A better use of corticosteroids.
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Acute Disease↗
Biomedical subjects
S Lightman
Publications and source records attributed to S Lightman.
Assessment of the effect of oral clarithromycin on visual outcome following presumed bacterial endophthalmitis.
PURPOSE: The use of clarithromycin was assessed as a biofilm reducing agent in the management of bacterial endophthalmitis. METHODS: 84 eyes of 83 patients presenting with clinical signs highly suggestive of bacterial endophthalmitis were treated using a standard regimen of intraocular vancomycin, amikacin and systemic steroids, which in addition included oral clarithromycin. Ocular penetration of oral clarithromycin in healthy and inflamed eyes was also assessed. RESULTS: Comparing visual acuities at presentation and 6 months, 66% of patients demonstrated an improvement. Intraocular samples were culture positive in 58% of eyes. As compared to culture positive cases, more culture negative cases achieved a visual acuity of 6/12 or better (p = 0.0047). As compared to patients receiving the standard protocol but without clarithromycin, a greater number of culture negative cases demonstrated an improvement in vision of > or = + 6 Snellen lines (p = 0.023). The ocular penetration of clarithromycin into the anterior chamber of inflamed eyes appears sufficient to allow anti-biofilm activity against bacteria at the basic pH encountered in eyes with endophthalmitis. CONCLUSIONS: The ocular penetration of clarithromycin appears adequate for anti-biofilm activity in inflamed eyes. The beneficial effects of oral clarithromycin on visual outcome has been demonstrated in culture negative eyes with clinical signs highly suggestive of bacterial endophthalmitis. The final visual outcome for culture positive cases remains poor.
Administration, Oral↗
Behçet's disease in Japan and in Great Britain: a comparative study.
Behçet's disease (BD) is an important cause of visual morbidity throughout the world, but shows striking differences in racial predilection. Despite important advances in the therapeutic management of acute intraocular inflammation, the long-term impact of these new strategies on visual outcome of BD and their efficacy in different ethnic groups is unknown. A comparative study of patient characteristics, clinical ocular features and inflammatory score, and current therapy was undertaken on all patients fulfilling the International Study Group criteria for Behçet's disease and the Behçet's Disease Research Committee of Japan, who attended the Uveitis Clinics of Moorfields Eye Hospital (n=19) and Kurume University School of Medicine (KUS) (n=35) during a continuous consecutive four-week period. Japanese patients were significantly older (43.2+/-11.8 years) than the patients seen in London (35.4+/-8. 9 years). There was a predominance of male patients in both groups. All patients seen in KUS were Japanese, while the patients in London included 12 Caucasians, five Middle Eastern, one African, and one Asian. No significant differences were seen between the two populations in the duration of systemic disease or systems affected by the disease, such as mouth ulcers, genital ulcers, skin lesions including erythema nodosum, or arthritis. The duration of ocular disease was similar in both centres: around seven years. There was, however, a significant difference in the number of eyes with active anterior uveitis (59.7% KUS vs 18.4% London (chi-square: 5.4; p=0.006)) and/or posterior uveitis (31.3% KUS vs 18.4% London (chi-square: 5.42; p<0.02)). No significant differences were found in the number of eyes with optic disc swelling or optic atrophy and in each centre the number of eyes with vision greater than 6/9 or worse than 6/60 were the same. The treatment schedules were very different between the two centres. More patients were treated with topical steroids in Japan (68.7% KUS vs 10.5% London (chi-square: 30.5; p=0.001), but a similar number used concomitant intraocular pressure-lowering agents. More patients received systemic steroids in London (84.2% London vs 17% KUS (chi-square: 20.25; p<0.001)). Three patients received systemic steroids alone, five had prednisolone and cyclosporin, four had prednisolone and azathioprine, and four had triple therapy with prednisolone, cyclosporin, and azathioprine. Only one patient used colchicine. Cyclosporin use was similar in London and KUS (47.4% and 42.8%, respectively). In Japan, three patients used prednisolone alone and three tacrolimus (FK506). In addition, two patients, who were on steroids alone, took colchicine as well. More patients in Japan had undergone surgery for cataract and glaucoma (chi-square: 4.0; p=0.045). In KUS, seven of 67 eyes had cataract surgery. A further three eyes had visually significant cataract and two eyes had undergone glaucoma surgery. In contrast, no patients in London had undergone any surgery up to and including this period.
Administration, Topical↗
Use of PCR in endophthalmitis.
