Metastatic malignant melanoma.

Metastatic malignant melanoma is an incurable malignancy with extremely poor prognosis. Patients bearing this diagnosis face a median survival time of approximately 9 months with a probability of surviving 5 years after initial presentation at less than 5%. This is contrasted by the curative nature of surgical resection of early melanoma detected in the skin. To date, no systemic therapy has consistently and predictably impacted the overall survival of patients with metastatic melanoma. However, in recent years, a resurgence of innovative diagnostic and therapeutic developments have broadened our understanding of the natural history of melanoma and identified rational therapeutic targets/strategies that seem poised to significantly change the clinical outcomes in these patients. Herein we review the state-of-the-art in metastatic melanoma diagnostics and therapeutics with particular emphasis on multi-disciplinary clinical management.

Chorioretinitis and vitreitis due to Tropheryma whipplei after transplantation: case report and review.

Whipple's disease is a very rare chronic multisystemic bacterial disease characterized by diarrhea, malabsorption, fever, and polyarthritis. Ocular manifestations occur very rarely. Previous reports have suggested that the use of immunosuppressive drugs appears to accelerate or exacerbate the clinical course of Whipple's disease; however, the illness has yet to be reported in the setting of transplantation. Herein, we describe what we believe is the first reported case of Whipple's disease after transplantation. The patient is a 51-year-old woman who developed progressive visual floaters and blurring of vision 30 years after living-related kidney transplantation for an autosomal-dominant polycystic kidney disease. Her allograft was functioning well on maintenance immunosuppressive therapy with azathioprine and prednisone when she developed visual abnormalities. Transient weight loss, gastrointestinal symptoms, and migratory polyarthralgia predated the onset of ocular disease by several years. The diagnosis of Whipple's bilateral vitreitis and chorioretinitis was confirmed by polymerase chain reaction analysis demonstrating Tropheryma whipplei nucleic acid in vitreous fluid and peripheral blood sample as well as by demonstration of the bacilli by cytopathology. Intraocular vancomycin, intravenous ceftriaxone, and prolonged course of oral trimethoprim-sulfamethoxazole therapy led to clinical improvement and recovery of visual acuity.

Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report.

BACKGROUND: Primary intraocular lymphoma (PIOL) is an uncommon subset of primary central nervous system lymphoma. Because it is rare and difficult to diagnose, the natural history and optimal management are unknown. PATIENTS AND METHODS: A retrospective study of 83 HIV negative, immunocompetent PIOL patients was assembled from 16 centers in seven countries. RESULTS: Median age at diagnosis was 65. Median ECOG performance status was 0. Presenting symptoms included blurred vision, decreased visual acuity, and floaters. Median time to diagnosis was 6 months. Diagnosis was made by vitrectomy (74), choroidal/retinal biopsy (6) and ophthalmic exam (3). Eleven percent had positive CSF cytology. Initial treatment was categorized as focal in 23 (intra-ocular methotrexate, ocular radiotherapy) or extensive in 53 (systemic chemotherapy, whole brain radiotherapy). Six received none; details are unknown in one. Forty-seven relapsed: brain 47%, eyes 30%, brain and eyes 15%, and systemic 8%. Median time to relapse was 19 months. Focal therapy alone did not increase risk of brain relapse. Median progression free (PFS) and overall survival (OS) were 29.6 and 58 months, respectively, and unaffected by treatment type. CONCLUSION: Treatment type did not affect relapse pattern, median PFS or OS. Focal therapy may minimize treatment toxicity without compromising disease control.

Replication of human cytomegalovirus in human retinal glial cells.

