Delay in treating age-related macular degeneration in Spain is associated with progressive vision loss.

PURPOSE: To assess the impact on visual acuity of delays between diagnosis and treatment in patients with subfoveal neovascular age-related macular degeneration (NV-AMD) and to evaluate NV-AMD patients' emotional status before therapy initiation. METHODS: This retrospective, multicenter, epidemiological study included newly diagnosed NV-AMD patients registered in the Spanish national health system and referred to regional health centers for evaluation/treatment by a retinal specialist from 09/2005 to 03/2006. Records were reviewed and data abstracted at referring physicians' offices (diagnosis visit) and regional health centers (treatment visit). Treatment was at physicians' discretion. The Hospital Anxiety and Depression Scale was administered at the treatment visit (before therapy). RESULTS: Median time from the diagnosis to treatment visit was 2.3 months (95% confidence interval: 0.2-10.8 months). Vision loss had progressed at the treatment visit with a doubling in the percentage of patients with a visual acuity of 20/400 or worse (from 12.4 to 24.7%). The decrease in visual acuity from the diagnosis to the treatment visit was highly statistically significant (P<0.0001) as was the correlation between months to treatment and visual acuity change (r=0.5234, P<0.0001). Time from the diagnosis to the treatment visit remained a significant predictor of progressive vision loss when visual acuity at diagnosis and change in lesion size between diagnosis and treatment were controlled (P<0.0001). Patients with more severe vision loss prior to treatment tended to report more depression. CONCLUSIONS: Delayed treatment of patients newly diagnosed with NV-AMD is associated with substantial visual acuity loss.

Pegaptanib sodium for neovascular age-related macular degeneration: third-year safety results of the VEGF Inhibition Study in Ocular Neovascularisation (VISION) trial.

AIMS: To evaluate the safety of up to 3 years of pegaptanib sodium therapy in the treatment of neovascular age-related macular degeneration (NV-AMD). METHODS: Two concurrent, prospective, multicentre, double-masked studies randomised subjects with all angiographic lesion compositions of NV-AMD to receive intravitreous pegaptanib sodium (0.3, 1 and 3 mg) or sham injections every 6 weeks for 54 weeks. Those initially assigned to pegaptanib were rerandomised to continue or discontinue therapy for 48 more weeks; sham-treated subjects continued sham, discontinued or received pegaptanib. At 102 weeks, subjects receiving pegaptanib 0.3 mg or 1 mg in years 1 or 2 continued; those receiving pegaptanib 3 mg or who did not receive treatment in years 1 and 2 were rerandomised to 0.3 mg or 1 mg for year 3. RESULTS: As in years 1 and 2, pegaptanib was well tolerated in year 3. Adverse events were mainly ocular in nature, mild, transient and injection-related. Serious adverse events were rare. No evidence of systemic safety signals attributed to vascular endothelial growth factor inhibition arose in year 3. There were no findings in relation to vital signs or electrocardiogram results suggesting a relationship to pegaptanib treatment. CONCLUSION: The 3-year safety profile of pegaptanib sodium was favourable in patients with NV-AMD.

[Humanistic burden and health resource utilization among neovascular age-related macular degeneration patients in France]. / Impact de la dégénérescence maculaire néovasculaire: données françaises.

OBJECTIVE: To assess the impact of bilateral neovascular age-related macula degeneration (NV-AMD) on function and health resource utilization (HRU) in France. PATIENTS AND METHODS: Cross-sectional study including 401 NV-AMD patients and 471 controls conducted in five countries in 2006. In both groups, demographic and clinical data were collected and the National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), the EuroQoL (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), and questionnaires on HRU were administered. RESULTS: Eighty-seven NV-AMD patients and 92 controls were recruited in France. The mean age of the NV-AMD patients was 79 (range, 65-95), and 64% were female. After adjusting for age, gender, and co-morbidities, compared to controls, NV-AMD patients reported substantially worse vision-related quality of life on the NEI-VFQ (adjusted mean, 44.4 [36.2-52.7] versus 91.8 [86.2-97.5], p<0.0001). HADS anxiety and depression scores were significantly worse in NV-AMD patients (anxiety score, 8.5 [6.3-10.8] versus 5.1 [3.5-6.7] p=0.0005; depression score: 7.1 [5.1-9.1] versus 2.9 [1.5-4.4] p<0.0001). Per patient yearly cost analysis showed significantly higher direct medical costs: 3396 euro versus 85 euro (p<0.0001), and indirect nonmedical-related costs (mainly for assistance with activities of daily living): 2985 euro versus 494 euro (p=0.014). CONCLUSIONS: NV-AMD patients in France reported substantially worse QoL and more anxiety and depression symptoms. The functional impact of blindness led to significantly higher health resource utilization in the AMD patients, resulting in higher total health costs compared to a similarly aged control group.

