Determination of iris thickness development in children using swept-source anterior-segment optical coherence tomography.

PURPOSE: The uvea comprises the iris, ciliary body, and choroid. However, the development of the anterior part (iris and ciliary body) in children is not yet fully elucidated. We investigated the iris thickness (IT) in children using swept-source anterior-segment optical coherence tomography (ASOCT). METHODS: In this retrospective, clinic-based study, we enrolled 41 children (mean ± standard deviation: 6.8 ± 3.3 years; range: 3-16; 17 males) with normal or mild refractive error. Horizontal scanning images of swept-source ASOCT were analyzed in temporal and nasal angle areas. The ITs at 1 and 2 mm from the pupil edge were measured using swept-source ASOCT. The association between IT and age, sex, and ocular morphological parameters (i.e., axial length, average corneal curvature, central corneal thickness, inter-scleral spur distance, and anterior chamber depth) was assessed using Pearson's correlation coefficient (r) and linear regression analysis. RESULTS: The average IT (temporal and nasal) at 1 and 2 mm were 0.432 ± 0.060 (0.302-0.569 mm) and 0.337 ± 0.045 (0.229-0.414 mm), respectively. There was a significant correlation between age and average IT (r = 0.45, P = 0.002 at 1 mm and r = 0.31, P = 0.042 at 2 mm). Multiple linear regression analysis revealed that age (coefficient: 0.01), axial length (-0.02), average corneal curvature (0.01), and anterior chamber depth (0.01) at 1 mm as well as age (0.00), average corneal curvature (0.09), anterior chamber depth (0.06), and male (-0.02) at 2 mm were identified as predictors of IT. CONCLUSIONS: IT in children increases with age. Additionally, IT was thinner with longer axial length and in males, thicker in eyes with deeper anterior chamber and flatter corneal curvature. Our study may partly explain the development of eyeball structures in children.

Difference of uveal parameters between the acute primary angle closure eyes and the fellow eyes.

PURPOSE: To measure the anterior and posterior ocular biometric characteristics concurrently and to explore the relationship between iris, ciliary body and choroid in acute primary angle closure eyes (APAC) and fellow eyes. METHODS: It is a prospective, cross-sectional study. Thirty patients with recent APAC were finally enroled in it. Anterior and posterior uveal parameters were measured simultaneously by anterior segment optical coherence tomography (AS-OCT), swept-source optical coherence tomography (SS-OCT) and ultrasound biomicroscopy (UBM). The parameters were measured including: pupil diameter (PD); iris thickness, curvature (ICURV), area (IAREA); anterior chamber depth (ACD), width (ACW), area (ACA), volume (ACV); lens vault (LV); choroidal thickness and retinal thickness; maximum ciliary body thickness (CBTmax); ciliary body thickness at the point of the scleral spur (CBT0) and 1000 mm away (CBT1000); anterior placement of the ciliary body (APCB); and trabecular-ciliary angle (TCA). RESULTS: Compared with fellow eyes, APAC eyes had narrower anterior biometric parameters and presented with smaller anterior segment parameters (including ACD and ACW); (p < 0.01)), smaller IAREA and ICURV (p < 0.001), larger LV (p = 0.035), thinner ciliary body and less anterior ciliary process (p < 0.01). After adjustment for potential confounders (axial length, spherical equivalent and PD), APCB was positive correlated with choroidal thickness and CBT, and CBT was positive correlated with choroidal thickness. CONCLUSIONS: Compared with fellow eyes, APAC eyes had narrower anterior biometric parameters, thinner ciliary body and smaller iris area and curvature. APCB, CBT and choroidal thickness were positively correlated. However, further studies are required before these conclusions are generalised.

A Novel Uveolymphatic Drainage Pathway-Possible New Target for Glaucoma Treatment.