PURPOSE: The purpose of these studies was to characterize the replication cycle of human cytomegalovirus (HCMV) in human retinal glial cells in vitro. METHODS: Cultured human retinal glial cells were exposed to HCMV strain AD169 or low-passage clinical isolates for a 2-hour adsorption period and then incubated in the appropriate growth medium at 37 degrees C. Cultures were examined by microscopy for cytopathic effect and by immunofluorescence staining using monoclonal antibodies directed against immediate-early, early, and late HCMV proteins. Viral DNA was analyzed by field inversion gel electrophoresis and detected using Southern blot analysis or the polymerase chain reaction. RESULTS: Immunocytochemical staining revealed that the glial cells expressed all three classes of HCMV proteins and that infectious virus could be transferred from the medium of the infected cultures to susceptible MRC-5 cell monolayers. Less than 1% of the glial cells expressed the S-phase enzyme, thymidine kinase, at the time of infection compared to MRC-5 fibroblasts, of which 81% expressed it. Progeny virus was found to be highly cell associated in glial cells (80%) at peak virus titer compared to MRC-5 cells (39% cell associated at peak titer). Four low-passage clinical isolates of HCMV from patients with acquired immune deficiency virus also productively infected cultures of human retinal glial cells. Field inversion gel electrophoresis of HCMV-infected glial cell lysates was performed to identify the replicative forms of DNA. Southern blots probed with HCMV-specific probes showed that HCMV DNA replication proceeds through high molecular weight intermediates before forming the 230-kb unit length genome. CONCLUSIONS: The full permissive replication of HCMV in human retinal glial cells indicates that glial cells are a likely site of HCMV replication in the retina and thus may play an important role in the pathogenesis of HCMV retinitis.

2 peripheral scatter photocoagulation for neovascularization associated with pars planitis.

BACKGROUND: Peripheral cryotherapy appears to be efficacious in the treatment of neovascularization of the vitreous base in patients with pars planitis, although it may be associated with the development of rhegmatogenous retinal detachments. OBJECTIVE: To evaluate the safety and efficacy of peripheral scatter photocoagulation for treatment of neovascularization of the vitreous base when used alone or combined with pars plana vitrectomy. METHODS: Six patients (10 eyes) presented with vitritis, cystoid macular edema, and neovascularization of the vitreous base, unresponsive to corticosteroid therapy. Three patients (five eyes) received scatter diode or argon photocoagulation treatment alone. The other three patients (five eyes) underwent pars plana vitrectomy coupled with argon or diode photocoagulation, placed in three rows, posterior to the area of inferior neovascularization of the vitreous base. RESULTS: Pretreatment visual acuity ranged from 20/20 to 20/200. All patients were followed up for a minimum of 6 months. After placement of photocoagulation (with or without concurrent pars plana vitrectomy), the neovascularization regressed, inflammation was stabilized, and cystoid macular edema improved in all eyes. There were no retinal detachments or other complications of treatment. Posttreatment visual acuity ranged from 20/20 to 20/100. When final visual acuity was 20/40 or less, cataract formation was generally responsible. CONCLUSIONS: Peripheral scatter photocoagulation is efficacious and appears at least equal to peripheral cryotherapy in causing regression of neovascularization of the vitreous base in patients with pars planitis.

Barbiturates protect retinal cells from hypoxia in cell culture.

A culture system was used to screen for drugs that can protect mammalian retinal cells from damage induced by hypoxia. Using a special incubator, cultures could be made hypoxic for defined periods. Phase contrast photomicroscopy facilitated comparison of retinal cells before hypoxia and 1 to 2 days after hypoxia. Using 2- to 3-week-old cultures, certain glutamate antagonists, anesthetics, calcium blockers, and thiopental sodium were screened for their effect in protecting cells from hypoxia. The most remarkable effect was noted with thiopental. Quantitative measurements showed a significant increase in the percent of cells surviving after exposure to hypoxia in the presence of 100 mumol/L of thiopental sodium compared with control hypoxic cultures--82% vs 59% at 48 hours. A dose-response curve demonstrated maximal effect at 50 mumol/L of thiopental sodium, with toxic effects noted at 200 mumol/L of thiopental sodium. Our results show that thiopental reduces hypoxia-induced damage to retinal cells in culture.

Pars plana vitrectomy in the management of complications of proliferative sickle retinopathy.

