laser tomographs register light originating from multiple layers within the human macula and that intraretinal structures might also be observable. To test this hypothesis we examined the axial intensity distribution in human maculas of normal volunteers, patients with cystic and other macular abnormalities and in an artificial retina in a plastic eye model. A total of over 140 patients and volunteers were examined. We analysed this distribution in 20 normal healthy volunteer eyes found the origin of the artifacts that cause retinal vessels to appear elevated. We examined four patients with cystic maculas and were able to detect the presence of two structures in axial direction contributing to the axial intensity distribution. A plastic eye model with a cellophane sheet covering a fluid pocket was developed to mimic the appearance of a large macular cyst. The axial intensity distribution analysis showed the presence of two distinct gaussian profiles. The results of this study show that confocal scanning laser tomographic imaging of the human fundus allows extraction of information regarding the axial position of intraretinal layers and that correction for the deeper retinal reflections may allow more precision in imaging of the retinal surface.

Adult↗