In eyes with suspected endophthalmitis, early diagnosis and appropriate treatment have been noted to be associated with a better visual outcome. Currently, however, confirmation of the diagnosis of endophthalmitis (bacterial and/or fungal) is dependent on conventional techniques of microbiological isolation of organisms which require between one and twelve days. Furthermore, many samples prove to be culture-negative. In order to improve the rate of microbiological diagnosis, PCR technology has been successfully applied to the detection of bacteria and fungi in ocular samples. Specific oligonucleotide primers have been used to detect the presence of pathogens, which have been subsequently identified using RFLP analysis, DNA sequencing, and/or cloning techniques. Results demonstrated that PCR-based methods are rapidly able to confirm the presence of pathogens with high specificity and sensitivity. PCR-based techniques have also been used to rule out with confidence the presence of pathogens, a unique advantage of this methodology. The use of molecular methods has significantly increased the number of intraocular samples from which a confirmed diagnosis is made and reduced the time to laboratory diagnosis. PCR-based methods promise to be useful diagnostic tools in the management of these patients, especially those from whom ocular samples prove to be culture-negative.
Aged↗
Retinochoroiditis is induced by oral administration of Toxoplasma gondii cysts in the hamster model.
Administration of Toxoplasma cysts by intraperitoneal innoculation in the Syrian Golden Hamster provides a reproducible animal model of acquired Toxoplasmic retinochoroiditis and cysts are observed in the brain. However, toxoplasmosis is frequently acquired by oral ingestion of contaminated foodstuffs and it is recognised that the route by which disease is acquired may influence its pathogenesis and clinical expression. This study aimed to determine whether retinochorioiditis and cysts in the brain develop after oral ingestion in the Syrian Golden Hamster model as this is the route of induction akin to that in man and may therefore be more relevant in the study of disease pathogenesis. All animals developed disease by 4 weeks. Ocular and cerebral inflammation was confirmed by histology at 16 weeks and this was milder than in the original model.
Administration, Oral↗
Mycophenolate mofetil. A useful immunosuppressive in inflammatory eye disease.
OBJECTIVE: To assess the usefulness of mycophenolate mofetil (MMF) (Cellcept, Roche), a potent selective uncompetitive and reversible inhibitor of ionisine monophosphate dehydrogenase involved in purine synthesis, as an immunosuppressive and steroid-sparing agent in the management of ocular inflammatory disease. DESIGN: Open-label, prospective, uncontrolled pilot study. PARTICIPANTS: Eleven patients with uncontrolled ocular inflammation. INTERVENTION: Mycophenolate mofetil, at a dosage of 1 g twice daily, was given in conjunction with steroids, as a steroid-sparing agent, or as an additional agent with cyclosporine (CsA), or instead of CsA or azathioprine. MAIN OUTCOME MEASURES: The inflammatory response, side effects, and toxicity were monitored. RESULTS: The addition of MMF to immunosuppressive regimens led to the improvement in symptoms and the ability to reduce the dose of prednisone in most patients. Ten of 11 patients showed a favorable response to MMF, with few side effects noted. CONCLUSION: These findings suggest that MMF is a useful immunosuppressive drug for controlling ocular inflammation with minimal side effects.
Adult↗
Posterior scleritis: clinical features, systemic associations, and outcome in a large series of patients.
OBJECTIVE: To document the clinical features, systemic associations, and visual outcome in a large number of patients with posterior scleritis. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: There were 137 patient records showing patients with a diagnosis of posterior scleritis who were attending or had attended the scleritis clinic at Moorfields Eye Hospital between 1974 and 1996. Ninety-nine records were suitable for detailed analysis. METHODS: The medical records and B-mode ultrasound examinations were reviewed. MAIN OUTCOME MEASURES: The clinical features, systemic associations, treatment, and outcome of each patient were determined. RESULTS: Posterior scleritis occurred at all ages. The mean age at onset was 49.3 years. Posterior scleritis began before age 40 in 30% of patients and was twice as common in women as in men. The B-mode ultrasound examination showed diffuse and nodular changes in the posterior sclera. Necrotizing posterior scleritis was not identified. Twenty-nine percent of patients had an associated systemic disease that included systemic vasculidites, autoimmune diseases, and lymphoma. Such patients more commonly had nodular changes on B-mode ultrasound examination. Early treatment controlled posterior scleral inflammation and limited visual loss. Thirty-one percent of patients lost two or more lines of vision. Statistical analysis revealed that patients older than age 50 had an increased risk of having an associated systemic disease and were more likely to experience visual loss. Patients with associated systemic disease required more aggressive immunosuppressive therapy and more frequently had accompanying anterior scleritis. There was no association between unilateral, bilateral, or recurrent disease and the presence of systemic disease or visual loss from posterior scleritis. CONCLUSIONS: The B-mode ultrasound examination reveals that posterior scleritis occurs far more often than previously thought and can lead to rapid and permanent visual loss. All patients with posterior scleritis must be assumed to be at risk of visual loss. Forty percent of patients had no anterior scleral inflammation, and 9% had no detectable physical signs. All patients need to be investigated for an associated systemic disease and all require early treatment to minimize loss of vision.