Alpha tropomyosin as a self-antigen in patients with Behçet's disease.

We report for the first time a significant increased lymphoproliferative response to alpha tropomyosin as well as observing autoantibodies to tropomyosin observed in Behcet's disease (BD) patients with posterior uveitis. Peripheral blood mononuclear cells (PBMCs) from 18 BD patients with posterior uveitis, 18 patients with other forms of noninfectious uveitis, 9 patients with retinal damage due to photocoagulation as well as 18 healthy donors were evaluated for antigen-specific lymphoproliferative responses to alpha tropomyosin and its derivative peptides. The proliferative responses of PBMCs to these antigens were studied using (3)H thymidine incorporation assay. Serum samples were also screened by ELISA for autoantibodies against tropomyosin. Six of the 18 (33%) BD patients with posterior uveitis showed increased proliferative response to alpha tropomyosin or its derivative peptides, while none of the healthy, disease controls were positive. The mean lymphoproliferative responses to tropomyosin were significantly higher (P < 0.02) in the BD patients compared to healthy or disease controls. Higher titres of anti-tropomyosin antibodies were also seen in four of the 18 BD patients but none in the healthy or disease control groups (P < 0.002). The occurrence of these abnormalities supports a possible role for alpha tropomyosin as a self-antigen in a subset of patients with Behcet's disease.

A correlation of pregnancy term, disease activity, serum female hormones, and cytokines in uveitis.

BACKGROUND/AIMS: Pregnancy and the postpartum period are associated with the activity of autoimmune diseases including uveitis. Although the exact mechanism is unknown, hormones are reported to alter inflammatory cytokines and influence disease activity. The authors studied ocular inflammation, female hormones, and serum cytokine levels during and after pregnancy. METHODS: A prospective, observational case study was conducted. Four pregnant women in their first trimester with chronic non-infectious uveitis were followed monthly until 6 months after delivery. Serum female hormones (oestrogen, progesterone, prolactin) and various cytokines (IL-2, IL-4, IL-5, IL-6, IL-10, IFN-gamma, and TGF-beta) were measured by ELISA. RESULTS: The four patients had five full term pregnancies. Uveitis activity decreased after the first trimester but flared in the early postpartum period. Serum female hormones, highly elevated during pregnancy, drastically dropped post partum. Cytokine levels except TGF-beta were mostly undetectable. CONCLUSION: Female hormones and TGF-beta may contribute to the activity of uveitis during pregnancy and the postpartum period.

Detection of Toxoplasma gondii DNA in primary intraocular B-cell lymphoma.

Primary intraocular lymphoma, a variant of primary central nervous system lymphoma with ocular involvement, is a large B-cell non-Hodgkin's lymphoma. Some cases of primary intraocular lymphoma have been reported to be associated with microorganisms including Epstein-Barr virus (EBV) and human herpes virus-8 (HHV-8), but not parasites. We analyzed 10 cases of primary intraocular lymphoma using microdissection and PCR. Tumor and normal cells were microdissected from ocular tissue on slides and subjected to PCR for genes from Toxoplasma gondii, EBV, and HHV-8. We detected Toxoplasma gondii, not HHV-8 or EBV, DNA in the lymphoma but not in normal cells of two cases that resembled ocular toxoplasmosis clinically. We speculate that Toxoplasma gondii may play a role in some forms of primary intraocular B-cell lymphoma.

Involvement of apoptosis and interferon-gamma in murine toxoplasmosis.