Glaucoma is a heterogeneous group of ophthalmic diseases leading to irreversible damage to the optic nerve. While the overall mechanism responsible for glaucoma remains obscure, the most important risk factor is elevated intraocular pressure. The current therapies, whether pharmacological or surgical, are primarily symptomatic with the aim to lower the intraocular pressure (IOP). Poorer response to treatment is associated, for example, with pseudoexfoliation glaucoma, which is determined by blocking the trabecular meshwork (TM) both by pigment grains and the pseudoexfoliation material. It was thought that aqueous humor is drained from the eye by two main pathways: conventional outflow through the TM and Schlemm's canal; and unconventional outflow through the ciliary body through uveal tissue. In 2009 Yucel et al. described and proved the presence of a third pathway for aqueous humor drainage using two specific lymphatic markers: podoplanin, and lymphatic vessel endothelial hyaluronan receptor-1 to identify lymphatic channels in the human ciliary body. The discovery identifies a novel target for IOP-lowering therapies. The most promising group are prostaglandins, which are widely prescribed for glaucoma patients. An intriguing new possibility in glaucoma therapy is using ANGPT agonist. It is still not known if the lymphatic drainage in glaucoma is decreased or dysfunctional and whether lymphatic stimulation can help in removing the improperly accumulated substances, as is seen in pseudoexfoliation glaucoma. However, this new target for glaucoma treatment appears very promising.

Protein Tyrosine Phosphatase 4A3 (PTP4A3) Promotes Human Uveal Melanoma Aggressiveness Through Membrane Accumulation of Matrix Metalloproteinase 14 (MMP14).

PURPOSE: To study PTP4A3 phosphatase and MMP14 metalloprotease synergy in uveal melanoma aggressiveness. METHODS: Cell membrane localization of matrix metalloprotease 14 (MMP14) in uveal melanoma cells expressing protein tyrosine phosphatase A3 (PTP4A3) was assessed by flow cytometry or immunohistochemistry. The vesicular trafficking of MMP14 in the presence of PTP4A3 was evaluated in OCM-1 cells expressing either the wild-type or mutated phosphatase. Finally, MMP14 localization at the cell membrane of OCM-1 cells was impaired using RNA interference, and the PTP4A3-related migration in vitro and invasiveness in vivo of the treated cells were evaluated. RESULTS: We found that the membrane-anchored MMP14 is enriched at the cell surface of OCM-1 cells, patient-derived xenograft cells, and human primary uveal melanoma tumors expressing PTP4A3. Moreover, we show that PTP4A3 and MMP14 colocalize and that the vesicular trafficking of MMP14 is faster in the presence of active PTP4A3. Finally, we demonstrate that inhibition of MMP14 expression in uveal melanoma cells expressing PTP4A3 impairs their migration in vitro and invasiveness in vivo. CONCLUSIONS: Our observations indicate that PTP4A3 increases cell membrane accumulation of MMP14 as a result of increased cellular trafficking of the metalloprotease. We also show that downregulation of MMP14 expression reduced PTP4A3-induced cell migration and invasiveness. Taken together, our findings suggest that PTP4A3-related subcellular localization of MMP14 is an important event in metastasis induction.

Ocular inflammation in uveal tract in aged obese type 2 diabetic rats (Spontaneously Diabetic Torii fatty rats).

We report uveitis observed in an obese type 2 diabetes rat model, Spontaneously Diabetic Torii Lepr(fa) (SDT fatty) rats aged over 50 weeks. The eyes of SDT fatty rats (16 animals: 7 males and 9 females with 50 or 60 weeks of age) were examined histopathologically. Infiltration of inflammatory cells in the uveal tract was observed in 13 of 16 animals. One female showed severe inflammation affecting the entire uveal tract including the iris, ciliary body, and choroid with a variety of inflammatory cells (neutrophils, lymphocytes, and macrophages). Those changes clinically mimic the findings of diabetic iridocyclitis in diabetic patients. Uveitis associated with diabetes can occur in diabetic patients but the pathogenesis still remains unknown. Since increased extramedullary hematopoiesis in the spleen and abscess in the genital and lower urinary tracts were observed in some SDT fatty rats, increased susceptibility to infection, prolongation of inflammatory states, and disorders of the immune system were considered to be possible factors of the uveitis in aged SDT fatty rats. There have been few reports on how diabetes has influence on the development of uveitis associated with bacterial infection. The SDT fatty rat can be an animal model to investigate diabetes-associated uveitis.