Adolescent↗
Incidence of symptomatic toxoplasma eye disease: aetiology and public health implications.
Ocular disease is the commonest disabling consequence of toxoplasma infection. Incidence and lifetime risk of ocular symptoms were determined by ascertaining affected patients in a population-based, active reporting study involving ophthalmologists serving a population of 7.4 million. Eighty-seven symptomatic episodes were attributed to toxoplasma infection. Bilateral visual acuity of 6/12 or less was found in seven episodes (8%) and was likely to have been transient in most cases. Black people born in West Africa had a 100-fold higher incidence of symptoms than white people born in Britain. Only two patients reported symptoms before 10 years of age. The estimated lifetime risk of symptoms in British born individuals (52% of all episodes) was 18/100000 (95% confidence interval: 10.8-25.2). The low risk and mild symptoms in an unscreened British population indicate limited potential benefits of prenatal or postnatal screening. The late age at presentation suggests a mixed aetiology of postnatally acquired and congenital infection for which primary prevention may be appropriate, particularly among West Africans.
Adolescent↗
Cytokine production and mRNA expression by conjunctival T-cell lines in chronic allergic eye disease.
BACKGROUND: Activated CD4+ T cells, mast cells and eosinophils are the main cytokine-producing cell-types infiltrating the conjunctiva during chronic allergic eye diseases. Interactions between these cells are thought to play an important immunopathogenic role in these disorders (giant papillary conjunctivitis; vernal keratoconjunctivitis; atopic keratoconjunctivitis). OBJECTIVE: The objective was to compare the cytokine profiles of conjunctival T-cell lines from patients with different forms of chronic allergic eye disease. METHODS: T cells were isolated from conjunctival biopsies and non-specifically expanded into lines. The lines were immunophenotyped by flow cytometry. Cytokine production was quantified by immunoassays and more sensitive molecular techniques were used to investigate cytokine mRNA expression to identify the presence of interleukin (IL) -2, IL-4 and interferon (IFN) -gamma transcripts. RESULTS: Following four to six rounds of stimulation, the conjunctival T-cell populations were CD3+ (> 93%), with variable levels of CD4 and CD8 expression. All were HLA-DR+ (> 80%) with some HLA-DQ expression. Conjunctival T-cell lines from atopic keratoconjunctivitis produced selective increases in IFN-gamma, IL-10 and IL-13 (P<0.01), those from vernal keratoconjunctivitis produced increased IL-5 (P<0.01) whereas T-cell lines from giant papillary conjunctivitis produced only low levels of cytokines. IL-4 was only detected at the mRNA level and was expressed in four out of five T-cell lines in the vernal keratoconjunctivitis group. In contrast there was moderate to strong expression of IFN-gamma in five out of six T-cell lines in atopic keratoconjunctivitis. CONCLUSION: Different patterns of T-cell cytokine profiles were observed for each disease, with low-level, non-polarized cytokine production in giant papillary conjunctivitis, a TH2-like profile in vernal keratoconjunctivitis and a shift towards a TH1-like profile in atopic keratoconjunctivitis.
Adult↗
Characterization of phenotype and cytokine profiles of T cell lines derived from vitreous humour in ocular inflammation in man.
Intermediate uveitis (IU) and Fuchs' heterochromic cyclitis (FHC) are two chronic ocular inflammatory disorders. They differ considerably in ocular morbidity, which is higher in IU. T cell lines were derived from the vitreous humour (VH) and peripheral blood (PB) of 10 patients with IU and four patients with FHC. There was a predominance of CD8+ in all the lines. However, there was a significantly higher percentage of CD4+ T cells in the T cell lines derived from VH of IU (32.0 +/- 8.6%) compared with FHC patients (19. 2 +/- 8.9%) (P = 0.04). The VH-derived T cell lines (VDTC) produced significantly higher levels of IL-2, interferon-gamma (IFN-gamma) and IL-10, but not IL-4, compared with PB-derived T cell lines (PBDTC) in both entities. There was significantly higher IL-2 production by VDTC from IU when compared with FHC patients (1810 +/- 220 pg/ml versus 518 +/- 94 pg/ml; P = 0.009), which could account for the more aggressive clinical features of this condition. In contrast IL-10 production was significantly higher by the VDTC from FHC compared with IU patients. The high IL-10 production by T cells infiltrating VH of FHC patients could down-regulate the inflammatory responses, thereby contributing to the benign clinical course seen in these patients. The accumulation of T cells with differing cytokine profiles in the VH suggests an important role for these cytokines in the pathogenesis of these chronic uveitides.