Ten patients (11 eyes) with sickle-C hemoglobinopathy with complications of proliferative sickle retinopathy were treated using pars plana vitrectomy with or without the use of a scleral buckle. Postoperative visual acuity was improved in ten of 11 cases. Three cases of retinal detachment were managed by internal vitreoretinal techniques alone without the use of a scleral buckle. Although exchange transfusions were used in only five of the 11 cases, no cases of recognized anterior segment ischemia occurred during the postoperative course of these patients. Because of exchange transfusion risks and awareness of intraoperative and postoperative measures to reduce this complication, the use of exchange transfusions probably should be discontinued as prophylaxis for vitreoretinal surgery in these patients.

Tissue effects of subclinical diode laser treatment of the retina.

OBJECTIVE: To determine whether consistent tissue effects are obtained when laser lesions are produced with a commercially available diode laser that are near the limit of clinical detection at the time of treatment. METHODS: Continuous-wave or micropulse diode laser was used to produce clinically undetectable (subthreshold) or barely detectable (threshold) retinal lesions in pigmented rabbits. Tissue effects at intervals after treatment were determined in retinal pigment epithelial (RPE) whole mounts by fluorescence microscopy, and in sections of retina and RPE by light and electron microscopy. RESULTS: Continuous-wave and micropulse laser lesions that were originally clinically undetectable were detectable as zones of pigment mottling after 5 days. By microscopy, compaction and/or swelling was seen in the outer retina, and cells in the RPE monolayer became heterogeneous in size, shape, and pigmentation, but the tissue responses in the outer retina and RPE were variable even within and among lesions in the same eye. CONCLUSIONS: Subthreshold energies used to create both continuous-wave and micropulse laser lesions produced variable effects on the RPE and the overlying neurosensory retina. It appears that, near the minimum effective dose of laser irradiation, individual RPE cell heterogeneity becomes detectable as variability in sensitivity to laser injury. CLINICAL RELEVANCE: As laser energy is reduced to limit collateral tissue damage in clinical applications, it may be difficult to generate reproducible lesions because of heterogeneity among individual cells.

Maintenance of replicative intermediates in ganciclovir-treated human cytomegalovirus-infected retinal glia.

OBJECTIVES: To characterize the molecular structure of the human cytomegalovirus (HCMV) DNA maintained in cultures of human retinal glia following ganciclovir treatment and to determine the biological activity of the DNA. METHODS: Cultures of human retinal glia were established, infected with HCMV, treated with ganciclovir, and embedded in agarose, and the viral DNA was analyzed by field inversion gel electrophoresis. RESULTS: The HCMV DNA was found to persist in cultures of infected, ganciclovir-treated retinal glial cells in the form of replicative intermediates. After removal of ganciclovir, processed forms of DNA in the 500-to 1000-kilobase range were found as well as 230-kb unit length genome. Infectious virus was recovered after termination of ganciclovir treatment. CONCLUSION: The data are consistent with the concept that ganciclovir's virostatic nature permits maintenance of HCMV DNA in retinal glia in a biologically active form that is capable of replication after removal of the drug.

Ocular manifestations of patients with circulating antineutrophil cytoplasmic antibodies.

Antineutrophil cytoplasmic antibodies are seen in patients with systemic vasculitides, especially Wegener's granulomatosis. Antineutrophil cytoplasmic antibodies are helpful laboratory markers for these disease. We report on the ocular findings of six patients with systemic vasculitis who had antineutrophil cytoplasmic antibodies. Four patients had systemic Wegener's granulomatosis, one had microscopic polyarteritis, and in one a specific histopathologic diagnosis could not be made. Two patients were first evaluated for systemic vasculitis because of their ocular manifestations. Ocular findings included ptosis, bilateral lacrimal gland masses, proptosis, choroidal folds, episcleritis, phlebitis, retinal and vitreous hemorrhage, keratitis sicca, and bilateral central scotomas. It was difficult to make a systemic diagnosis in all cases. If systemic vasculitis is in the differential diagnosis of a patient with suggestive ocular findings, antineutrophil cytoplasmic antibody testing should be considered. A prospective study of antineutrophil cytoplasmic antibody testing should be considered in patients with ocular findings that suggest the possibility of vasculitis.

