Anti-tumor necrosis factor alpha for retinal diseases: current knowledge and future concepts.

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine produced by macrophages and T-cells. It plays an important role both in inflammation and apoptosis. In the eye, TNF-α appears to have a role in the pathogenesis of inflammatory, edematous, neovascular and neurodegenerative disorders. Several TNF-blocking drugs have been developed and approved, and are in clinical use for inflammatory diseases such as rheumatoid arthritis, psoriasis and ankylosing spondylitis. TNF-α blockers are widely used in ophthalmology as an off-label alternative to "traditional" immunosuppressive and immune-modulatory treatments in noninfectious uveitis. Preliminary studies suggest a positive effect of intravenously administered TNF-α blockers, mainly infliximab, for treating refractory diabetic macular edema and neovascular age-related macular degeneration. Unfortunately, much of the current data raises considerable safety concerns for intravitreal use of TNF-α inhibitors, in particular, intraocular inflammatory responses have been reported after intravitreal injection of infliximab. Results of dose-finding studies and humanized antibody or antibody fragments (e.g. adalimumab) are anticipated in the coming years; these will shed light on potential benefits and risks of local and systemic TNF-α blockers used for treatment of diseases of the retina and choroid.

MFGE8 does not influence chorio-retinal homeostasis or choroidal neovascularization in vivo.

PURPOSE: Milk fat globule-epidermal growth factor-factor VIII (MFGE8) is necessary for diurnal outer segment phagocytosis and promotes VEGF-dependent neovascularization. The prevalence of two single nucleotide polymorphisms (SNP) in MFGE8 was studied in two exsudative or "wet" Age-related Macular Degeneration (AMD) groups and two corresponding control groups. We studied the effect of MFGE8 deficiency on retinal homeostasis with age and on choroidal neovascularization (CNV) in mice. METHODS: The distribution of the SNP (rs4945 and rs1878326) of MFGE8 was analyzed in two groups of patients with "wet" AMD and their age-matched controls from Germany and France. MFGE8-expressing cells were identified in Mfge8(+/-) mice expressing ß-galactosidase. Aged Mfge8(+/-) and Mfge8(-/-) mice were studied by funduscopy, histology, electron microscopy, scanning electron microscopy of vascular corrosion casts of the choroid, and after laser-induced CNV. RESULTS: rs1878326 was associated with AMD in the French and German group. The Mfge8 promoter is highly active in photoreceptors but not in retinal pigment epithelium cells. Mfge8(-/-) mice did not differ from controls in terms of fundus appearance, photoreceptor cell layers, choroidal architecture or laser-induced CNV. In contrast, the Bruch's membrane (BM) was slightly but significantly thicker in Mfge8(-/-) mice as compared to controls. CONCLUSIONS: Despite a reproducible minor increase of rs1878326 in AMD patients and a very modest increase in BM in Mfge8(-/-) mice, our data suggests that MFGE8 dysfunction does not play a critical role in the pathogenesis of AMD.

Iridolenticular block in heavy silicone oil tamponade.

BACKGROUND: The purpose of this study was to report the adverse effect of iridolenticular block glaucoma after vitreoretinal surgery and endotamponade with heavy silicone oil in cases of complicated retinal detachment. METHODS: A retrospective analysis of 23 eyes of 23 patients who underwent a pars plana vitrectomy and heavy silicone oil (Densiron 68) endotamponade for repair of complex inferior retinal detachment. RESULTS: Two patients developed high intraocular pressure postoperatively. The mechanism of secondary glaucoma in both patients was a prolapse of heavy silicone oil into the anterior chamber. When lying in a supine position for a prolonged period, the heavy silicone oil occluded the pupil, causing an iridolenticular block. CONCLUSION: In the presence of heavy silicone oil in the anterior chamber, lying in a supine position causes the oil drop to sink, blocking the entire diameter of the pupil, and inducing an iridolenticular block with acute angle-closure glaucoma. We conclude that every case of heavy silicone oil migration into the anterior chamber should be regarded as an emergency. The possible treatment could include pupil dilation, anterior chamber irrigation, or an Nd YAG-laser iridotomy.

Retinal vein occlusion and low-dose fibrinolytic therapy (R.O.L.F.): a prospective, randomized, controlled multicenter study of low-dose recombinant tissue plasminogen activator versus hemodilution in retinal vein occlusion.

