Urrets-Zavalia Syndrome After Combined Trabeculotomy-Trabeculectomy Surgery.

We report a case of a rare complication after trabeculotomy combined with a small trabeculectomy with mitomycin C in a young patient with juvenile glaucoma. The patient underwent uneventful surgery. However, postoperatively, he experienced a long-lasting hypotony with the need of 2 revision surgeries and 2 short episodes of high-intraocular pressure. He developed a fixed dilated pupil over time.

Ciliary body location in eyes with and without primary congenital glaucoma.

OBJECTIVE: To compare the location of ciliary body (CB) in children with and without primary congenital glaucoma (PCG). METHODS: In this cross-sectional study, we enrolled Saudi children who were less than 5 years old. CB distance (CBD) was measured and compared in eyes with PCG (PCG group) and without PCG (control group). CBD was measured with a caliper and defined as the distance between the edge of the corneoscleral limbus and the anterior edge of CB as delineated by transillumination. The difference in the CBD between groups was correlated with the axial length, corneal thickness, and corneal diameter. RESULTS: CBD was measured in 15 eyes in the PCG and control groups. The mean CBD (1.6 ± 0.4 mm) in the PCG group was significantly greater than that in the control group (1.3 ± 0.3 mm) (p < 0.001). The mean difference in the CBD of 2 groups was 0.33 mm (95% CI 0.15-0.54). In PCG eyes, the CBD was farthest in the superior quadrant (1.7 mm) followed by inferior (1.6 mm), temporal (1.6 mm), and nasal (1.5 mm) quadrants. The variability in CBD between quadrants in PCG eyes was greater than that in the control group. CBD in the PCG group showed a significant correlation with increasing axial length (p = 0.05), corneal thickness (p < 0.001), and corneal diameter (p = 0.0002). CONCLUSIONS: The CBD from the limbus was greater in PCG eyes compared to the controls and varied significantly in different quadrants. The knowledge regarding the greater CBD and its variability in PCG eyes could enable better planning of surgical treatment in congenital glaucoma.

Differences in Optic Disc Characteristics of Primary Congenital Glaucoma, Juvenile, and Adult Onset Open Angle Glaucoma Patients.

OBJECTIVE: To comparatively evaluate morphometric features of the optic discs of primary congenital glaucoma (PCG), juvenile onset primary open angle glaucoma (JOAG), and adult onset primary open angle glaucoma (POAG) using scanning laser ophthalmoscopy (HRT3). METHODS: Optic discs of previously treated 89 PCG, 136 JOAG, and 139 adult onset POAG patients, were evaluated. One eye of each patient was analyzed in the study.The optic disc characteristics studied included disc area, cup area, rim area, cup depth, cup volume, cup to disc area ratio, horizontal cup to disc ratio, vertical cup to disc ratio, and mean retinal nerve fiber layer (RNFL). A regression analysis was performed to assess the effect of age, sex, and disc area on the disc characteristics in the 3 categories of primary glaucomas. RESULTS: Mean disc area of PCG, JOAG and POAG eyes was 2.58±0.75, 2.61±0.51, and 2.44±0.58 mm, respectively. The cup characteristics that demonstrated significantly greater means among JOAG compared with POAG and PCG eyes, included cup depth (P=0.001), cup volume (P=0.024), and cup to disc area ratio (P=0.049). The mean horizontal cup to disc ratio=0.73 was greater than mean vertical cup to disc ratio=0.61 (P=0.026) among PCG eyes as well as among JOAG eyes (P=0.001). For POAG, the mean horizontal cup to disc ratio=0.73 was not different from the mean vertical cup to disc ratio=0.69 (P=0.077). CONCLUSIONS: The optic discs of juvenile onset open angle glaucoma tend to be larger in size than adult onset POAG discs. A 3-dimensional enlargement of the cup is seen among treated JOAG discs compared with POAG and PCG eyes. The greater horizontal cup disc ratio in PCG and JOAG compared with POAG eyes indicates a concentric enlargement of the cup in these patients.

LRP2 Acts as SHH Clearance Receptor to Protect the Retinal Margin from Mitogenic Stimuli.