Adult↗
Posterior uveitis in Hodgkin's disease.
PURPOSE: To describe the features of posterior uveitis in patients who either developed or were known to have, biopsy-proven Hodgkin's disease (HD). METHODS: Four patients were identified who were attending the uveitis clinic. Their charts were reviewed retrospectively and information on their HD was obtained from other hospitals where necessary. Their case histories are presented. RESULTS: Two patients presented with uveitis prior to the diagnosis of HD and in the other two, the HD was thought to be in remission. The commonest ocular signs were of vitritis and discrete, white, chorioretinal lesions. No difference in the ocular findings were apparent between those who had a known diagnosis of HD and the those that did not. CONCLUSIONS: HD can occur in the eye and can mimic posterior uveitis. In two of the patients, the uveitis preceded the diagnosis of HD and at the time of presentation all investigations were normal. No specific diagnostic features were apparent, though three of the patients had vitritis and chorioretinal lesions.
Adult↗
Polymerase chain reaction in the diagnosis of bacterial endophthalmitis.
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Endophthalmitis↗
Insertion of an amino acid in the DNA-binding domain of the glucocorticoid receptor as a result of alternative splicing.
When the human glucocorticoid receptor (GR) was first sequenced, a predominant form (GRalpha) and a minor variant (GRbeta) were identified. In the present communication, we describe a new variant of the glucocorticoid receptor (GRgamma) in which, as a result of alternative splicing, three bases are retained from the intron separating exons 3 and 4. These three bases code for an additional amino acid (arginine) in the DNA binding domain of the receptor. Insertion of arginine at this site has previously been shown to decrease transcriptional activation by the GR to 48% that of GRalpha. Analysis of cDNA from different tissues shows that the novel form is widely expressed at a relatively high level (between 3.8 and 8.7% of total GR).
Alternative Splicing↗
Current and novel agents for the treatment of cytomegalovirus retinitis.
The incidence of cytomegalovirus (CMV) retinitis appears to be declining with improved treatment protocols for HIV and prophylaxis protocols for other high risk patients. Despite this, CMV retinitis remains a major cause of visual loss in patients who are severely immunocompromised. Treatment options are evolving in the light of viral resistance, new methods of drug delivery, new drugs, and the increased potential for improvement of immune function that modern antiretroviral therapy provides. In this article, we review the changing options available for the management of CMV retinitis and discuss possible therapeutic agents for the future.
Animals↗
Increased CD4+ expression and decreased IL-10 in the anterior chamber in idiopathic uveitis.
PURPOSE: To compare cell types and cytokines in aqueous humor from patients with uveitis either occurring in association with a systemic disease or apparently isolated and not associated with a systemic disease. METHODS: Cells were collected by centrifugation of fresh aqueous humor from uveitis and controls, and immunofluorescence techniques were performed with markers for T cells, B cells, and monocytes. Cytokines were measured in the aqueous supernatants, and serum samples were assayed for soluble interleukin-2 receptors. RESULTS: When aqueous samples from idiopathic uveitis were compared with those from uveitis associated with a systemic disease, there were increases in CD3+, CD4+ (p = 0.001), and activated CD4+ T cells (p = 0.02) and a decrease in B cells (p = 0.0013). This was not reflected in the peripheral blood where there were no differences in the cell types or in soluble interleukin-2 receptor levels. No cells were obtainable from control aqueous. Interleukins-10 and -12, interferon-gamma, and transforming growth factor-beta2 were detected in aqueous supernatants. Interleukin-10 was reduced (p = 0.024) in uveitis in comparison with controls. CONCLUSIONS: The results suggest a selective recruitment of CD4+ T cells within aqueous humor but only in idiopathic uveitis. In both disease groups there was a decrease in the immunoregulatory cytokine interleukin-10, which might enable an immune response to occur in an otherwise highly immunosuppressive microenvironment. Increases in activated CD4+ T cells combined with depressed interleukin-10 levels could partially explain why, for example, in acute anterior uveitis, the inflammatory disease is often more severe.
Adult↗
The immunomodulatory effect of topical cyclosporin A in atopic keratoconjunctivitis.