PURPOSE: To investigate the efficacy of intravenous thrombolysis with low-dose recombinant tissue plasminogen activator (rt-PA) in recent-onset central retinal vein occlusion (CRVO) or branch retinal vein occlusion. METHODS: This was a prospective, randomized, controlled multicenter trial in patients with CRVO or branch retinal vein occlusion, best-corrected visual acuity < or =20/50, and onset of symptoms within 11 days before treatment. In each group, patients were randomized to either hemodilution or thrombolysis with 50 mg of rt-PA with concomitant intravenous heparinization. The primary clinical outcome measure was improvement in best-corrected visual acuity from baseline at 1 year. RESULTS: Fifty-two subjects were enrolled in the study. Patients with CRVO (n = 41) who were treated with rt-PA exhibited a significant improvement in best-corrected visual acuity compared with those who received hemodilution (P < 0.0001). At 1-year follow-up, the proportion of eyes with CRVO achieving an improvement in visual acuity of three or more lines was 45% after treatment with rt-PA and 21% after hemodilution therapy. The median final best-corrected visual acuity among CRVO patients given rt-PA was 20/60 (light perception, 20/15) compared with 20/400 (light perception, 20/20) in the hemodilution group. There were no significant differences among patients with branch retinal vein occlusion (n = 11). We observed no serious adverse events. No significant differences were found regarding the development of ocular neovascularization. CONCLUSION: Treatment with intravenous low-dose rt-PA improved visual outcome in CRVO. Thrombolysis was not associated with a lower risk of ocular neovascularization, indicating that the mechanisms involved in this process occur at an early stage.

Posterior segment complications of laser in situ keratomileusis (LASIK).

Laser in situ keratomileusis (LASIK) is the most common surgical procedure for treatment of refractive errors worldwide. Most of its complications are related to the refractive outcome or to corneal and anterior segment injury and wound healing. We review published posterior segment complications of LASIK, current clinical and experimental hypotheses explaining the occurrence of these events, and their management and outcome. Vitreoretinal complications after LASIK are very rare, and a cause-effect relationship between LASIK and reported posterior segment complications has not been proven.

Comparison of standard and aberration-neutral profiles for myopic LASIK with the SCHWIND ESIRIS platform.

PURPOSE: To compare the induced corneal wavefront aberration of eyes treated for myopia by LASIK with the SCHWIND ESIRIS laser using an aspheric aberration-neutral (Aberration-Free) ablation profile versus a classical Munnerlyn standard profile. METHODS: Two consecutive groups of myopic eyes were analyzed. One group (70 eyes) was treated with a standard non-aspheric Munnerlyn profile (standard group, mean spherical equivalent refraction -4.09 +/- 1.77 diopters [D] [range: -7.75 to -0.75 D] and mean cylinder 0.78 +/- 0.76 D [range: 0.00 to 3.00 D]), and the second group (70 eyes) was treated with the ORK-CAM aspheric aberration-neutral profile (aberration-neutral group, mean spherical equivalent refraction -3.71 +/- 1.80 D [range: -8.25 to -0.75 D] and mean cylinder 1.00 +/- 0.97 D [range: 0.00 to 4.50 D]). Visual outcome, corneal wavefront data, and topographic changes after 3-month follow-up were compared. RESULTS: Both groups had a good visual acuity outcome with refractive predictability of +/- 0.50 D in approximately 96% of the cohort. In terms of safety, one eye in the standard group lost two lines of Snellen visual acuity. In the aberration-neutral group, no eye lost more than one line of Snellen visual acuity and 6% gained more than two lines. Corneal aberrations were measured up to the 7th order (36 Zernike terms). The induced postoperative corneal wavefront aberration at 4.0 and 6.0 mm was compared. At 6.0 mm, corneal coma increased after myopic LASIK by 0.09 microm in the standard group and by 0.07 microm in the aberration-neutral group. The induction of corneal spherical aberrations in the standard group was 0.17 microm (0.22 D) versus 0.09 microm (0.13 D) in the aberration-neutral group. The root-mean-square of induced higher order aberrations was 0.19 microm in the standard group and 0.16 microm in the aberration-neutral group. Topographies showed multifocality of 0.50 D in the standard group and 0.25 D in the aberration-neutral group. CONCLUSIONS: Both groups had good predictability and safety results. With the aspheric aberration-neutral profile, less corneal wavefront aberration was induced compared to eyes treated with the standard profile.

Aberration-neutral ablation pattern in hyperopic LASIK with the ESIRIS laser platform.

