Short-term complications of intravitreal injections of triamcinolone and bevacizumab.

AIMS: To evaluate the rate of complications after intravitreal injection of bevacizumab and triamcinolone. METHODS: The clinical interventional case-series study included 5403 intravitreal injections of about 20 mg triamcinolone acetonide (n=1588) or 1.5 mg bevacizumab (n=3818) consecutively performed in the period from 2000 to 2007 by three surgeons for treatment of various intraocular edematous or neovascular diseases. Follow-up after each injection was at least 4 weeks. RESULTS: An infectious endophthalmitis which necessitated pars plana vitrectomy was detected in two eyes (2/5403 or 0.04+/-0.03%) from the bevacizumab group. Two eyes (2/5403 or 0.04+/-0.03%) from the bevacizumab group showed a painless vitreous clouding which subsided after intensified topical antibiotic therapy; one eye (1/5403 or 0.02+/-0.02%) developed a retinal detachment; and three eyes (3/5403 or 0.06+/-0.03%) (two eyes from the bevacizumab group) showed a rapidly progressive cataract. The total rate of these complications was 8/5403 (0.15+/-0.05%). It was statistically independent of the surgeon (P=0.18), the drug injected (P=0.45), and the age of the patients (P=0.87). CONCLUSIONS: Injection-related complications such as infectious endophthalmitis, retinal detachment, and traumatic cataract may occur with a frequency of about 0.15+/-0.05% after intravitreal injections of bevacizumab or triamcinolone, independently of the drug injected.

Follow-up after intravitreal triamcinolone acetonide for exudative age-related macular degeneration.

PURPOSE: To report on the follow-up of patients who received an intravitreal triamcinolone acetonide injection (IVTA) as treatment of exudative age-related macular degeneration. METHODS: The clinical interventional case-series study included 205 patients (222 eyes) with progressive exudative age-related macular degeneration with subfoveal neovascularization who consecutively received an IVTA of about 20 mg as only therapeutic procedure and for whom follow-up was at least 3 months. Mean follow-up was 10.4+/-7.1 months (range, 3-35.7 months). RESULTS: Visual acuity improved significantly (P<0.001) from baseline (0.90+/-0.45 logarithm of the minimum angle of resolution (LogMar)) to a mean minimum of 0.79+/-0.42 LogMar during follow-up. In 86 (38.7%) eyes and in 55 (24.8%) eyes, best visual acuity increased by at least two and three Snellen lines, respectively. Comparing the measurements at specific postinjection examination dates showed that visual acuity measurements taken at 1, 2, and 3 months after injection were not significantly different from the baseline value. Measurements taken at 6, 9, and 12 months after the injection were significantly (P<0.001) lower than the measurements at baseline. Mean loss at 6 months was 1.4+/-3.8 Snellen lines, at 9 months, 2.5+/-4.6 lines, and at 12 months after the injection, 2.6+/-4.0 lines. Intraocular pressure increased significantly (P<0.001) during the first 6 months, and returned to baseline at 9 months after injection. CONCLUSIONS: Single injection high-dosage IVTA did not show an apparent benefit at 12 months after injection in patients with neovascular age-related macular degeneration.

Bevacizumab for occult subfoveal neovascularization in age-related macular degeneration.

PURPOSE: To report on the treatment of exudative age-related macular degeneration by intravitreal bevacizumab (Avastin). METHODS: A 78-year-old patient experienced a progressive loss of visual acuity in her right eye due to an occult subfoveal neovascular membrane in age-related macular degeneration. She received an intravitreal injection of 1.5 mg bevacizumab. RESULTS: Within 4 weeks after the injection, visual acuity improved from 0.40 to 0.60 with complete resolution of subretinal and intraretinal leakage and edema as shown on optical coherence tomography. Pre-existing metamorphopsias disappeared. Intraocular pressure remained in the normal range. During the follow-up, there were no sings of intraocular inflammation or any other intraocular pathology induced by the intravitreal injection. CONCLUSIONS: Intravitreal bevacizumab may potentially be helpful in the treatment of exudative age-related macular degeneration and may deserve further evaluation.

