Enzyme-induced posterior vitreous detachment in the rat produces increased lens nuclear pO2 levels.

It has been proposed that disruption of normal vitreous humor may permit O(2) to travel more easily from the retina to the center of the lens where it may cause nuclear cataract (Barbazetto, I.A., Liang, J., Chang, S., Zheng, L., Spector, A., Dillon, J.P., 2004. Oxygen tension in the rabbit lens and vitreous before and after vitrectomy. Exp. Eye Res. 78, 917-924; Harocopos, G.J., Shui, Y.B., McKinnon, M., Holekamp, N.M., Gordon, M.O., Beebe, D.C., 2004. Importance of vitreous liquefaction in age-related cataract. Invest. Ophthalmol. Vis. Sci. 45, 77-85). In the present study, we injected enzymes intravitreally into guinea pigs (which possess an avascular retina) and rats (which possess a vascular retina) to produce either vitreous humor liquefaction plus a posterior vitreous detachment (PVD) (with use of microplasmin) or vitreous humor liquefaction only (with use of hyaluronidase), and 1-2 weeks later measured lens nuclear pO(2) levels in vivo using a platinum-based fluorophore O(2) sensor (Oxford-Optronix, Ltd.). Experiments were also conducted in which the animals were allowed to breathe 100% O(2) following intravitreal injection with either microplasmin or hyaluronidase in order to investigate possible effects on O(2) exchange within the eye. Injection of guinea pigs with either of the two enzymes produced no significant differences in lens pO(2) levels 1-2 weeks later, compared to controls. However, for the rat, injection of microplasmin produced a 68% increase in O(2) level in the center of the lens, compared to the controls (5.6mm Hg increasing to 9.4mm Hg, p<0.05), with no corresponding effect observed following similar use of hyaluronidase. Treatment of guinea pigs with microplasmin dramatically accelerated movement of O(2) across the vitreal space when the animals were later allowed to breathe 100% O(2) (for example, O(2) traveled to a location directly behind the lens 5x faster than control; p<0.01); however, the effect following treatment with hyaluronidase was significantly less. When microplasmin-injected rats breathed 100% O(2), the time required for O(2) to reach the center of the lens was 3x faster than control (0.4 min compared to 1.4 min, p<0.01). The results have implication with regard to the occurrence of age-related PVD in the human, and a possible acceleration of maturity-onset nuclear cataract. In addition, enzymatic creation of a PVD to increase the rate of O(2) exchange within the vitreal space may have potential application for treatment of retinal ischemic disease.

Cosegregation of two unlinked mutant alleles in some cases of autosomal dominant familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is a bilateral, clinically and genetically heterogeneous hereditary eye disorder that affects both the retina and the vitreous body. The condition has a high degree of penetrance and variable expressivity. In some cases of autosomal dominant FEVR (AD FEVR), mutations in the frizzled-4 gene (FZD-4) have been shown to be involved in FEVR pathology. In this study, we report that a second unlinked gene (Factor V) is also mutated (Leiden mutation) in the same family, which harbors the FZD-4 gene mutation. These results show for the first time that some families with FEVR could be digenic. While this is unlikely to be a widespread problem, the occurrence of digenic disorders with apparently simple Mendelian inheritance patterns renders the current method of analysis of monogenic disorders by linkage and mutation screening incomplete.

Agreement between grating acuity at age 1 year and Snellen acuity at age 5.5 years in the preterm child. Cryotherapy for Retinopathy of Prematurity Cooperative Group.