PURPOSE: A murine toxoplasmosis model has been developed that results in central nervous system (CNS) and ocular inflammation characterized by encephalitis with numerous brain tissue cysts and milder inflammation with rare tissue cysts in the eye after 4 weeks of Toxoplasma gondii infection. In this model IFN gamma and inducible nitric oxide (iNO) are protective against T. gondii infection. In this study, the role of apoptosis in the pathogenesis of toxoplasmosis was investigated. METHODS: C57BL/6 (wild-type mice), B6MRL/lpr, and B6MRL/gld (defective Fas or FasL expression, respectively) mice were infected intraperitoneally with 20 to 30 tissue cysts of the ME-49 strain of T. gondii. Mice were killed at days 0, 14, or 28 after infection. The eyes and brains were harvested for histologic, immunohistochemical, and molecular studies. Analysis included immunostaining for Fas, FasL, Bcl-2, and Bax; in situ apoptosis detection (TUNEL assay); RT-PCR amplification for IFN gamma; and measurement of ocular nitrite levels. The control mice were naïve mice of each strain that received no inoculation or injection. RESULTS: Wild-type mice appeared to constitutively express apoptotic molecules at higher levels in the eye than in the brain. Consequently, during T. gondii infection, apoptosis was greater in the eyes than in the brain. Untreated naïve lpr and gld mice showed no expression of Fas and FasL, respectively. After infection, a slightly higher number of tissue cysts (lpr, 11.8 +/- 2.4; gld, 10.3 +/- 3.4) were found in the brains of the mutants than in the control animals (8.8 +/- 2.9). However, no significant differences between the number of apoptotic cells, inflammatory scores, or number of tissue cysts were noted in the eyes. IFN gamma mRNA in control mice was detected at day 28 after infection, whereas in both mutants, mRNA production occurred earlier, at day 14. Ocular nitrite levels were higher in lpr and gld mice than in wild-type mice. CONCLUSIONS: No significant difference in the degree of ocular inflammation and apoptosis was detected between the wild-type and Fas or FasL mutant mice. However, there was an earlier and subjectively greater expression of IFN gamma in the brain and eye and a higher level of nitrite in the ocular tissue of mutant strains than in the wild type. Multiple factors are likely to be involved in the pathogenesis of ocular toxoplasmosis.

Ocular manifestations of central nervous system lymphoma.

Primary intraocular lymphoma (PIOL) is a variant of primary central nervous system lymphoma in which lymphoma cells are initially present only in the eyes without evidence of disease in the brain or cerebrospinal fluid. Patients with PIOL are typically older adults who present with blurred vision and floaters. The ophthalmic examination characteristically shows a cellular infiltrate in the vitreous with or without the presence of subretinal infiltrates. Diagnostic evaluation for PIOL includes neuroimaging, cytologic examination of the cerebrospinal fluid, and a diagnostic vitrectomy with special handling of the vitreous specimen, if the former is nondiagnostic. Molecular and cytokine analyses are useful adjuncts to cytology for the diagnosis of PIOL. Recent molecular studies demonstrating viral DNA in the ocular lymphoma cells suggest a role for infectious agents in the pathogenesis of PIOL. To date, the best mode for treatment of PIOL or recurrent primary central nervous system lymphoma involving only the eyes remains undefined.

New corneal findings in human T-cell lymphotrophic virus type 1 infection.

PURPOSE: Human T-cell lymphotrophic virus type 1 is a RNA retrovirus that primarily affects CD4+ T-cells. Human T-cell lymphotrophic virus type 1 infection is the established cause of adult T-cell leukemia/lymphoma, an aggressive malignancy of CD4+ T-cells, and two nonneoplastic conditions: human T-cell lymphotrophic virus type 1-associated myelopathy/tropical spastic paraparesis and human T-cell lymphotrophic virus type 1 uveitis. Other reported ophthalmic manifestations of human T-cell lymphotrophic virus type 1 infection include lymphomatous and leukemic infiltrates in the eye and ocular adnexa in patients with adult T-cell leukemia/lymphoma, retinal pigmentary degeneration, and neuro-ophthalmic disorders in patients with human T-cell lymphotrophic virus type 1-associated myelopathy/tropical spastic paraparesis and keratoconjunctivitis sicca, episcleritis, and sclerouveitis in asymptomatic human T-cell lymphotrophic virus type 1 carriers. This report describes the ocular findings in three Jamaican patients with human T-cell lymphotrophic virus type 1 infection and adult T-cell leukemia/lymphoma. METHODS: The clinical records of three patients with human T-cell lymphotrophic virus type 1 infection and adult T-cell leukemia/lymphoma examined at the National Eye Institute were reviewed. Each patient had one or more complete ophthalmic evaluations. RESULTS: All three patients had corneal abnormalities, including corneal haze and central opacities with thinning; bilateral immunoprotein keratopathy; and peripheral corneal thinning, scarring, and neovascularization. All three patients had elevated serum immunoglobulin levels. CONCLUSIONS: We believe that the novel corneal findings in these patients are most likely a consequence of the hypergammaglobulinemia induced by the human T-cell lymphotrophic virus type 1 infection or the T-cell malignancy.

Conjunctival T-cell lymphoma caused by human T-cell lymphotrophic virus infection.