During forebrain development, LRP2 promotes morphogen signaling as an auxiliary SHH receptor. However, in the developing retina, LRP2 assumes the opposing function, mediating endocytic clearance of SHH and antagonizing morphogen action. LRP2-mediated clearance prevents spread of SHH activity from the central retina into the retinal margin to protect quiescent progenitor cells in this niche from mitogenic stimuli. Loss of LRP2 in mice increases the sensitivity of the retinal margin for SHH, causing expansion of the retinal progenitor cell pool and hyperproliferation of this tissue. Our findings document the ability of LRP2 to act, in a context-dependent manner, as activator or inhibitor of the SHH pathway. Our current findings uncovered LRP2 activity as the molecular mechanism imposing quiescence of the retinal margin in the mammalian eye and suggest SHH-induced proliferation of the retinal margin as cause of the large eye phenotype observed in mouse models and patients with LRP2 defects.

Dystrophic hyaloid artery remnants and other abnormalities in a buphthalmic eye with retinoblastoma.

Partial persistence of the hyaloid artery unaccompanied by hyperplastic primary vitreous has not been previously reported in association with retinoblastoma. We describe an 18-month-old child with such a finding who had a retinoblastoma that was undifferentiated, extensively necrotic, heavily calcified, and completely filled the eyeball. The enucleated globe harbored a nonperfused, fossilized remnant of the hyaloid artery due to DNA/calcium deposition in the vascular wall. This structure inserted into a lenticular, extracapsular, fibrous plaque corresponding to a Mittendorf dot. The tumor had induced a placoid cataractous lens, obliterated the anterior and posterior chambers, caused glaucoma leading to buphthalmos, and extended into the optic nerve and extraocularly to involve the orbit. We conclude that the retinoblastoma arose early in ocular morphogenesis, at around 4 months gestation, when the programmed involution of the hyaloid artery begins. This process would typically end at 7-8 months gestation, but was aborted by the tumor. The patient died 6 weeks after surgery without receiving further treatment because of the parents' resistance.

The location of sites and effect of semiconductor diode trans-scleral cyclophotocoagulation on the buphthalmic equine globe.

PURPOSE: To determine appropriate location and energy settings for trans-scleral cyclophotocoagulation (TSCPC) for buphthalmic equine globes. ANIMALS: Eleven horses with a buphthalmic eye blinded by glaucoma presented for enucleation. METHODS: Globe and corneal dimensions were measured via ultrasonography and calipers, and TSCPC was performed under general anesthesia immediately prior to enucleation. Part 1: In nine globes, sixty sites were lasered 4 mm posterior to the limbus in the dorsotemporal and ventrotemporal quadrants at settings of 1500 milliwatts and 1500 ms. Globes were processed and sectioned sagitally over the temporal aspect in two blocks, each with five histologic sections examined by light microscopy. A digital imaging system was used to determine the location and length of the pars plicata on one slide from each block. Part 2: Based on results in Part 1, two globes were measured and lasered using the same time and energy settings at the following distances posterior to the limbus: 8 mm dorsally, 6 mm dorsotemporally, 5 mm ventrotemporally, and 5 mm ventrally. RESULTS: Globe and corneal dimensions exceeded normal values in all globes. Part 1: In all nine globes, photocoagulation affected the anterior ciliary processes and iris base and in 8/9 coagulation of the pectinate ligaments was noted. Part 2: In both globes, coagulation was confined to the pars plicata. CONCLUSIONS: The previously recommended TSCPC sites are located too far anteriorly for a buphthalmic globe. Buphthalmic equine globes should have TSCPC performed at the following distances posterior to the limbus: 6-8 mm dorsally, 5-6 mm dorsotemporally, 4-5 mm ventrotemporally, and 4-5 mm ventrally.

Markedly asymmetric buphthalmos but without anisometropia in a girl with primary congenital glaucoma.

Amblyogenic anisometropia is common in children with primary congenital glaucoma who have asymmetric buphthalmos. We report the case of a 6-year-old girl with markedly asymmetric buphthalmos but without anisometropia. Biometry confirmed that the more buphthalmic eye was longer than the contralateral eye and also had flatter keratometry.

Corneal changes assessed using confocal microscopy in patients with unilateral buphthalmos.