PURPOSE: To examine the relation between grating acuity at age 1 year and Snellen acuity and grating acuity at 5.5 years, in preterm children with birth weights less than 1251 g. METHODS: Subjects were participants in the multicenter study of Cryotherapy for Retinopathy of Prematurity. The Teller acuity card (TAC; Vistech Consultants, Dayton, OH) procedure was used to measure monocular grating acuity in children at ages 1 and 5.5 years. Early-treatment diabetic retinopathy study (ETDRS) charts were used to measure the childrens' monocular recognition (Snellen) acuity at age 5.5 years. Data are presented for 575 eyes with measurable TAC grating acuity at 1 year and 111 eyes that had no measurable acuity at 1 year. RESULTS: Among eyes with normal acuity at 1 year, 86.8% showed normal Snellen acuity, and 94.3% showed normal grating acuity at 5.5 years. Among eyes that were blind (i.e., had no measurable TAC grating acuity) at 1 year, 96.8% showed no quantifiable Snellen acuity, and 89.2% showed no quantifiable grating acuity at 5.5 years. Only 2.4% of eyes had acuity in the range between normal and blind at 1 year (i.e., measurable grating acuity <1.6 cyc/deg); thus, the predictive value of acuity scores in this range could not be determined. Correlation analysis indicated that the relative position within the normal range of an eye's grating acuity score at 1 year was not predictive of the relative position within the normal range of that eye's acuity score at 5.5 years. CONCLUSIONS: Among a large population of low-birth-weight infants, eyes with normal grating acuity at age 1 year generally showed normal Snellen and grating acuity at age 5.5 years, and eyes that had no quantifiable acuity at 1 year remained blind at 5.5 years. Relative position of an eye's acuity score within the normal range was not predictive of the relative position of that eye's later acuity score.

A cell line derived from non-neoplastic human neuroretinal cells.

We have derived a cell line from an epiretinal membrane excised surgically from a premature female infant born at a gestational age of 25 weeks, and who developed stage 5 retinopathy of prematurity. The cell line, which in early passages appeared immunocytochemically to contain cells with both neuronal and glial characteristics, has been maintained in culture for 14 months at the time this manuscript was submitted, and has survived 20 passages. The cells have a diploid, human karyotype, with most cells possessing 46 normal appearing chromosomes, including 44 autosomes and two X-chromosomes. Morphologically, the cell line at early passages consisted of polygonal cells and also of cells possessing long, spindly branching processes. These two cell types were cloned. Nearly 100% of the cells of both morphologic types in mixed cultures stained immunocytochemically for neuron-specific enolase (NSE), a neuronal marker, and approximately 5-10% of the cells in mixed cultures (including about 50% of the cells with the spindly morphology, that were less prevalent in mixed cultures) stained for glial fibrillary acid protein (GFAP), a glial marker. We have not performed "double-label" immunocytochemistry, but it was evident from the proportion of cells that stained with each marker that many cells must contain both GFAP and NSE. At least 50% of the cells in most of the early cultures were positive for keratin, while all were (and remain) negative for muscle actin. No cells are found that are immunocytochemically positive for factor VIII, a vascular endothelial cell marker. These cultured cells have also been studied immunocytochemically for their production of extracellular matrix substances. The cultures are immunocytochemically positive for type IV (but not type I) collagen, laminin and fibronectin. In later passages, cells of both clones lost their immunocytochemical positivity for GFAP and NSE, and all became positive for keratin. Cells of both clones also developed a similar, polygonal morphology, lacking long processes. By electron microscopy, many of the cells were seen to possess nonmotile cilia, with a 9 + 0 pattern of microtubule doublets. This cell line may be useful for studies of human retinal cell development and metabolism, and responses to pathological processes.

Lens-sparing vitreoretinal surgery in infants.

Lensectomy is routinely performed in infant eyes undergoing vitreoretinal surgery. Using a two-port system, we performed pars plicata vitrectomy and membrane peeling without removal of the crystalline lens. Surgical manipulations were done in the postequatorial region in eyes with areas of attached peripheral retina. Eight of 10 eyes showed no evidence of postoperative cataract formation. In no instance was a peripheral retinal break created. In selected cases, vitreoretinal surgery can be performed in infant eyes without the need for lens removal.