[Functional morphology of the outflow pathways of aqueous humor and their changes in open angle glaucoma]. / Funktionelle Morphologie der Abflusswege des Kammerwassers und ihre Veränderungen beim Offenwinkelglaukom.

Aqueous humor exits the eye through the trabecular and uveoscleral outflow pathways. Under normal conditions intraocular pressure is maintained in the trabecular outflow pathways in which aqueous humor passes through the trabecular meshwork into Schlemm's canal. Intraocular pressure is generated through an outflow resistance in the juxtacanalicular region which consists of juxtacanalicular tissue and the inner wall endothelium of Schlemm's canal. The resistance of this region is under the influence of two contractile systems, the anterior longitudinal portion of the ciliary muscle and the contractile myofibroblast-like cells in the trabecular outflow pathways. Resistance is lowered through contraction of the ciliary muscle or relaxation of the contractile cells in the trabecular outflow pathways. In primary open angle glaucoma, resistance in the juxtacanalicular region is abnormally high. The cause of the increase is related to an increased activity in transforming growth factor beta and connective tissue growth factor signaling. The cells of the trabecular meshwork outflow pathways are stimulated to form a stronger contractile phenotype involving both an increase in the actin cytoskeleton and the surrounding fibrillar extracellular matrix. As a result there is an increase in cellular tone in the trabecular outflow pathways leading to an increase in rigidity and outflow resistance.

[Medication assisted activation of unveoscleral outflow of intraocular fluid in glaucoma: pathogenic aspects].

The article provides an overview of the main groups of IOP-lowering drugs which activate uveoscleral outflow in glaucoma and this activation is a key component of mechanism of action of these drugs. The issues related to the change of tone of ciliary muscle and its participation in uveoscleral outflow, and also relationship of accommodation and aqueous flow in glaucoma pathogenesis and possible pharmacological effects of these processes are being discussed.

Uveal and capsular biocompatibility of two foldable acrylic intraocular lenses in patients with endogenous uveitis--a prospective randomized study.

BACKGROUND: To compare a hydrophobic and a hydrophilic acrylic single-piece intraocular lens (IOL) in uveitis patients with respect to biocompatibility and visual outcome. METHODS: Prospective, randomized study in patients with noninfectious uveitis after phacoemulsification and implantation of either a hydrophobic AcrySof (group 1, n = 30) or a hydrophilic Akreos adapt (group 2, n = 30), sharp-edged acrylic IOL. The primary outcome was uveal biocompatibility, detected by giant-cell deposition, anterior chamber cell count and laserflare photometry over a 6-month follow-up period. Secondary outcome measures were capsular biocompatibility, as detected by posterior capsule opacification (PCO), lens epithelial cell outgrowth and Nd:YAG capsulotomies, and visual outcome. RESULTS: The groups did not differ with respect to anatomic type of uveitis, immunosuppressive treatment, associated systemic disease, and intraoperative manipulation. The number of giant cells on the anterior IOL surface was higher in group 1 than in group 2 (p = 0.03). The number of anterior chamber cells, laser flare photometry levels, and uveitis reactivations after surgery did not differ between the groups. After 6 months, the number of patients with PCO development (p = 1.0) and Nd:YAG capsulotomies (p = 0.21), lens epithelial cell outgrowth, visual outcome and uveitis complications were comparable in both groups. CONCLUSIONS: Both of the acrylic IOLs used had good uveal and capsular biocompatibility, leading to significant improvement in BCVA in patients with noninfectious uveitis. No obvious differences were detected at 6 months with respect to uveal and capsular biocompatibility and visual outcome.

Involvement of CCR5 in the passage of Th1-type cells across the blood-retina barrier in experimental autoimmune uveitis.