Retinal complications after aqueous shunt surgical procedures for glaucoma.

OBJECTIVES: To assess retinal complications and to identify risk factors for retinal complications following aqueous shunt procedures. MATERIALS AND METHODS: Records of 38 consecutive aqueous shunt procedures that were performed on 36 patients at the Eye Institute of the Medical College of Wisconsin, Milwaukee, from June 1993 to March 1995 (minimum follow-up, 6 months) were reviewed. The mean +/- SD follow-up was 11.4 +/- 5.2 months (median, 10.5 months). RESULTS: Twelve patients (32%) had the following retinal complications: 4 serous choroidal effusions (10%) that required drainage, 3 suprachoroidal hemorrhages (8%), 2 vitreous hemorrhages (5%), 1 rhegmatogenous retinal detachment (3%), 1 endophthalmitis (3%), and 1 scleral buckling extrusion (3%). Surgical procedures for retinal complications were required in 8 (67%) of these 12 patients. Visual acuity decreased 2 lines or more in 9 (75%) of these 12 patients. The median onset of a postoperative retinal complication was 12.5 days, with 10 patients (83%) experiencing complications within 35 days. Serous choroidal effusions developed in 10 other patients (26%), and these effusions resolved spontaneously. Visual acuity decreased 2 lines or more in 2 (20%) of these additional 10 patients. Patients who experienced serious retinal complications were significantly older, had a higher rate of hypertension, and postoperative ocular hypotony. Serious retinal complications were distributed evenly among patients with Krupin valves with discs and Molteno and Baerveldt devices. Experience with the Ahmed glaucoma valve implant was limited. CONCLUSION: Aqueous shunt procedures may be associated with significant retinal complications and subsequent visual loss.

Visual outcomes following lensectomy and vitrectomy for combined anterior and posterior persistent hyperplastic primary vitreous.

OBJECTIVE: To determine the visual outcome after surgery for persistent hyperplastic primary vitreous using modern vitreoretinal techniques. DESIGN: Retrospective medical record review during a 5-year period (June 1992 to June 1997). Information recorded for each patient included age, medical history, sex, results of preoperative ocular examination, age at diagnosis, procedure performed, intraoperative and postoperative complications, location and number of sclerotomy sites, type of aphakic rehabilitation, amblyopic therapy given, final visual acuity, and length of follow-up. RESULTS: Fourteen patients who underwent surgical management of combined anterior and posterior persistent hyperplastic primary vitreous were identified. Eleven patients underwent aphakic rehabilitation and aggressive amblyopic therapy consisting of occlusive therapy for several waking hours each day. One additional older patient received aphakic rehabilitation only. Ten eyes (71%) achieved a visual acuity of 20/300 or better, and 8 (57%) obtained a final visual acuity of 20/100 or better. Average length of follow-up was 22 months (range, 4-57 months). Nine patients were fitted with an aphakic soft contact lens, 2 older patients had a posterior chamber intraocular lens placed at the time of vitrectomy, and 1 patient wore aphakic spectacles. CONCLUSIONS: With modern vitreoretinal techniques, aphakic rehabilitation, and aggressive amblyopic therapy, useful vision can be obtained in the majority of patients with combined anterior and posterior persistent hyperplastic primary vitreous.

Long-term follow-up of iatrogenic phototoxicity.