PURPOSE: To analyze refractive power changes, topographical changes, and aberrations induction after aberration-neutral (Aberration-Free") hyperopic LASIK using the SCHWIND ESIRIS laser platform. METHODS: Thirty-three consecutive eyes of 19 patients were evaluated retrospectively. The outcomes were analyzed at 3 months. In all cases, standard examinations and pre- and postoperative topographical and corneal wavefront analysis with a Keratron topographer (OPTIKON 2000 SpA) were performed. The preoperative mean spherical equivalent refraction was +2.61 +/- 1.39 diopters (D) (range: +0.75 to +6.00 D) with a mean cylinder of 0.67 +/- 0.74 D (range: 0.00 to 4.00 D). Ablations were performed with the SCHWIND ESIRIS excimer laser system. Topographical changes of Maloney index, simulated keratometry (Sim-K), and K-readings at 5 and 7 mm were evaluated. RESULTS: Corneal aberrations up to the seventh order (36 Zernike terms) were measured. Corneal spherical aberration was +0.197 +/- 0.144 microm preoperatively and -0.040 +/- 0.206 microm postoperatively at the 6-mm analysis diameter. At 3 months postoperatively, 88% of eyes were within +/-0.50 D manifest refraction. Changes in refraction, Maloney indices, and Sim-K indices postoperatively were correlated with the intended correction. Induction of negative corneal spherical aberrations and increased prolate asphericity were correlated with the achieved defocus correction. No other Zernike mode was significantly correlated. Topographically, a corneal multifocality of <0.25 D was also observed. CONCLUSIONS: Analyzing the topographical maps, the corneal power change of the Maloney indices correlated with the intended correction. With the aberration-neutral (SCHWIND Aberration-Free) pattern, patients with hyperopia up to +5.00 D were treated safely and with good predictability. The induced corneal aberrations were less than those calculated with the classical profile and compared to the literature.

Intravenous thrombolysis with low-dose recombinant tissue plasminogen activator in central retinal artery occlusion.

PURPOSE: To evaluate the beneficial effect of intravenous thrombolysis aiming at rapid restoration of blood flow during the early hours of a central retinal artery occlusion (CRAO). DESIGN: Interventional case series. METHODS: In the present study, we prospectively evaluated the visual outcome after thrombolytic treatment with low-dose (50 mg) rt-PA (recombinant tissue plasminogen activator) and concomitant intravenous heparinization in patients with acute CRAO, best-corrected visual acuity (BCVA) < or = 20/100, and onset of symptoms within 12 hours prior to treatment. RESULTS: Twenty-eight patients (28 eyes) were included in this study. Final visual acuity was improved three or more lines in nine eyes (32%), stable in 18 (64%), and worse in one eye. Time to treatment < or = 6.5 hours was associated with a better gain of lines of vision (P = .004). Seven of 17 eyes (41%) that received thrombolytic treatment within the first 6.5 hours achieved a final BCVA > or = 20/50, compared to none in the subgroup of patients with onset to treatment >6.5 hours (P = .023). We observed no serious adverse events. CONCLUSIONS: Our findings indicate that thrombolytic treatment with intravenous low-dose rt-PA is of value for an improved visual recovery in patients with acute CRAO, if administered within the first 6.5 hours after the onset of symptoms.

Phacoemulsification does not induce neovascular age-related macular degeneration.

PURPOSE: To investigate whether cataract surgery by phacoemulsification induces progression of early age-related macular degeneration (AMD) to neovascular AMD. METHODS: Retrospective case-control study. Included were consecutive patients who had undergone phacoemulsification from January 2000 to February 2006 at the Recklinghausen Eye Centre, who had a preexisting diagnosis of early AMD and who were followed up for at least 1 year after surgery (n = 1152 eyes of 696 patients). The control group comprised phakic patients diagnosed with early AMD from January 2000 to February 2006, who did not undergo eye surgery and were followed up for at least 1 year (n = 334 eyes of 202 patients). RESULTS: At baseline, control eyes had significantly better visual acuity than those of patients who were going to have cataract surgery (0.30/0.35 +/- 0.34 vs. 0.40/0.49 +/- 0.34, respectively; median/mean +/- SD; P < 0.001, Mann-Whitney rank sum test). After 1 year, visual acuity in the control group was worse than in surgical eyes (0.30/0.39 +/- 0.38 vs. 0.20/0.26 +/- 0.30, respectively; median/mean +/- SD; P < 0.001, Mann-Whitney rank sum test). In the cataract surgery group, neovascular AMD developed in 28 (2.43%) of 1152 eyes in the first postoperative year. In the control group, it developed in 6 (1.74%) of 344 eyes within 1 year. There was no significant difference between the groups in the incidence of neovascular AMD (P = 0.57, odds ratio 1.30, 95% CI 0.52-3.24, logistic regression analysis, adjusted for age and baseline visual acuity). CONCLUSIONS: The results indicate that cataract surgery in eyes with early AMD is not a causative factor in neovascular AMD.