Chorioretinal juncture. Vascularization of Bruch's membrane in peripheral fundus.

Pathologic changes in chorioretinal juncture (pigment epithelium, drusen, Bruch's membrane, and choriocapillaris) were studied in the peripheral fundus of eyes removed at autopsy and surgically enucleated eyes by gross, light microscopic, and electron microscopic methods. Vascularization of Bruch's membrane (VBM) occurred in 430 (43%) of eyes at autopsy, was age related, and was most common in the ora zone and temporal sectors; a significant correlation was found with systemic oligemic conditions. Vascularization of Bruch's membrane occurs in the inner collagenous layer of the membrane, which always demonstrates collagenous thickening and often shows intrusion of interstitial-type cells; the vessels emanate from adjacent pars plana. While many degenerative changes of the pigment epithelium accompany VBM, only direct ophthalmoscopic visualization of linear-dendritic depigmentation of overlying pigment epithelium provides diagnostic evidence of vessels. Thus, VBM seems pathogenically related to the fact that the peripheral fundus is a vascular watershed and is selectively vulnerable to senile involutional changes.

Diode laser ablation for threshold retinopathy of prematurity: short-term structural outcome.

OBJECTIVE: To describe short-term structural outcomes and associated ocular complications in premature infants treated with diode laser ablation for retinopathy of prematurity. METHODS: The records of all infants who were diagnosed as having threshold retinopathy of prematurity and treated with diode laser therapy at our hospital from January 1, 1992, through December 31, 1996, were retrospectively reviewed. Sixty-four eyes reached threshold during this period. Three eyes received cryotherapy in addition to laser treatment and were excluded, leaving 61 eyes eligible for review. RESULTS: Of the 61 eyes with threshold disease treated exclusively with diode laser, 4 (7%) had zone I disease and 57 (93%) had zone II disease at the time of initial laser treatment. Three (5%) of the 61 eyes progressed to stage 4 disease (2 eyes, stage 4A; 1 eye, stage 4B). There were no cataracts or other ocular complications noted secondary to laser treatment based on short-term follow-up (mean follow-up, 120 days). CONCLUSION: In this population of infants, diode laser ablation appears to be a safe and effective treatment for threshold retinopathy of prematurity.

Refractive changes associated with scleral buckling and division in retinopathy of prematurity.

OBJECTIVE: To examine the refractive changes that occur in infant eyes with retinopathy of prematurity (ROP) retinal detachments that are subjected to scleral buckling and subsequent division of the scleral buckle. METHODS: A retrospective medical record review of infants with ROP who were managed with an encircling scleral buckle that was subsequently divided and who underwent refraction evaluation during and after division of the scleral buckle. RESULTS: Seven eyes from 6 patients had scleral exo-plants placed for stage 4 ROP retinal detachments at a mean postconceptional age of 48 weeks. The mean refractive error in eyes with the scleral buckle was -11 diopters (D) (range, -5 to -25 D) with an induced mean anisometropia of -9.5 D. After division of the scleral buckle at a mean of 36 weeks postoperatively, the average post-scleral buckle refractive error was -5.68 D, resulting in a mean myopic reduction of 5.5 D. CONCLUSIONS: Scleral buckling in infants with ROP results in large myopic shifts, which are significantly reduced after division of the scleral buckle. This highlights the importance of repeated refraction testing in infants after placement and division of the scleral buckle to avoid refractive amblyopia.

Burkitt's lymphoma with cranial nerve involvement.

A 22-year-old white native Californian acquired multiple cranial nerve palsies. He was found to have a Burkitt's-type lymphoma involving the ethmoid and sphenoid sinuses, with orbital invasion. Bone marrow involvement developed. Despite aggressive therapy, he died 18 weeks after the onset of his illness. Poor prognostic indicators included CNS symptoms at the time of initial onset, bone marrow involvement, and postadolescent occurrence. The absence of viable tumor at autopsy indicates sensitivity of Burkitt's lymphoma cells to combination chemotherapy and irradiation treatment.