PURPOSE: To compare corneal structures in buphthalmic eyes and healthy eyes in patients with unilateral congenital glaucoma using a corneal confocal microscope. METHODS: Ten patients with unilateral buphthalmos (mean ± SD age, 14.85 ± 5.12 years) were examined using corneal confocal microscopy. The cell density and cell area of endothelial cells and superficial and basal epithelial cells and the number of keratocytes were evaluated. RESULTS: There was no significant difference between the cell density of superficial epithelial cells in buphthalmic eyes relative to healthy eyes (P = 0.1944). The cell density of basal epithelial cells was significantly higher (P = 0.0234) and the cell area was significantly smaller (P = 0.0181) in buphthalmic eyes relative to healthy eyes. There was no difference between the number of keratocytes in buphthalmic eyes and healthy eyes in the anterior stroma (P = 0.273) or in the posterior stroma (P = 0.0799). The cell density of endothelial cells was significantly lower and the cell area was significantly larger in buphthalmic eyes relative to healthy eyes (P = 0.0009). CONCLUSIONS: We demonstrated a lower cell density of endothelial cells in buphthalmic eyes. We found no differences in keratocyte density between the buphthalmic eyes and healthy eyes. The cell density of basal epithelial cells was higher in buphthalmic eyes. These differences could be due to buphthalmos or due to the previous surgical and medical therapies. Monitoring of these changes could help to contribute to accurate assessments regarding future ocular surgical procedures.

Bilateral buphthalmia in a 4-month-old Texas longhorn steer.

Congenital ocular disease occurs uncommonly in cattle, with multiple abnormalities reported only sporadically in the literature. This report describes a case of anterior segment dysgenesis resulting in glaucoma in a 4-month-old Texas Longhorn steer. On clinical exam, bilateral buphthalmia was present and intraocular pressures exceeded 47 mm Hg in both eyes. On histopathologic examination, the iridocorneal angle and filtration apparatus were distorted due to collapse of the ciliary cleft and anterior displacement of the anterior portion of the ciliary body. No evidence of inflammation or other causes of glaucoma were recognized.

Flt1 and Flk1 mediate regulation of intraocular pressure and their double heterozygosity causes the buphthalmia in mice.

Flt1 and Flk1 are receptor tyrosine kinases for vascular endothelial growth factor-A which play a crucial role in physiological and pathological angiogenesis. To study genetic interaction between the Flt1 and Flk1 genes, we crossed between Flt1 and Flk1 heterozygous (Flt1(+/-) and Flk1(+/-)) mice. We found that Flt1; Flk1 double heterozygous (Flt1(+/-); Flk1(+/-)) mice showed enlarged eyes similar to the buphthalmia detected in human congenital glaucoma with elevation of intraocular pressure (IOP). Actually, IOP was elevated in Flt1(+/-); Flk1(+/-) mice and also in Flt1 or Flk1 single heterozygous mice. However, none of these mutants showed hallmarks of glaucoma such as ganglion cell death and excavation of optic disc. To clarify the pathological causes for enlarged eyes and elevated IOP, we investigate the mice from matings between Flt1(+/-) and Flk1(+/-) mice. Flt1(+/-) mice showed enlarged Schlemm's canal and disordered collagen fibers in the sclera, whereas Flk1(+/-) mice showed atrophied choriocapillaris in the choroid. These tissues are a part of the main outflow and alternative uveoscleral outflow pathway of the aqueous humor, suggesting that these pathological changes found in Flt1(+/-) and Flk1(+/-) mice are associated with the buphthalmia in Flt1(+/-); Flk1(+/-) mice.

The retinal nerve fibre layer thickness in glaucomatous hydrophthalmic eyes assessed by scanning laser polarimetry with variable corneal compensation in comparison with age-matched healthy children.