Although the recruitment of T helper cell type 1 (Th1)/Th2 cells into peripheral tissues is essential for inflammation and the host response to infection, the traffic signals that enable the distinct positioning of Th1/Th2 cells are unclear. We have determined the role of CC chemokine receptor 5 (CCR5) in this using experimental autoimmune uveitis (EAU) as a model system. In EAU, Th1-like cells are preferentially recruited into the retina across the blood-retina barrier, partly as a result of expression of the adhesion molecules P-selectin glycoprotein ligand 1 and lymphocyte function-associated antigen-1 on these cells. CD3+ T cells, infiltrating the retina, also expressed the chemokine receptor CCR5, and CCR5 ligands, macrophage-inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and regulated on activation, normal T expressed and secreted (RANTES), were strongly expressed in the retina at peak EAU. Th1-like cells, polarized in vitro, expressed high levels of CCR5. The trafficking of these CCR5+ cells was examined by tracking them after adoptive transfer in real time in vivo at an early disease stage using scanning laser ophthalmoscopy. Treatment of the cells with antibody against CCR5 prior to transfer resulted in a reduction in their infiltration into the retina. However, rolling velocity, rolling efficiency, and adherence of the cells to retinal endothelium were not reduced. CCR5 is clearly important for Th1 cell recruitment, and this study demonstrates for the first time in vivo that CCR5 may act at the level of transendothelial migration rather than at the earlier stage of rolling on the endothelium.

The mechanism of presbyopia.

Accommodation in humans refers to the ability of the lens to change shape in order to bring near objects into focus. Accommodative loss begins during childhood, with symptomatic presbyopia, or presbyopia that affects one's day to day activities, striking during midlife. While symptomatic presbyopia has traditionally been treated with reading glasses or contact lenses, a number of surgical interventions and devices are being actively developed in an attempt to restore at least some level of accommodation. This is occurring at a time when the underlying cause of presbyopia remains unknown, and even the mechanism of accommodation is occasionally debated. While Helmholtz' theory regarding the mechanism of accommodation is generally accepted with regard to broad issues, additional details continue to emerge. Age-related changes in anterior segment structures associated with accommodation have been documented, often through in vitro and/or rhesus monkey studies. A review of these findings suggests that presbyopia develops very differently in humans compared to non-human primates. Focusing on non-invasive in vivo human imaging technologies, including Scheimpflug photography and high-resolution magnetic resonance imaging (MRI), the data suggest that the human uveal tract acts as a unit in response to age-related increasing lens thickness and strongly implicates lifelong lens growth as the causal factor in the development of presbyopia.

Angle-closure glaucoma: impact, etiology, diagnosis, and treatment.

PURPOSE OF REVIEW: Recent studies underscore the importance of angle-closure glaucoma (ACG) as a cause of world blindness. A major contribution in assessing the true impact of this disease has been an article estimating the number of persons with occludable angles, angle closure, and blindness from ACG in China as 28.2 million, 9.1 million, and 1.7 million, respectively. Although these numbers are based on data from Singapore and Mongolia, which may be applied to China only with caution, they emphasize the blinding potential of ACG, which is three times as likely to be associated with blindness as open-angle glaucoma (OAG). RECENT FINDINGS: Recent reports in the Chinese literature on ACG prevalence suffer from definitional problems that would appear to lead to systematic overestimates of ACG prevalence and underestimates of OAG prevalence. Nonetheless, data from studies by Chinese investigators further emphasize the strong association between ACG and blindness, with fully 16% of subjects with ACG blind in one report-a far higher proportion than for OAG in China and elsewhere. The importance of topiramate as a cause of secondary angle closure has recently been understood, in part, because of a series of 19 such cases reported by investigators at the Food and Drug Administration. SUMMARY: Angle closure in this setting appears to be caused by uveal effusion and anterior rotation of the ciliary body with resultant closure of the angle. The condition is not always responsive to laser iridectomy, and elimination of the causative agent appears to be critical. Ultrasonic biomicroscopy is a potential new diagnostic modality for ACG, allowing the measurement of novel parameters, such as the angle opening distance (AOD) at 500 microm (AOD 500). The efficacy of such parameters in improving screening for ACG can only be established by prospective studies of potentially at-risk eyes. A number of novel treatments for AC and angle closure have recently been proposed, including cataract extraction, paracentesis, and argon laser iridoplasty. As with proposed new diagnostic modalities, the efficacy of these treatments remains to be demonstrated with prospective studies, ideally organized in a controlled, randomized fashion.