Pharmacologic induction of posterior vitreous detachment in the rabbit.

OBJECTIVE: To assay the proteolytic activity of plasmin on the vitreoretinal junction and to assess a potential facilitating effect on posterior vitreous detachment. METHODS: We injected 1 U of plasmin into the vitreous of rabbits. Some eyes underwent vitrectomy after plasmin injection. Electroretinography and electron microscopy were performed. RESULTS: In plasmin-treated eyes, electroretinography displayed a transient (3 days) decreased b-wave amplitude. Histologic examination demonstrated posterior vitreous detachment in eyes that received intravitreal plasmin followed by vitrectomy. CONCLUSION: Plasmin may prove to be a useful biochemical adjunct to mechanical vitrectomy.

Orbital embryonal rhabdomyosarcoma and intracranial schwannoma.

A 39-year-old woman had a large benign intracranial schwannoma of the Gasserian ganglion. Thirty-two years previously, she had an embryonal rhabdomyosarcoma of the orbit. She had been treated by enucleation, local excision, and low-dose supplemental irradiation (1,400 rads). This is the longest survival of which we are aware following any treatment modality in such tumors. No correlation between the two tumors has been established.

Identification of missense mutations in the Norrie disease gene associated with advanced retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity (ROP) is a retinal vascular disease occurring in infants with short gestational age and low birth weight and can lead to retinal detachment (ROP stages 4 and 5). X-linked familial exudative vitreoretinopathy is phenotypically similar to ROP and has been associated with mutations in the Norrie disease (ND) gene in some cases. OBJECTIVE: To determine if similar mutations in the ND gene may play a role in the development of advanced ROP. METHODS: Clinical examination and molecular genetic analysis were performed on 16 children, including 2 dizygotic and 1 monozygotic twin pairs, and their parents from 13 families. RESULTS: Sequencing of the amplified products revealed missense mutations (R121W and L108P) in the third exon of the ND gene in 4 patients. These mutations were not present in an unaffected premature twin, 2 children with regressed stage 3 ROP, the parents, or in 50 unrelated healthy control subjects. CONCLUSION: These findings suggest that mutations in the ND gene may play a role in the development of severe ROP in premature infants.

The incidence of corneal abnormalities in the Silicone Study. Silicone Study Report 7.

OBJECTIVE: To determine factors that were prognostic of corneal abnormalities in eyes following surgery for severe proliferative vitreoretinopathy. DESIGN: Subgroup analysis of the Silicone Study. SETTINGS: Community and university-based ophthalmology clinics. MATERIALS: Eyes with attached maculae at the 24-month follow-up examination that did not have a pre-existing corneal abnormality. INTERVENTIONS: Vitrectomy surgery with long-acting gas or silicone oil. OUTCOME MEASURES: Epithelial and/or stromal edema, corneal opacity and/or previous corneal transplant. RESULTS: The incidence of corneal abnormalities at 24 months was 27% and did not differ significantly between treatment groups. Prognostic factors were preoperative aphakia or pseudophakia (P = .003), preoperative iris neovascularization (P = .006), reoperation (P = .001), the absence of a fluid/gas exchange (P = .03), corneal touch by silicone oil (P = .02), and the presence of aqueous cells (P = .009) or aqueous flare (P = .08). In a multivariate analysis, independent prognostic factors were iris neovascularization (relative risk [RR] = 13.1), aphakia or pseudophakia (RR = 3.0), postoperative aqueous flare (RR = 5.4), and reoperations (RR = 3.4). Corneal abnormalities were correlated with poor visual acuity and hypotony (P < .001). CONCLUSIONS: To our knowledge, this is the first study to document that the incidence rates of corneal abnormalities are equivalent between oil and gas. The incidence of corneal abnormalities in gas-filled eyes was higher than expected, and remained high in oil-filled eyes, despite the use of an inferior iridectomy. Successful surgical repair of the retinal detachment with a single operation, and prevention and early management of corneal touch by silicone oil should help to prevent corneal abnormalities. If rubeosis iridis or severe aqueous flare is present, preoperative treatment with intense topical and possibly periocular steroids might reduce inflammation, which might mediate corneal damage.