Follow-up after intravitreal triamcinolone acetonide for diabetic macular edema.

PURPOSE: To report on the follow-up of patients who received an intravitreal high-dosage injection of triamcinolone acetonide (IVTA) as treatment of diffuse diabetic macular edema. METHODS: The clinical interventional case-series study included 109 eyes (90 patients) with diffuse diabetic macular edema who consecutively received an IVTA of about 20 mg. Mean follow-up was 11.2 +/- 6.2 months. RESULTS: Visual acuity improved significantly (p<0.001) from 0.89 +/- 0.33 logMAR to a best minimum of 0.65 +/- 0.35 logMAR. An increase in best visual acuity by at least 1 Snellen line, 2 lines, and 3 lines was found in 91 (83%) eyes, 68 (62%) eyes, and 45 (41%) eyes, respectively. Differences in visual acuity between baseline and follow-up examinations were significant for measurements performed at 1 month (p<0.001), 2 months (p<0.001), 3 months (p<0.001), and at 6 months (p=0.001) after the injection. At 9 months after the injection, mean visual acuity regressed significantly so that visual acuity at 9 months (p=0.83) and at 12 months after the injection (p=0.58) compared with baseline values did not differ significantly. Forty-seven (43%) eyes developed a rise in intraocular pressure (pressure >21 mmHg) for 6 to 8 months after the injection. No other severe complications were detected. CONCLUSIONS: The duration of a visual acuity increase and intraocular pressure rise after high-dosage IVTA in diffuse diabetic macular edema is about 6 to 8 months. Compared with data in the literature, the high-dosage IVTA may not have a markedly higher profile of side effects than low-dosage IVTA.

Sympathetic ophthalmia in vater association combined with persisting hyperplastic primary vitreous after cyclodestructive procedure.

PURPOSE: To report on the occurrence of histology-proven sympathetic ophthalmia in a patient with VATER association and persisting hyperplastic primary vitreous (PHPV) after a cyclodestructive procedure was performed to treat secondary angle-closure glaucoma. METHODS: The left eye of a 13-year-old boy with VATER association was microphthalmic from birth and had been diagnosed with PHPV at age 1 year. It developed iris neovascularization and secondary angle-closure glaucoma, which was treated by combined cyclocryocoagulation and cyclophotocoagulation. Six weeks later, a bilateral fibrinous iritis developed. Despite intensive topical and systemic steroid treatment, the iritis persisted so that the left blind eye was enucleated. RESULTS: Histology of the enucleated eye showed a marked intraocular inflammation with lymphocytes, epithelioid cells, and multinuclear giant cells grouped around remnants of melanin-bearing cells. CONCLUSIONS: Sympathetic ophthalmia may occur in patients with VATER association and PHPV after a secondary angle-closure glaucoma is treated by a combined cyclocryocoagulation and cyclophotocoagulation.

Proteins with an endostatin-like domain in a mouse model of oxygen-induced retinopathy.

Neovascularization in the retinopathy of prematurity (ROP) mouse eye is a self-limiting phenomenon. Free endostatin is known to be anti-angiogenic. In this study, we identified the localization of endostatin-like protein (ELP) sequences and investigated their possible role in this process. ROP was induced in C57Bl/6 mice and the eyes observed 1-11 days after termination of high oxygen supply (P13-P21). Sagittal sections and retinal flatmounts were double-stained with antibodies against a protein-sequence of endostatin, vascular endothelial growth factor (VEGF), lectin, and smooth-muscle alpha actin. The fluorescence was visualized by traditional and confocal microscopy. Intense staining for VEGF in the inner retina was limited to the early stages of neovascularization and diminished at P19-P21. In contrast, staining for ELPs appeared at P15 around the newly formed vessels and remained even after degeneration of their endothelial cells. Staining of the inner retinal vasculature for ELPs was restricted to P17-P19, the known maximum of the neovascular response. Outer retinal vessels did not show presence of ELPs at any time. Our study demonstrates that ELPs, absent at the beginning of neovascular sprouting, increases with the amount of neovascularization and thus, varies reciprocally to VEGF in the time period investigated. ELPs remain during the regression of the vessels and might therefore play an important role in the self-limiting process of ROP neovascularization.