Topographic changes after hyperopic LASIK with the SCHWIND ESIRIS laser platform.

PURPOSE: To analyze and compare refractive power changes with topographic changes after hyperopic LASIK using the ESIRIS laser platform. METHODS: Sixty-six consecutive eyes of 37 patients were evaluated retrospectively. Outcomes were evaluated at 3 months. In all cases, standard examinations including pre- and postoperative topographic and corneal wavefront analysis with a Keratron topographer were performed. Preoperative mean spherical equivalent was +/- 2.74 diopters (D) with a mean cylinder of 0.67 D. The ESIRIS excimer laser system was used to perform ablations. Topographic changes of Maloney index, simulated keratometry (sim-K), and K-reading at 5 and 7 mm were evaluated. RESULTS: Ninety-two percent of eyes were within +/- 0.50 D manifest refraction at 3 months postoperatively. Changes in refraction, Maloney indices, and sim-K indices after surgery were strongly correlated with the intended correction. Induction of negative corneal spherical aberrations and increased prolate asphericity was correlated with the achieved defocus correction. No other Zernike mode was significantly correlated. Topographically, an overcorrection within the central 3 mm and a gradual peripheral undercorrection also was observed. CONCLUSIONS: Analyzing the topographic maps, the corneal power change of the Maloney indices correlated with the intended correction. After hyperopic LASIK, an overcorrection was observed in the 3-mm central zone, and progressive undercorrections were observed in the 5- and 7-mm zones.

SKGEL® implant versus T-Flux® implant in the contralateral eye in deep sclerectomy with phacoemulsification: long-term follow-up.

PURPOSE: To intraindividually compare the efficacy and safety of the SKGEL(®) implant versus the T-Flux(®) implant in deep sclerectomy. METHODS: In a retrospective analysis 17 patients were identified who underwent combined phacoemulsification-deep sclerectomy and implantation of SKGEL(®) in one eye and T-Flux(®) in the contralateral eye. RESULTS: In eyes with SKGEL(®) the IOP decreased from 20.6+7.3 mm Hg to 14.8+5.3 mm Hg (-5.8 mm Hg or -28.1%), and in eyes with T-Flux(®) from 19.9+7.2 mm Hg to 14.7+3.3 mm Hg (-5.2 mm Hg or -26.1%, no statistically significant difference, p >0.05). Antiglaucoma medications with either implant decreased from initially 2.0+0.8 to 0.3+0.7. A qualified success was found in 17/17 eyes with T-Flux(®) and in 16/17 eyes with SKGEL(®). Complete success was achieved in 14/17 eyes with T-Flux(®) and in 13/17 eyes with SKGEL(®). CONCLUSIONS: The IOP-lowering effect and safety of SKGEL(®) and T-Flux(®) seem to be comparable.

Age distribution of patients presenting with uveitis.

BACKGROUND: Endogenous uveitis has long been considered to be uncommon in elderly patients. Recently, population-based studies have shown an increase in the incidence of uveitis with inreasing age. It was the aim of this study to analyse the age distribution of patients presenting with endogenous uveitis in the setting of an eye centre. METHODS: Retrospective cohort analysis. RESULTS: 278 patients with endogenous uveitis showed the following age distribution: 0 - 15: 9, 15 - 30: 28, 30 - 45: 73, 45 - 60: 78, >60: 90 (age group: number of patients). Localization of uveitis was 82,4% anterior, 9,4% intermedia, 12,9% posterior. Two patients >60y were diagnosed with a masquerade syndrome. CONCLUSIONS: A large number of patients presenting with endogenous uveitis is in the elderly age group. An early and appropriate diagnostic work-up for uveitis is recommended for the elderly.

Enhanced visualization of acute macular neuroretinopathy by Heidelberg Retina Tomography.

We report Heidelberg Retina Tomography (HRT) findings in a case of bilateral acute macular neuroretinopathy in a 22-year-old man. In addition to fundus photography, fluorescein and indocyanine green angiography, and visual field testing, HRT scans of the macula were performed early in the disease and at a follow up of 2 months. We found typical paracentral scotomata in visual field testing corresponding to sharply delineated, hyporeflective areas of the macula as visualized in HRT II scans. Those lesions were almost invisible on regular fundus photographs. Angiography results were unremarkable. The lesion size decreased over time. The visibility of the lesions was markedly enhanced by HRT scans, thus the diagnosis and follow up of acute macular neuroretinopathy could be facilitated by this non-invasive imaging technique.