PURPOSE: To compare the thickness of the retinal nerve fibre layer (RNFL) in hydrophthalmic glaucomatous eyes in children with age-matched healthy controls using scanning laser polarimetry with variable corneal compensation (GDxVCC). METHODS: Twenty hydrophthalmic eyes of 20 patients with the mean age of 10.64 ± 3.02 years being treated for congenital or infantile glaucoma were included in the analysis. Evaluation of RNFL thickness measured by GDxVCC in standard Temporal-Superior-Nasal-Inferior-Temporal (TSNIT) parameters was performed. The results were compared to TSNIT values of an age-matched control group of 120 healthy children published recently as referential values. The correlation between horizontal corneal diameter and RNFL thickness in hydrophthalmic eyes was also investigated. RESULTS: The mean ± SD values in TSNIT Average, Superior Average, Inferior Average and TSNIT SD in hydrophthalmic eyes were 52.3 ± 11.4, 59.7 ± 17.1, 62.0 ± 15.6 and 20.0 ± 7.8 µm, respectively. All these values were significantly lower compared to referential TSNIT parameters of age-matched healthy eyes (p = 0.021, p = 0.001, p = 0.003 and p = 0.018, respectively). A substantial number of hydrophthalmic eyes laid below the level of 5% probability of normality in respective TSNIT parameters: 30% of the eyes in TSNIT average, 50% of the eyes in superior average, 30% of the eyes in inferior average and 45% of the eyes in TSNIT SD. No significant correlation between enlarged corneal diameter and RNFL thickness was found. CONCLUSIONS: The mean values of all standard TSNIT parameters assessed using GDxVCC in hydrophthalmic glaucomatous eyes in children were significantly lower in comparison with referential values of healthy age-matched children.

Retinal proliferation response in the buphthalmic zebrafish, bugeye.

The zebrafish retina regenerates in response to acute retinal lesions, replacing damaged neurons with new neurons. In this study we test the hypothesis that chronic stress to inner retinal neurons also triggers a retinal regeneration response in the bugeye zebrafish. Mutations in the lrp2 gene in zebrafish are associated with a progressive eye phenotype (bugeye) that models several risk factors for human glaucoma including buphthalmos (enlarged eyes), elevated intraocular pressure (IOP), and upregulation of genes related to retinal ganglion cell pathology. The retinas of adult bugeye zebrafish showed high rates of ongoing proliferation which resulted in the production of a small number of new retinal neurons, particularly photoreceptors. A marker of mechanical cell stress, Hsp27, was strongly expressed in inner retinal neurons and glia of bugeye retinas. The more enlarged eyes of individual bugeye zebrafish showed disrupted retinal lamination, and a persistent reduced density of neurons in the ganglion cell layer (GCL), although total numbers of GCL neurons were higher than in control eyes. Despite the presence of a proliferative response to damage, the adult bugeye zebrafish remained behaviorally blind. These findings suggest the existence of an unsuccessful regenerative response to a persistent pathological condition in the bugeye zebrafish.

CYP1B1-related anterior segment developmental anomalies novel mutations for infantile glaucoma and von Hippel's ulcer revisited.

PURPOSE: To determine the prevalence of CYP1B1 mutations in a cohort of patients with congenital corneal opacification (CCO), infantile glaucoma, or both and to describe a developmental CCO associated with CYP1B1 mutation that may explain von Hippel's original description of an internal ulcer. DESIGN: Retrospective genotyping of a cohort of patients with infantile glaucoma and CCO. PARTICIPANTS: Thirty-three patients with CCO, infantile glaucoma, or both. METHODS: All patients underwent a full clinical evaluation with or without examination under anesthetic including anterior segment photography, ultrasound biomicroscopy (for CCO patients; n = 22), and histopathologic analysis in patients in whom penetrating keratoplasty (PK) was performed (n = 10). Patient DNA and DNA from 50 normal control individuals who had undergone a full ophthalmologic examination were screened for CYP1B1 mutations. MAIN OUTCOME MEASURES: Classification of the developmental corneal opacity phenotype in infantile glaucoma patients with CYP1B1 mutations. RESULTS: Nine distinct pathogenic recessive CYP1B1 mutations were found in 11 patients from 6 unrelated families, including 1 patient with an entire deletion of the CYP1B1 gene. Two of these patients, including the patient with the deletion, had isolated infantile congenital glaucoma with no other abnormalities. No CYP1B1 mutations were found in another 13 patients (7 of whom underwent PK in at least 1 eye) who had CCO with iridocorneal or keratolenticular adhesions (Peters' anomaly types I and II, respectively). Eight further children with CYP1B1 mutations who had CCO from birth and glaucoma underwent successful glaucoma treatment but had persistent diffuse CCO without iridocorneal or keratolenticular adhesions. Three of these underwent bilateral PK, and the histologic results were not consistent with any hitherto recognized congenital corneal dystrophy and showed abnormalities of the central corneal endothelium. CONCLUSIONS: Both severe CCO and isolated infantile glaucoma are associated with CYP1B1 mutations. The severe CCO phenotype reported herein often requires PK and has typical histopathologic changes. The mutations associated with this phenotype have not been reported previously. This phenotype may explain the patient described by Von Hippel in 1897.