PURPOSE: To perform a detailed examination of the immunomodulatory effects of topical cyclosporin A (CsA) in conjunctival tissue from patients with atopic keratoconjunctivitis (AKC). METHODS: Patients with active AKC were randomly allocated into two groups of four patients. For 3 months one group received 2% CsA drops, and the other group received placebo drops. Superior tarsal conjunctival biopsy specimens were harvested before and after treatment and examined by one- and two-color immunohistochemistry to compare leukocyte counts, HLA-DR+ and IL-2R+ cell counts, HLA-DR positivity of conjunctival epithelial cells, and counts of T cells expressing the cytokines interleukin (IL)-2, IL-3, IL-4, IL-5, and interferon (IFN)-gamma. RESULTS: Posttreatment values were significantly less than pretreatment values for the total number of leukocytes and in the numbers of CD3+ T cells, CD4+ cells, CD8+ cells, CD20+ B cells, neutrophils, and macrophages, and there was a decrease in the CD4-CD8 ratio (P = 0.03) in the CsA group. There was a reduction from before CsA treatment to after CsA-treatment in the numbers of HLA-DR+ and IL-2R+ cells (P = 0.03), but the reduction in the epithelial cell HLA-DR expression did not reach significance. The number of T cells staining for IL-3 and IL-5 was reduced, although not to statistical significance, but there was a significant reduction in the number of T cells expressing IL-2 and IFN-gamma (P = 0.03) after CsA treatment compared with initial values. There were no statistically significant differences between pretreatment and posttreatment values in the placebo group. There was a clinical improvement in the CsA group and a clinical worsening in the placebo group. CONCLUSIONS: The in vitro effects of CsA translate into a reduction in T cells, a normalization of the CD4-CD8 ratio, a decrease in T-cell activation, and a reduction in T-cell cytokine expression, especially IL-2 and IFN-gamma. The decrease in HLA-DR expression may be mediated by the change in IFN-gamma. There were fewer B cells but not fewer plasma cells after CsA and no change in IL-4 expression, suggesting minimal effects on type I hypersensitivity responses. There was no significant reduction in mast cell or eosinophil numbers, but direct effects of topical CsA on their function may play a role in the therapy of ocular allergic disease. These results show that the beneficial effects of topical CsA in AKC are accompanied by important changes in conjunctival immune cell profiles.
Administration, Topical↗
Multifocal choroiditis: clinicopathologic correlation.
Many of the white dot syndromes are considered to have a granulomatous pathogenesis. The histopathologic characteristics of this case of multifocal choroiditis seen within 15 months of apparent clinical onset show that the white dot lesions were nongranulomatous perivascular choroidal infiltrates, consisting mainly of B lymphocytes. Early choroidal neovascularization was also seen.
Adult↗
A randomized, placebo-controlled trial of topical cyclosporin A in steroid-dependent atopic keratoconjunctivitis.
OBJECTIVE: This study aimed to investigate the therapeutic effect of topical cyclosporin A (CsA) 2% in maize oil as a steroid-sparing agent in steroid-dependent atopic keratoconjunctivitis. DESIGN: Prospective, randomized, double-masked, placebo-controlled trial. PARTICIPANTS: Twenty-one patients with steroid-dependent atopic keratoconjunctivitis were studied. INTERVENTION: Patients used either topical CsA or vehicle four times daily for 3 months in addition to their usual therapy, and the clinical response was used to taper or stop topical steroids when possible. MAIN OUTCOME MEASURES: Steroid drop usage per week, ability to cease steroid use, scores for symptoms and clinical signs, drop side effects, and overall subjective rating of trial drop by patients and clinician were measured. RESULTS: Cyclosporin A had a greater steroid-sparing effect than did placebo. Nine of 12 CsA patients ceased steroids compared to 1 of 9 placebo patients (P = 0.01), the final steroid use was lower in the CsA group (2.6 +/- 1.4 vs. 27.7 +/- 17.7, P = 0.005), and the mean reduction in steroid use was greater for CsA (85.5 +/- 14.7 vs. 13.9 +/- 16.0, P = 0.005). Clinical signs and symptom scores were reduced to a greater level for CsA. Serious side effects were lid skin maceration in one patient using CsA and an allergic reaction in one placebo patient. Marked blurring of vision after drop instillation was common in both groups, but intense stinging was more common in CsA patients (9/12 vs. 1/9, P = 0.01), limiting frequency of drop use. The clinician rated the trial drops as good or excellent more frequently for CsA (11/12 vs. 0/9, P < 0.0001). CONCLUSIONS: Topical CsA is an effective and safe steroid-sparing agent in atopic keratoconjunctivitis and, despite difficulties in patient tolerance, also improves symptoms and signs.
Administration, Topical↗