Reactivation of toxoplasma retinochoroiditis under atovaquone therapy in an immunocompetent patient.

PURPOSE: To report a case of toxoplasma retinochoroiditis reactivation in an immunocompetent patient under atovaquone therapy. METHODS: Case report. RESULTS: A healthy woman with a history of bilateral toxoplasma retinochoroiditis since childhood presented with a reactivation of toxoplasma retinochoroiditis. Because earlier treatment regimens had either produced intolerable side effects and/or were deemed ineffective for the prevention of reactivation, the patient was started on atovaquone suspension (750 mg three times a day). After initial regression of the lesion and still under atovaquone therapy, the patient presented again five weeks later with worsened best-corrected visual acuity. Examination showed that the lesion had expanded again and more cells were present in the vitreous. CONCLUSIONS: To our knowledge, this is the first report of a reactivation of toxoplasma retinochoroiditis in an immunocompetent patient under atovaquone therapy, possibly indicating tachyzoite resistance to atovaquone.

Junctional adhesion molecules (JAM)-B and -C contribute to leukocyte extravasation to the skin and mediate cutaneous inflammation.

Leukocyte extravasation is a finely tuned process, in which transmigration is the final step. Transmigration depends on molecules located at borders of endothelial cells; e.g., junctional adhesion molecules (JAM-A, -B and -C). In vivo blockade of JAM-A lead to decreased migration of monocytes into the skin. In contrast, the role of JAM-B and -C in development of cutaneous inflammation is unknown. We therefore elicited an allergic contact dermatitis in mice using 2,4-dinitro-1-fluorobenzene. RT-PCR and immunofluorescent staining of healthy skin revealed a constitutive JAM-B (66.4%+/-6.7% of all vessels) and -C expression (88.6+/-13.2%), which remained constant after induction of contact dermatitis. Functional studies, in which either JAM-B or -C neutralizing antibodies were injected into sensitized mice prior to allergen challenge showed a concentration-dependent reduction of the contact dermatitis. Decreased ear swelling was accompanied by reduction of leukocyte infiltration as analyzed by hematoxylin and eosin (H&E) histology and enzyme activity. Combined antibody treatment at doses of 1.25 mg per kg bodyweight lead to additive inhibition of allergic contact dermatitis, indicating that JAM-B and -C may have distinct functions. In conclusion, interactions with JAM-B and -C are essential for development of cutaneous inflammation.

Intraocular levels of methotrexate after oral low-dose treatment in chronic uveitis.

PURPOSE: To determine the intraocular levels of methotrexate in low-dose treatment of noninfectious uveitis. METHODS: One day after oral administration, the methotrexate level was measured in the aqueous humor and serum of a patient with noninfectious uveitis, who underwent cataract surgery. A fluorescence polarization immunoassay was used for determination. RESULTS: After oral administration, methotrexate was only measurable in aqueous humor but not in serum. CONCLUSION: In uveitis, orally administered low-dose methotrexate reaches detectable levels in aqueous humor, even in the absence of detectable levels in serum.

Activated, not resting, platelets increase leukocyte rolling in murine skin utilizing a distinct set of adhesion molecules.

Selectin-mediated tethering and rolling initiates the multi-step process of leukocyte extravasation which is crucial for the formation of an inflammatory infiltrate. We studied the impact of platelets on this process in the skin. Using intravital microscopy, we analyzed platelet interactions with cutaneous post-capillary venules of mouse ears and observed an increase in platelet rolling if platelets were activated (41.6+/-20.2% vs. 13.1+/-8.5% rolling of resting platelets). Experiments with P-selectin deficient mice and antibodies blocking either P-selectin, GPIIb/IIIa or GPIb showed that rolling depends on platelet PSGL-1 and GPIIb/IIIa on one hand, and endothelial P-selectin on the other. Next, formation of platelet-leukocyte aggregates was demonstrated by simultaneous observation of platelets and leukocytes in vivo utilizing a newly developed two-color technique. Aggregates increased overall leukocyte rolling (leukocytes alone: 27.4+/-11.2%, leukocytes with resting platelets: 25.3+/-10.2%, leukocytes with activated platelets 38.1+/-11.8%). To investigate if activated platelets may contribute to the pathogenesis of chronic cutaneous inflammation, platelet P-selectin expression was studied in 8 patients with psoriasis. A correlation between platelet P-selectin expression and disease severity was established. In summary, we show that activated, not resting, platelets increase leukocyte rolling in murine skin. This increased rolling is due to the aggregate formation of platelets with leukocytes. We also provide evidence for a potential role of this mechanism in the pathogenesis of chronic inflammatory skin diseases.