Genotype/phenotype correlation in primary congenital glaucoma patients from different ethnic groups of the Israeli population.

PURPOSE: To investigate the roles of CYP1B1 and MYOC mutations and characterize the phenotype of primary congenital glaucoma in Israeli patients from 3 different ethnic backgrounds. DESIGN: Interventional case series. METHODS: This institutional study included 34 Israeli primary congenital glaucoma patients (26 families) comprising 9 Jews (9 families), 17 non-Bedouin Muslim Arabs (10 families), and 8 Druze (7 families). The patients and their relatives (n = 99) were screened for CYP1B1 and MYOC mutations. RESULTS: Mutations in the CYP1B1 gene were detected in 12 of 26 families (46%) with primary congenital glaucoma (5 Muslim Arab, 5 Druze, and 2 Jewish). The Jewish families had compound heterozygous mutations and digenic mutations (ie, an Ashkenazi family had mutations in the CYP1B1 gene [Arg368His, R48G, A119S, and L432V haplotypes] and an Ashkenazi-Sephardic family had a mutation on the CYP1B1 gene [1908delA, Sephardic] with a second missense mutation on the MYOC gene [R76K, Ashkenazi]). The Muslim Arabs and Druze tended to have a more severe phenotype than that of the Jews. CONCLUSION: The phenotype and spectrum of the CYP1B1 and MYOC mutation roles in the clinical characteristics of primary congenital glaucoma varied according to ethnicity. The rarity of mutations in the CYP1B1 gene among Ashkenazi primary congenital glaucoma patients indicates that a different locus may be involved in the phenotype.

Anterior segment alterations and comparative aqueous humor proteomics in the buphthalmic rabbit (an American Ophthalmological Society thesis).

PURPOSE: To use an integrated proteohistologic approach to gain insight into the anterior segment alterations in the buphthalmic rabbit. METHODS: Eyes from 2- and 5-year-old buphthalmic and normal rabbits (n=20) were studied histologically. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) of aqueous humor (AH) was used to determine differential protein expression between animal groups. Western blot and immunohistochemistry were performed on selected differentially expressed proteins identified by LC-MS/MS. RESULTS: The buphthalmic rabbits manifested a mild clinical phenotype with typical angle anomalies that appeared progressive by histology. Significantly thickened Descemet's membrane (DM) and anterior lens capsule in all buphthalmic rabbits showed increased fibronectin and collagen-IV immunolabeling. LC-MS/MS applying stringent filtering criteria revealed significant differential expression of several AH proteins in these rabbits. The protein of interest in the 2-year-old group was histidine-rich glycoprotein, and those in the 5-year-old group included alpha-2-HS-glycoprotein, clusterin, apolipoprotein E, interphotoreceptor retinoid-binding protein, transthyretin, cochlin, gelsolin, haptoglobin, hemopexin, and beta-2 microglobulin. The proteomic data for selected proteins was validated by Western blot and immunohistochemistry. A wide range of functional groups were affected by the altered AH proteins. These included extracellular matrix modulation, regulation of apoptosis, oxidative stress, and protein transport. CONCLUSIONS: Multiple anterior segment alterations were histologically identified in the buphthalmic rabbits that showed progressive changes with age. The differentially expressed AH proteins in these rabbits suggest a multifunctional role for AH in modulating pathologic changes in DM, anterior lens capsule, and the angular meshwork in these animals.

Some clinical findings at presentation can predict high-risk pathology features in unilateral retinoblastoma.