Potential mechanism for the additivity of pilocarpine and latanoprost.

PURPOSE: To determine the ocular hypotensive mechanism underlying the additivity of latanoprost and pilocarpine. METHODS: This randomized, double-masked study included 30 patients with ocular hypertension on no ocular medications for at least 3 weeks. On each of six visits to the clinic, measurements were taken of aqueous flow and outflow facility by fluorophotometry, intraocular pressure by tonometry, and episcleral venous pressure by venomanometry. Uveoscleral outflow was calculated. Clinic visits were scheduled on baseline day; on day 8 of four times daily pilocarpine (2%) to one eye and vehicle to the other; on day 8 of continued pilocarpine/vehicle treatment plus latanoprost (0.005%) once daily to both eyes; after a 3-week washout period; on day 8 of once-daily latanoprost to one eye and vehicle to the other; and on day 8 of continued latanoprost/vehicle treatment plus pilocarpine four times a day to both eyes. Drug-treated eyes were compared with contralateral vehicle-treated eyes and with baseline day by paired t tests. Combined pilocarpine and latanoprost-treated eyes were compared with individual drug-treated eyes and with baseline day using the Bonferroni test. RESULTS: Compared with baseline, pilocarpine reduced intraocular pressure from 18.9 to 16.2 mm Hg (P =.001) and increased outflow facility from 0.18 to 0.23 microl per minute per mm Hg (P =.03). No other parameters were affected. Adding latanoprost further reduced intraocular pressure to 13.7 mm Hg (P <.001) and increased uveoscleral outflow from 0.82 to 1.36 microl per minute (P =.02). Latanoprost alone reduced intraocular pressure from 17.6 to 14.3 mm Hg (P <.0001) and increased uveoscleral outflow from 0.89 to 1.25 microl per minute (P =.05). Adding pilocarpine to the latanoprost treatment further reduced intraocular pressure to 12.7 mm Hg (P <.001) and increased outflow facility from 0.21 to 0.30 microl per minute per mm Hg (P =.03). CONCLUSIONS: Latanoprost and pilocarpine predominantly increase uveoscleral outflow and outflow facility, respectively, when given alone. These drugs are additive because pilocarpine does not inhibit the uveoscleral outflow increase induced by latanoprost.

Regulation of uveal and retinal blood flow in STZ-diabetic and non-diabetic rats; involvement of nitric oxide.

PURPOSE: In experimental and human diabetes mellitus evidence for an impaired function of the vascular endothelial cells has been found. The purpose of the present experiments was to measure uveal and retinal blood flow and vascular resistance at an early stage of experimental diabetes mellitus and to evaluate the effects of acetylcholine and L-arginine in control and L-NAME-pretreated animals. METHOD: The radioactively labelled microsphere method was applied to normal Sprague-Dawley rats and rats with STZ-induced diabetes of three weeks duration. RESULTS: In the present study, similar blood flow and vascular resistance were observed in the uvea of normal and STZ-diabetic rats. Evidence for a basal vasodilating NO-tone was found both in the uvea and in the retina of both groups. In the normal rats as well as in the diabetic animals, acetylcholine induced choroidal vasodilation. Local blood flow increased from 54 +/- 17 to 142 +/- 32 mg x min(-1) in normal rats and from 57 +/- 18 to 112 +/- 23 mg x min(-1) in diabetic rats (P < 0.05 respectively). No hemodynamic changes were observed in the anterior uvea, demonstrating a difference in reactivity between these vascular beds. In animals pretreated with the NO-synthase inhibitor L-NAME, acetylcholine did not significantly affect local blood flow in the choroid, suggesting NO as a mediator of the vasodilation. CONCLUSION: The results indicate a normal action of NO in the ocular vascular beds at this stage of experimental diabetes mellitus in the rat.

[Consensual inflammatory reaction in chemical eye burn of the rabbit eye]. / Untersuchungen zur konsensuellen Entzündungsreaktion bei Verätzung des Kaninchenauges.