Sympathetic ophthalmia in vater association combined with persisting hyperplastic primary vitreous after cyclodestructive procedure.

PURPOSE: To report on the occurrence of histology-proven sympathetic ophthalmia in a patient with VATER association and persisting hyperplastic primary vitreous (PHPV) after a cyclodestructive procedure was performed to treat secondary angle-closure glaucoma. METHODS: The left eye of a 13-year-old boy with VATER association was microphthalmic from birth and had been diagnosed with PHPV at age 1 year. It developed iris neovascularization and secondary angle-closure glaucoma, which was treated by combined cyclocryocoagulation and cyclophotocoagulation. Six weeks later, a bilateral fibrinous iritis developed. Despite intensive topical and systemic steroid treatment, the iritis persisted so that the left blind eye was enucleated. RESULTS: Histology of the enucleated eye showed a marked intraocular inflammation with lymphocytes, epithelioid cells, and multinuclear giant cells grouped around remnants of melanin-bearing cells. CONCLUSIONS: Sympathetic ophthalmia may occur in patients with VATER association and PHPV after a secondary angle-closure glaucoma is treated by a combined cyclocryocoagulation and cyclophotocoagulation. (Eur J Ophthalmol 2006; 16: 171-172).

Dosage dependency of intravitreal triamcinolone acetonide as treatment for diabetic macular oedema.

AIM: To evaluate the effect of different doses of intravitreal triamcinolone acetonide on diffuse diabetic macular oedema. METHODS: The prospective, randomised, double masked, clinical interventional study included 27 eyes (27 patients) with diffuse diabetic macular oedema. They were randomly divided into three study groups receiving an intravitreal injection of filtered triamcinolone acetonide of about 2 mg (n = 8 eyes), 5 mg (n = 10), or 13 mg (n = 9), respectively. Dosage measurement was performed before filtration. Mean follow up was 6.6 (SD 2.4) months (3-12 months). Main outcome measures were visual acuity and intraocular pressure. RESULTS: Maximal increase in visual acuity was significantly (p = 0.046; 95% CI: 0.032 to 2.99; r = 0.38) correlated with the dosage of intravitreal triamcinolone acetonide. Additionally, the duration of the effect of intravitreal triamcinolone acetonide increased significantly with the dosage of intravitreal triamcinolone acetonide (r = 0.45; p = 0.014). Increase in intraocular pressure during follow up was statistically not significantly associated with the dosage used (p = 0.77). CONCLUSIONS: In patients with diffuse diabetic macular oedema receiving intravitreal triamcinolone acetonide, treatment response may last longer and be more pronounced with a dosage of 13 mg than in lower doses of 5 mg or 2 mg. Triamcinolone acetonide induced increase in intraocular pressure may not be markedly associated with the dosage used.

Effect of triamcinolone acetonide on proliferation of retinal endothelial cells in vitro and in vivo.

AIM: To assess the effect of crystalline triamcinolone acetonide on retinal endothelial cell proliferation in vivo and in vitro. METHODS: For in vitro analysis, a sprouting assay was employed. Bovine retinal endothelial cells were stimulated with basic fibroblast growth factor (bFGF) and incubated with different concentrations of triamcinolone acetonide (0.05 mg/ml to 8 mg/ml). For in vivo analysis, a retinopathy of prematurity (ROP) model was used. 16 C57BL/J6 mice were exposed to 75% oxygen from postnatal day 7 to day 12. On day 12, triamcinolone acetonide was intravitreally injected into one eye ("study eye") and isotonic saline into the contralateral eye ("control eye"). On day 17, the mice were sacrificed and the eyes removed for quantitative analysis of preretinal neovascularisation. Four non-exposed mice served as negative control. RESULTS: The sprouting assay demonstrated a dose dependent inhibition of bovine retinal endothelial cell proliferation from 0.05 mg triamcinolone acetonide/ml (no inhibition) to 3 mg triamcinolone acetonide/ml (complete inhibition). Dosages of more than 2 mg/ml resulted in cytotoxic changes of endothelial cells. The ROP model demonstrated a significantly lower neovascular cell count of 58% in the study group compared to the control group (6.35 (SD 2.1) cells per histological section versus 14.9 (SD 5.3) cells; p<0.005). CONCLUSIONS: Triamcinolone acetonide inhibits bFGF induced proliferation of retinal endothelial cells in vivo and in vitro. These findings contribute to understanding the mode of action and effects of triamcinolone acetonide on retinal neovascularisation.

CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness.

Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP-like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia.

A new clinical classification for Usher's syndrome based on a new subtype of Usher's syndrome type I.

OBJECTIVES: Usher's syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss and progressive visual loss secondary to retinitis pigmentosa. Usher's syndrome is both clinically and genetically heterogeneous. Three clinical types are known today. METHODS: We conducted a study on 74 patients with Usher's syndrome, performing complete audiological and neurotological examinations. RESULTS: Twenty-six patients had total profound hearing loss and retinitis pigmentosa (Usher's syndrome type I), and 48 patients had moderate to severe sensorineural hearing loss and retinitis pigmentosa (Usher's syndrome type II). We identified 9 of the 26 Usher's syndrome patients with profound hearing loss who showed a normal response to bithermal vestibular testing. CONCLUSIONS: The combination of profound hearing loss and normal response to bithermal vestibular testing has not been previously described in Usher's syndrome. Therefore we describe a new subtype of Usher's syndrome type I and suggest a modified clinical classification for Usher's syndrome.

[Utilization of a new night vision enhancement device (DAVIS)]. / Einsatz einer neuen Nachtsichtbrille (DAVIS).

PATIENTS AND METHODS: Following complete ophthalmologic examination 37 patients with night blindness due to Retinitis Pigmentosa (sometimes Usher-Syndrome) and Choroideremia (n = 3) performed several tests with DAVIS during darkness. We evaluated the improvement of visual function on a special outside course in the city of Heidelberg (duration 1.5 to 4 hours). RESULTS: Twenty six of the patients were able to better recognize obstacles, 28 could see objects which were not seen without DAVIS. Twenty two of the 37 patients would use the DAVIS. Patients needed a visual acuity of more than 0.1 and more than 6 degree of central visual field to experience improvement with DAVIS. However, in patients with only minimal changes of the visual field, the restriction due to the presence of the device was a drawback. Sudden occurrence of light sources leads to blinding and limits the indoor use. CONCLUSION: DAVIS enhances contrast acuity especially during night and twilight. This leads to improvement of orientation due to better recognition of obstacles and allows rehabilitation of patients with night blindness for outdoor mobility. Individual test and adjustment of DAVIS is necessary to allow exact and adequate prescription.

MIG is a dominant lymphocyte-attractant chemokine in lichen planus lesions.

Dense accumulation of mononuclear cells (lymphocytes >> macrophages) in the dermal-epidermal interface and a T cell-mediated cytotoxic reaction against basal keratinocytes are hallmarks of lichen planus lesions. In this study, we focused on the chemotactic signals responsible for the selective recruitment of these cells. Using in situ hybridization and immunohistochemistry, the expression and localization of the lymphocyte-and/or monocyte/macrophage-attractant CC chemokines macrophage chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed, and secreted (RANTES), macrophage inflammatory protein-1alpha and -1alpha (MIP-1alpha/beta), I-309 and the CXC chemokines monokine induced by interferon-gamma (MIG), interferon-gamma-inducible protein-10 (IP-10), interleukin-8 (IL-8), epithelial-derived neutrophil attractant-78, and growth-related oncogene-alpha were investigated. Strong mRNA expression of MIG, IP-10, and MCP-1 and moderate mRNA expression of RANTES and MIP-1alpha were detected exclusively within foci characterized by strong infiltration with CD3+ lymphocytes (CD4+ cells > CD8+ cells) and CD68+ macrophages. All other chemokines investigated were minimally expressed or absent. With more than 11% of total cells strongly expressing MIG transcripts, this selectively lymphotactic chemokine was by far the dominant chemokine and thus may significantly contribute to the inflammatory reaction in lichen planus lesions. According to the mRNA expression profiles, MIG, IP-10, and MCP-1 were expressed by both basal keratinocytes above and mononuclear cells within the inflammatory foci. Our findings indicate that a set of chemokines composed of IP-10, MCP-1, RANTES, MIP-1alpha, and especially MIG contributes to the cytokine network and preferential trafficking of mononuclear cells to the interface region of lichen planus lesions.