OBJECTIVE: To evaluate the outcomes of a group of patients who suffered iatrogenic phototoxic injury. METHODS: The medical records of 24 patients (24 eyes) with iatrogenic phototoxicity from 3 medical centers were reviewed. We report the findings from long-term follow-up of these patients with particular attention to visual outcome, type and duration of procedure, and location of the phototoxic lesion. RESULTS: Phototoxic injury occurred after anterior segment surgery in 20 eyes and after vitrectomy in 4 eyes. The mean duration of surgery was 109 minutes; there was no statistically significant difference in duration between the anterior segment procedures and the vitrectomies. Mean final visual acuity was 20/40 for all cases (range, 20/15 to counting fingers) and 20/25 for all anterior segment cases. In vitrectomized eyes, the mean final visual acuity was 20/900. Phototoxic lesions tended to spare the fovea after anterior segment surgery and involve the foveal center after vitrectomy. CONCLUSIONS: In general, patients who suffer phototoxicity do well, and the prognosis is good for extrafoveal lesions. Foveal injury, which often occurs with vitrectomy, usually leads to a worse visual outcome. The development of choroidal neovascularization may have an effect on the ultimate visual outcome as well.

Differentiation of human neural stem cells into retinal cells.

We have previously reported that transplanted human neural stem cells (HNSCs) display extensive migration and positional incorporation into the aged rat brain, which is associated with an improvement in cognitive function. In the current study, to investigate whether HNSCs are capable of differentiating into retinal cells, we treated HNSCs with human transforming growth factor-beta3 (TGF-beta3) under a serum-free differentiation condition. After 5 days of differentiation in vitro we detected opsin-immunopositive cells in the culture treated with TGF-beta3. We also transplanted TGF-beta3-treated HNSCs into the rat vitreous cavity. The donor cells migrated and differentiated into opsin-positive cells in the host retinal cell layer. Here we show for the first time that TGF-beta3-treated HNSCs differentiate into retinal cells.

Insulin in the vitreous of the normal and streptozotocin-induced diabetic rat.

Insulin has been detected by ELISA in the vitreous of the normal and streptozotocin-diabetic rat at levels for both about 1% of those in serum. 131I-labeled insulin, administered to conscious rats via an indwelling cannula in the right atrium, was found to cross the blood-ocular barrier into the vitreous. Autoradiographic gel analysis showed the peptide was transferred as an intact molecule. Vitreous insulin levels reflected serum levels as seen in relatively constant vitreous-to-serum insulin ratios over a wide range of serum insulin concentrations. The rate of blood-to-vitreous passage of insulin was about the same in normal as in diabetic rats (fasting serum glucose greater than or equal to 21 mM). At least a portion of vitreous insulin is therefore of pancreatic origin, and retinal tissue in the normal and diabetic animal is thus accessible to circulating hormone. The blood-ocular barrier is unaltered in streptozotocin diabetes with regard to insulin passage.

Vitrectomy for proliferative diabetic retinopathy with severe equatorial fibrovascular proliferation.

PURPOSE: We studied the surgical treatment and visual outcome in a consecutive series of eyes with an unusual syndrome of diabetic retinopathy and severe peripheral fibrovascular proliferation involving the equatorial and pre-equatorial fundus. METHODS: In a retrospective study of 276 eyes (245 patients) that underwent pars plana vitrectomy for diabetic retinopathy between November 1988 and February 1993, nine eyes of eight patients (3.3% of eyes and 3.3% of patients) had severe equatorial fibrovascular proliferation. The condition occurred primarily in previously unoperated-on eyes (except for panretinal photocoagulation) and resulted in peripheral traction or traction-rhegmatogenous retinal detachment (six eyes), severe vitreous hemorrhage (two eyes), and severe hypotony (one eye). Relief of traction from peripheral fibrovascular membranes was obtained with an encircling scleral buckle (nine eyes) and limited delamination and segmentation (five eyes) or relaxing retinectomy (two eyes). Lensectomy was required for adequate membrane dissection in three eyes. RESULTS: After follow-up of six to 52 months (mean, 20.4 months), the visual acuity was 20/200 or better in seven of nine eyes, with complete retinal attachment in seven of nine eyes and postequatorial attachment in all eyes (100%). Poor outcome resulted from a persistent response resembling Coats' disease in one eye and preexistent long-standing retinal detachment in one eye. CONCLUSIONS: Vitrectomy for severe equatorial fibrovascular proliferation differs from conventional approaches to diabetic retinopathy in that relief of retinal traction must be attained by scleral buckling and adequate dissection of peripheral fibrovascular tissue. In advanced cases, lensectomy and relaxing retinotomy may be required.