BACKGROUND: Consensual ocular response has been known to occur following intracranial stimulation of the trigeminal nerve, intracameral injection of prostaglandins and other substances, after paracentesis and contusio bulbi. MATERIAL AND METHOD: We have examined the prostacyclin formation in both eyes after experimental alcali burn (0.25 mo/l NaOH) on 30 rabbits with ELISA over a follow up period of 14 days. RESULTS: After the alcali burn the aqueous prostacyclin level on the right eye is increased from 327 pg/ml aqueous to 27098 pg/ml aqueous, but on the left it stays normally. In conjunctiva and anterior uvea we measured normal amounts of prostacyclin. CONCLUSIONS: We could not find a consensual increase in prostacyclin formation in the anterior part of the fellow eye following alcali burn.

[Static and dynamic infrared thermometry and thermography in malignant melanoma of the uvea and conjunctiva]. / Statische und dynamische Infrarotthermometrie und -thermographie beim malignen Melanom der Uvea und Konjunktiva.

BACKGROUND: Thermometry and -graphy prove asymmetries of the circulation. Contact-free thermometry of the cornea is applied to find out whether this method can contribute to differential diagnosis of ocular melanomas. MATERIALS AND METHODS: Under standardized conditions the temperature of the cornea was measured in 30 patients with malignant melanoma of the choroid and the conjunctiva and 35 healthy subjects. The instruments were a handpyrometer (HPM, Messgerätewerk, Magdeburg) and the thermovision camera of AGA Infrared System, Sweden, with dynamic recording in colour. RESULTS: In healthy subjects there are no significant asymmetries in temperature under standardized conditions. The temperature of the cornea is elevated in both malignant melanomas of the choroid and the conjunctiva. CONCLUSIONS: Thermometry and -graphy of the cornea can contribute to the differentiation of malignant ocular melanomas from other ophthalmological diseases. They are also suited in long term observation of the course of the melanomas.

Cataract surgery and intraocular lens implantation in patients with uveitis.

The authors reviewed the outcome of extracapsular cataract extraction (ECCE) in 44 eyes of 38 patients with uveitis. Thirty-two of the 44 eyes received a posterior chamber lens implant; 87% of these achieved a stable visual acuity of 20/40 or better. Sixty-seven percent (8 of the 12 eyes) not receiving an implant achieved this level. The authors' results and current literature suggest that absolute control, preoperatively and postoperatively, of all uveitis inflammation and careful selection of patients as lens implant candidates are crucial for successful cataract surgery in uveitis patients. Complete removal of lens cortex and placement of an all-PMMA posterior chamber lens within the capsular bag are also believed to be important.

Uveoscleral outflow using different-sized fluorescent tracers in normal and inflamed eyes.

Sodium fluorescein and fluorescinated dextrans (FD) of selected molecular weights were combined and perfused into the anterior chamber of normal and inflamed eyes of cynomolgus monkeys. The eyes were dissected into iris, anterior and posterior uvea, anterior and posterior sclera, retina and intraocular fluids (excluding aqueous). Each tissue was homogenized and centrifuged and the supernatant was run through a gel-filtration column to separate the fluorescent tracers. Each of the resultant peaks was quantitated and facility of uveoscleral outflow was determined. In control eyes the calculated facility of uveoscleral outflow was very similar with all tracers (from 0.047-to 0.052 microliter min-1 mmHg-1) and each tracer was found in highest concentration in the anterior sclera and anterior uvea. In inflamed eyes the calculated facility of uveoscleral outflow increased two- to five-fold with each tracer (0.12-; 0.17-; 0.29-; and 0.24 microliter min-1 mmHg-1 with fluorescein, and the fluorescinated dextrans of MWs 4000, 40,000 and 150,000, respectively). Each tracer was found in the anterior sclera and uvea in inflamed eyes whereas the posterior sclera and uvea contained predominantly the higher molecular-weight tracers (MWs 40,000 and 150,000). It is concluded that iridocyclitis causes an increase in uveoscleral outflow by increasing the permeability of the anterior uvea to all tracers and fluid. Small tracers may then diffuse into uveal blood vessels or across the sclera, yielding lower values for uveoscleral outflow. Of the four tracers studied, the optimal tracer size for studying uveoscleral outflow in either normal or inflamed eyes is MW 40,000.