A technique for suturing peripapillary radioactive plaques.

PURPOSE: To describe a technique for suturing radioactive plaques positioned posteriorly and adjacent to the optic nerve. METHODS: Posterior and juxtapapillary notched radioactive iodine-125 plaques were sutured using four 5/0 nylon sutures. Two sutures were placed in the sclera at the anterior border of the plaque position and passed through the eyelets at the anterior edge of the plaque. Two sutures were attached to the posterior eyelets and brought to either side of the optic nerve, under the rectus muscles, to be sutured to sclera anterior to the insertion of the recti muscles. The position of the plaques was documented intraoperatively using sterile B-scan ultrasonography. RESULTS: Plaques positioned and sutured using this technique were found by ultrasonography to be tight up against the sclera and optic nerve.

Vitreoretinal surgery for complications of congenital retinoschisis.

PURPOSE: To report the results of vitreoretinal surgery for the management of complications associated with congenital retinoschisis in children. METHODS: We conducted a review of consecutive children with complications of congenital retinoschisis treated with advanced vitreoretinal techniques. Nine eyes of seven patients with congenital retinoschisis had vitreoretinal surgery for one of the following complications of congenital retinoschisis: hemorrhage within a large schisis cavity with a dense vitreous hemorrhage; rapid progression of schisis threatening the macula; obscuration of the macula by the overhanging inner wall of a schisis cavity; a combined schisistraction retinal detachment; or a combined schisis-rhegmatogenous retinal detachment. Vitreoretinal surgery consisted of vitrectomy, inner schisis wall retinectomy, fluid-gas exchange, endolaser treatment, and perfluoropropane gas injection. After vitreoretinal surgery, patients were followed up for a mean of 26 months (range, 9 to 67 months). Retinal reattachment, visual acuity, and visual fields were used as outcome measures. RESULTS: Eight of nine eyes had successful retinal reattachment. Six eyes postoperatively had improved visual acuity or visual field, or both. One eye had stabilization of visual acuity, and two eyes had a decrease in visual acuity. CONCLUSION: In children with complications of congenital retinoschisis, vitreoretinal surgery with excision of the inner wall of the peripheral schisis cavity may be effective in achieving retinal reattachment, thereby improving visual acuity or visual field size.

Improved surgical treatment of familial exudative vitreoretinopathy in children.

PURPOSE: To evaluate current surgical results in patients with familial exudative vitreoretinopathy and study the histologic findings of epiretinal membranes obtained at the time of surgery. METHODS: We performed phakic pars plana vitrectomy and membrane peeling on five patients (six eyes) with familial exudative vitreoretinopathy, who ranged in age from 18 months to 9 years and had traction retinal detachment. Membranes from two eyes (two patients) were analyzed by light and electron microscopy. RESULTS: The macula was reattached in all six eyes. Visual acuity improved after surgery in five of the six eyes, with two eyes improving from a preoperative visual acuity of 20/400 to a postoperative visual acuity of 20/25 and 20/60. Electron microscopic analysis of the membranes from two patients disclosed thick fibrocellular fragments with vascular elements and astrocytes. CONCLUSION: With current surgical techniques, there appears to be improvement in the anatomic reattachment rate and visual outcome in patients with familial exudative vitreoretinopathy. Amblyopia, reproliferation, and vitreous hemorrhage may limit long-term improvement in vision.

Vitrectomy for diffuse diabetic macular edema associated with a taut premacular posterior hyaloid.