The association of HLA-DR15 and intermediate uveitis.

PURPOSE: To evaluate the association between human leukocyte antigen (HLA-DR15) specificity and intermediate uveitis. METHODS: Eighteen patients diagnosed with intermediate uveitis underwent HLA-DR15 serotyping. Additionally, DNA-based phenotyping for a specific HLA-DR15 allele was performed in four patients. The clinical features of HLA-DR15-positive intermediate uveitis were compared with those of HLA-DR15-negative intermediate uveitis. RESULTS: Thirteen of 18 patients (72%) were positive for HLA-DR15. The frequency of the HLA-DR15 specificity in intermediate uveitis patients was significantly higher than in the control subjects (relative risk, 6.36; P < .001). Each of four patients tested carried the specific allele, DR beta 1*1501, which has been associated with multiple sclerosis. In the HLA-DR15-positive group were four patients (31%) with coexisting multiple sclerosis or optic neuritis, one patient with coexisting narcolepsy, and three patients (23%) with a family history of multiple sclerosis. Retinal periphlebitis, especially if bilateral, was a frequent ophthalmoscopic finding in HLA-DR15-positive intermediate uveitis. CONCLUSIONS: This study identifies a significant association between intermediate uveitis and the HLA-DR15 specificity. Patients who are HLA-DR15-positive and have intermediate uveitis may have systemic findings of another HLA-DR15-related disorder. Intermediate uveitis may belong to a constellation of HLA-DR15-related disorders, which includes multiple sclerosis, optic neuritis, and narcolepsy.

Improvement in visual acuity in chronic aphakic and pseudophakic cystoid macular edema after treatment with topical 0.5% ketorolac tromethamine.

Ketorolac tromethamine 0.5% ophthalmic solution treatment was compared to placebo treatment in 120 patients with chronic aphakic or pseudophakic cystoid macular edema (six-month or more duration of distance visual acuity of 20/40 or less and angiographic evidence of cystoid changes) during a four- to five-month double-masked, multicenter study in which patients were randomly assigned. A statistically significant improvement in distance visual acuity (two lines or more) was observed in the ketorolac-treated group as compared to the placebo-treated group after 30 days (P = .038), 60 days (P = .017), and 90 days (P = .008) of treatment. This improvement in visual acuity remained statistically significant one month after cessation of treatment (P = .001). Nine ketorolac-treated patients and two placebo-treated patients demonstrated a decrease in visual acuity one month after treatment was discontinued. Seven of the nine ketorolac-treated patients experienced an improvement in visual acuity after retreatment as compared to none of the placebo-treated patients. This study offers evidence for a more optimistic outlook in the medical treatment of chronic aphakic and pseudophakic cystoid macular edema.

Protein levels in the vitreous of rats with streptozotocin-induced diabetes mellitus.

The vitreous is a neural extracellular space separated from the blood-vascular compartment by the blood-retinal barrier. Study of the appearance of serum proteins in this space have been carried out in rats with streptozotocin-induced diabetes mellitus, a condition associated with barrier dysfunction. A vitreous sampling technique that avoids contamination with surrounding tissue was employed. In rats 1 month after administration of streptozotocin (fasting serum glucose > or = 375 mg/dl), significant increases in vitreous protein were observed in the absence of discernible eye pathology. Two-dimensional isoelectric focusing and SDS-polyacrylamide gel analysis of the soluble fraction demonstrated 85 polypeptides, 28 of whose electrophoretic positions coincided with positions of serum polypeptides. The remainder were unrelated to serum polypeptide loci. Overall patterns of soluble protein from the vitreous of streptozotocin-injected and normoglycemic-uninjected control animals were virtually identical. Results support a system for selective transfer for certain proteins into the extraneural vitreous space as suggested by Chen and Chen (6).