AIMS: To identify clinical features at presentation to help in detecting patients with retinoblastoma and pathology risk factors (PRFs) preoperatively, and therefore selecting a high-risk population that could benefit from preoperative treatment. METHODS: A retrospective analysis of a prospectively filled form of 182 consecutive patients with unilateral retinoblastoma treated with initial enucleation from 1988 to 2006. Univariate and multivariate analyses were carried out. Major choroidal invasion and postlaminar optic nerve and scleral extension were considered PRFs. Within this subgroup, a higher-risk cohort (microscopical residual disease caused by trans-scleral invasion or invasion to the resection margin of the optic nerve) was analyzed separately. RESULTS: One hundred sixty-four patients had completely resected and 18 had microscopical residual disease. Seventy three had at least 1 PRF (massive invasion to the choroid in 25, to the postlaminar optic nerve in 41, intrascleral in 10, to the resection margin of the optic nerve in 12, and trans-scleral in 6). Seventy-one patients had glaucoma and 19 had buphthalmia. Intraocular pressure, glaucoma, and buphthalmia correlated significantly with the occurrence of both PRF and microscopical residual disease in multivariate analysis. Buphthalmia was the most specific factor but the sensitivity was lower. Glaucoma and buphthalmia had a high negative predictive value. CONCLUSIONS: Patients presenting with glaucoma and/or buphthalmia have a significantly higher risk for the occurrence of PRF, including those resulting in microscopically residual disease.

[Eye growth in children with primary congenital glaucoma after trabeculectomy]. / Rozwój galki ocznej u dzieci z pierwotna jaskra wrodzona po trabekulektomii.

PURPOSE: Evaluation of the influence of intraocular pressure (IOP) after trabeculectomy on the axial length and refraction of eyeballs in children with primary congenital glaucoma. MATERIAL AND METHODS: Thirty six eyes of 23 children at the age from 7 days to 6.5 years (mean 17.1 months), were examined. Measurements of corneal diameter, axial length, IOP and refraction were done before trabeculectomy and in the long-term follow-up (mean 7.9 years) after surgery. RESULTS: Horizontal corneal diameter didn't change and ranged from 10 to 15 mm, mean 13.22 mm. Mean value of axial length before trabeculectomy was 22.45 mm and 23.27 mm at last visit. The difference was statistically significant. The axis decreased in 3 eyes, was the same in 3 eyes. In the others the eye growth changed proportionally to the age of child. IOP values were statistically lower after surgery (mean 16 mmHg) than before treatment (mean 35.51 mmHg). There was no correlation between IOP and axial length of eyeballs (p = 0.69) and between IOP and refraction changes (p = 0.42) in the long-term follow-up. CONCLUSIONS: There is small influence of normalised IOP after trabeculectomy on size of eyeballs and refraction in children with primary congenital glaucoma. The development of eyeballs even buphthalmic is proportionally to the age.

Enlargement of the globe with ocular malformations in c-Myc transgenic mice.

PURPOSE: To study the ocular development in transgenic mice carrying the mouse c-myc gene under the control of the Mx gene promoter (Mx-c-myc). METHODS: Transgenic mice were generated by standard techniques. For histological studies, the tissues were fixed with 10% buffered formalin, embedded in paraffin according to the standard procedure and sliced in 4-microm sections. c-Myc expression was investigated by reverse transcriptase-polymerase chain reaction and Southern blot analysis. RESULTS: A line of the Mx-c-myc mice displayed progressive enlargement of the globe with other ocular malformations. Histologically, the enlarged eyes exhibited closed cornea-iris angle, microphakia, corneal epithelial disorders, and attenuation of the inner retinal layers. Developmental analysis of eyes from these Mx-c-myc mice revealed irregular development of the iris and ciliary body at embryonic day 15.5 and the closed angle at 1 week of age. Leaky exogenous c-myc expression was detected in cornea, iris, lens, and retina from the Mx-c-myc mice by reverse transcriptase-polymerase chain reaction and Southern blot analysis. No other developmental abnormalities were observed in the Mx-c-myc mice. The anterior segment of the enlarged eyes showed the closed angle with elongation of the iris and ciliary body. There was no attenuation in the outer retinal layers from the outer plexiform layer to the retinal pigment epithelium. CONCLUSIONS: We conclude that the buphthalmos and accompanying changes were not due to expression of the exogenous c-myc in cornea and retina but may be the secondary changes of elevated intraocular pressure. We suggest that Mx-c-myc mice can serve as a useful model for investigating the development of the anterior segment and the genesis of buphthalmos.