PURPOSE: To examine the cause of adult T-cell leukemia/lymphoma. METHODS: We examined a conjunctival biopsy from a 29-year-old Jamaican man who developed bilateral conjunctival masses. Adult T-cell leukemia/lymphoma was diagnosed using routine histology, immunohistochemistry, electron microscopy, microdissection, and the polymerase chain reaction. RESULTS: Histopathologic examination revealed a conjunctival lymphoma. Clonality of the T-cell receptor gamma gene and human T-cell lymphotrophic virus gag gene were detected in the malignant cells. The demonstration of the human T-cell lymphotrophic virus gene and the rearrangement of the T-cell receptor gene in this neoplasm provide proof that human T-cell lymphotrophic virus is the cause of this conjunctival T-cell lymphoma. CONCLUSION: Human T-cell lymphotrophic virus is the cause of adult T-cell leukemia/lymphoma, an aggressive malignancy of CD4+ lymphocytes.

Apoptosis in cytomegalovirus retinitis associated with AIDS.

PURPOSE: To determine the role of apoptosis in the pathogenesis of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. METHODS: Forty-three eyes from patients with cytomegalovirus retinitis treated before the introduction of highly active anti-retroviral therapy were examined by routine histopathology and in situ techniques to detect apoptosis (TUNEL assay). Apoptosis was graded on a scale from 0 to 3+ by quantitating the number of TUNEL positive cells per case using a standard grading procedure. Statistical analysis describing the association between apoptosis grade and the proportions of eyes with active CMV infection, with choroidal inflammation and treated with the sustained-release intravitreal ganciclovir implant was performed using the Armitage procedure. RESULTS: Apoptosis in both CMV infected and uninfected retinal cells was detected in 28 of 41 eyes (68%); 13 (45%) with active and 15 (55%) with inactive cytomegalovirus retinitis. The degree of apoptosis was mild (1+) in 14 eyes, moderate (2+) in 6 eyes and severe (3+) in 8 eyes. Apoptosis was not identified in two eyes without CMVR. An increase in apoptosis grade was positively associated with active CMVR (p = 0.014). There was no significant association between apoptosis and choroidal inflammation. The presence and the severity of apoptosis was less in eyes treated with the sustained-release intravitreal ganciclovir implant compared to those treated with systemic anti-viral therapy, however, the difference was not statistically significant. CONCLUSIONS: Apoptosis contributes to retinal cell loss in eyes with cytomegalovirus retinitis associated with AIDS but did not correlate with the progressive loss of retinal cell function in patients with treated, inactive CMVR.

Biphasic ocular inflammatory response to endotoxin-induced uveitis in the mouse.

OBJECTIVE: To examine the kinetics and mechanisms of endotoxin-induced uveitis in the mouse. METHODS: C3H/HeN mice were injected subcutaneously with 0.3 mg of Salmonella typhimurium lipopolysaccharide (LPS) in 0.1 mL of phosphate-buffered saline solution or phosphate-buffered saline solution alone in 3 separate experiments; mice were killed after 1, 3, 5, and 7 days. In 2 other separate experiments, mice were killed 1, 3, 6, and 24 hours after LPS injection. All eyes were collected for histological examination, immunohistochemical analyses, aqueous protein level determination, and reverse transcriptase-polymerase chain reaction for ocular interleukin (IL)1alpha, IL-6, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor messenger RNA (mRNA). Enzyme-linked immunosorbent assay was used to measure tumor necrosis factor alpha and IL-6 levels in aqueous and serum samples. RESULTS: Results were consistent for all experiments. Numbers of ocular inflammatory cells and levels of aqueous protein peaked 1 and 5 days after LPS injection. Control mice did not develop inflammation. Serum and aqueous IL-6 and ocular IL-6 mRNA levels peaked at 1 day and subsided at 3 days. However, ocular IL-1alpha, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor mRNA appeared, peaked, and subsided at 3, 5, and 7 days, respectively. Predominant infiltrating cells were neutrophils at 1 day and macrophages at 5 days. Although no ocular inflammatory cells were detected before 24 hours after LPS injection, tumor necrosis factor alpha mRNA was noticed at 1 hour, peaked at 3 hours, and disappeared at 6 hours and granulocyte-macrophage colony-stimulating factor mRNA was spotted only at 3 hours after LPS injection. CONCLUSIONS: The ocular inflammatory response to C3H/ HeN mouse endotoxin-induced uveitis is biphasic for 7 days. The first wave appears at day 1 and subsides by day 3. A second, higher peak appears at day 5. The 2 inflammatory waves are related to the kinetics of the different cytokines released in the eye. This is in contrast to the rat monophasic endotoxin-induced uveitis model, which has only one peak of intense inflammation associated with cytokine release. CLINICAL RELEVANCE: A biphasic inflammatory response associated with cytokine release lasting several days is observed in C3H/HeN mice with endotoxin-induced uveitis. Because human anterior uveitis has a tendency to be recurrent in nature, this might be a better experimental model.