PURPOSE: To evaluate the role of vitrectomy in eyes with diffuse diabetic macular edema associated with a taut posterior hyaloid. METHODS: Records of 55 eyes of 50 patients with diabetic retinopathy and diffuse clinically significant diabetic macular edema who underwent vitrectomy with stripping of the premacular posterior hyaloid were reviewed. In all 55 eyes, diffuse diabetic macular edema was present on contact lens examination and confirmed with fluorescein angiography. On fundus examination, the premacular posterior hyaloid was attached and appeared taut. RESULTS: The mean preoperative best-corrected visual acuity was 20/160, and the mean final best-corrected visual acuity was 20/80 (P <.0001, Wilcoxon signed rank test), with 27 (49.1%) of the 55 eyes demonstrating improvement in best-corrected visual acuity of 2 or more lines. Fifty-two (94.5%) of the 55 vitrectomized eyes showed improvement in clinically significant macular edema and in 45 eyes (81.8%) the macular edema resolved completely during a mean period of 4.5 months (range, 1 to 13 months). Eyes with macular ischemia and preoperative best-corrected visual acuity of 20/200 or less tended to respond less favorably to vitrectomy than eyes lacking these characteristics. All eyes had at least 6 months of follow-up after surgery, with a mean follow-up of 23.2 months. CONCLUSION: In eyes with persistent diffuse diabetic macular edema with a taut premacular posterior hyaloid face unresponsive to laser therapy, vitrectomy with removal of the posterior hyaloid appears to be beneficial in some cases. Careful selection of eyes with favorable preoperative clinical characteristics may improve surgical outcomes.

X-linked recessive familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy is an inherited disorder characterized by retinal traction, peripheral vitreous opacities, and subretinal and intraretinal exudates. We observed a family in which four boys (the children of three sisters) were affected with this disorder and an X-linked recessive inheritance was apparent. The differential diagnosis includes retinopathy of prematurity, primary hyperplastic primary vitreous, Coats' disease, peripheral uveitis, retinoblastoma, and Norrie's disease, but this differentiation can usually be made on the basis of clinical findings alone. Knowledge of X-linked recessive transmission is important for correct diagnosis and for genetic counseling.

Infantile cystoid maculopathy.

Three premature infants with no family history of eye disease showed bilateral cystoid maculopathy on post-mortem examination. These macular lesions are indistinguishable macroscopically from the macular lesions of sex-linked juvenile retinoschisis. Cystoid change was observed at various vertical retinal levels. The oldest child had a schisis cavity within the nerve fibre layer. All cases had reduced numbers of retinal ganglion cells and central nervous system (CNS) abnormalities. The authors believe these are the first reported cases of a cystoid macular lesion present at birth and the first description of the pathological features of a cystoid macular lesion in infants.

Factor V Leiden mutation (R506Q) and the risk of advanced retinopathy of prematurity.

The coagulation factor V Leiden mutation was reported to be a significant (10.7%) risk factor for pre-term deliveries. It is also well known that a portion (10%) of very low birth weight premature babies develop advanced retinopathy of prematurity (ROP) which is a leading cause of blindness in children. However, the relationship between the Leiden mutation and development of advanced ROP is not known. In order to understand this relationship as well as genetic contribution to ROP, in this study, we have analyzed 100 pre-term infants with advanced ROP (stage 4B/5), 20 term babies with a clinically similar disease called familial exudative vitreoretinopathy (FEVR) and 16 normal babies from four different ethnic backgrounds. Our extensive analysis has identified a heterozygous Leiden mutation in four patients (4%) with advanced ROP and in one patient (5%) with sporadic FEVR. DNA sequence analysis has further confirmed this base change as well as heterozygosity. However, the frequency observed in the patients analyzed in our study is lower than reported frequency in the general population (5.4%). Therefore, statistically factor V mutation on its own is not a major risk factor for the above two disorders. However, it may be associated with other additive factors as might be expected for a complex genetic trait.