The C-X-C chemokine Mig is highly expressed in the papillae of psoriatic lesions.

A prominent feature within the histopathological changes of psoriatic lesions is the particular spatial distribution of neutrophils, macrophages, and T-cell which are considered to participate in the pathogenesis of psoriasis. In this study, an attempt has been made to examine the microanatomical localization and magnitude of expression of the T-cell-attractant and -stimulating C-X-C and C-C chemokines Mig, interferon-inducible protein-10 (IP-10), macrophage inflammatory protein-1 alpha and 1 beta (MIP-a alpha and 1 beta), and regulated on activation, normal T-cell expressed and secreted (RANTES). Employing in situ hybridization, Mig message was strongly and selectively expressed in the upper lesional dermis with pronounced clustering in the tips of the papillae, whereas expression in normal or uninvolved skin was quiescent. In contrast, message for all the other chemokines investigated was much weaker or lacking. Expression of Mig transcripts in cell clusters of the papillae was paralleled by Mig immunoreactivity on endothelial and mononuclear cells. The expression profile, with high levels of Migs virtually limited to those lesional papillae with a pronounced infiltration of mononuclear leukocytes, strongly suggests that Mig is produced by a local population of highly activated macrophages and dermal microvascular endothelial cells. Considering the T-cell-attracting and -stimulating capacity of Mig and the importance of T-cells in the pathogenesis of psoriasis, this study indicates that this novel C-X-C chemokine plays an important role as a mediator of T-cell recruitment and activation in the papillae and thus contributes significantly to the cytokine network of inflammation in psoriasis.

Differential expression of GRO-alpha and IL-8 mRNA in psoriasis: a model for neutrophil migration and accumulation in vivo.

Dense focal accumulation of neutrophils in the upper epidermis is a hallmark of psoriasis. Because the signals for neutrophil diapedesis and migration in vivo are not fully understood, psoriatic lesions with pronounced migration of neutrophils may serve as an important model for studying neutrophil chemotaxis. In this study, we present evidence for differential expression of the neutrophil chemotactic cytokines growth-related oncogene alpha, interleukin-8, and ENA-78 (epithelial cell derived and neutrophil-activating properties, 78 amino acids) in psoriatic lesions. In situ hybridization and immunohistochemistry of serial sections were employed to identify and microanatomically localize the cells producing these chemokines. High levels of focal interleukin-8 message were found to be expressed in the upper epidermis by keratinocytes and, most importantly, neutrophils themselves. Growth-related oncogene alpha transcripts were detected in clusters of keratinocytes of the upper epidermis at the same sites where interleukin-8 mRNA was abundant. In contrast to interleukin-8, growth-related oncogene alpha was also detected in the papillary dermis produced by vessel-associated cells. Sites of interleukin-8 and growth-related oncogene alpha mRNA expression were associated with infiltration of neutrophils. Interestingly, mRNA expression of the highly homologous chemokine ENA-78 was quiescent. In conclusion, our data indicate that growth-related oncogene alpha is an important chemoattractant for neutrophil diapedesis in vivo, whereas further migration of neutrophils and formation of micropustules appears to be influenced by the cooperative action of both growth-related oncogene alpha and interleukin-8.