Retrolental Membrane Research Articles

Favourable outcome after cataract surgery with IOL implantation in uveitis associated with juvenile idiopathic arthritis

Management of uveitic cataract in patients with juvenile idiopathic arthritis (JIA) is challenging, and intraocular lens (IOL) implantation is controversial. This study investigated the outcome after minimally invasive surgery with IOL implantation. Retrospective analysis after phacoemulsification with in-the-bag IOL implantation was performed in 16 patients (17 operations) with ANA-positive JIA-associated chronic uveitis. In these patients, 25 G capsulectomy and anterior vitrectomy was performed and they received an intravitreal triamcinolone (TA) injection. Mean age at uveitis onset was 5 ± 2 years, and surgery was performed at a mean age of 11 ± 2.2 years. Preoperatively, uveitis was inactive in all patients, and visual acuity was logMAR 0.8 ± 0.44; additional uveitis complications were present in all patients, and 15 patients were receiving systemic immunosuppression/biologicals. After surgery (mean follow-up 26.5 ± 11.7 months), presence of cystoid macular oedema, papilloedema, ocular hypertension/glaucoma and hypotony did not increase compared with baseline. There was no significant worsening of AC inflammation (by cell numbers and laser flare values). IOL deposits persisted in four patients, and synechiae developed in eight. The visual acuity was improved (≥2 lines) in all patients (mean logMAR 0.3 ± 0.24). Retrolental membrane formation was not noted. Secondary capsular opacification was observed in seven patients, requiring Nd:YAG capsulotomy in five of them. Phacoemulsification and in-the-bag IOL implantation may improve visual outcome in JIA-associated uveitis with minimally invasive surgical technique and intravitreal TA injection. Well-controlled uveitis with appropriate use of topical steroids and systemic immunosuppression or biologicals appears as a perioperative requirement.

Histopathological study of retrolental membranes secondary to persistent hyperplastic primary vitreous

To study the pathological characteristics of retrolental membranes (RLMs) secondary to persistent hyperplastic primary vitreous (PHPV), and to discuss the possible pathogenesis of PHPV. Experimental study. Six RLMs obtained from six patients with PHPV during vitrectomy were examined by light microscopy (HE & PAS staining). All of them were observed with proliferating cell nuclear antigen (PCNA) immunostaining, together with collagen I, factor VIII related antigen, smooth muscle actin (SMA), epithelial membrane antigen (EMA), neuron specific enolase (NSE) and glial fibrillary acidic protein (GFAP) staining. Apoptosis were detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling (TUNEL). Light microscopy showed that the RLM was a dense connective tissue with numerous inflammatory cells including mast cells and lymphocytes. PAS staining showed that RLMs contained a larger amount of polysaccharides. Histopathology and immunohistochemistry showed that there were vascular channels, smooth muscle cells, nervous cells and epithelial cells scattered in RLMs. Collagen I was the main component of RLMs. PCNA-positive nuclei were widely found in RLMs. TUNEL-positive nuclei were also found in all RLMs, as well as in the posterior subcapsular epithelial cells of lens. The cell types of RLMs secondary to PHPV are similar to those of the primary vitreous. It is possible that the mechanism of the progression of RLMs is the over-development and incomplete regression of the retrolental vascular system. Inflammation may play an important role in the regression of RLMs.

Identification of a retrolental membrane during laser capsulotomy in eyes with a Hydroview intraocular lens

We report our observation of a distinct membrane on the posterior surface of the Hydroview (Bausch & Lomb Surgical) intraocular lens during laser capsulotomy in 6 patients. In 3 patients, the retrolental membrane was noted during 4 to 6 weeks of follow-up after laser capsulotomy. The technique of a 2-stage laser capsulotomy in this group of patients is described. The possible cause and significance for this observation are also discussed.

Type 1 Stickler syndrome: a histological and ultrastructural study of an untreated globe

To present a histological and ultrastructural study of an untreated globe in a patient with genetically confirmed type 1 Stickler syndrome. Histological and electron microscopic examinations were performed on the enucleated globe from the proband of a pedigree with type 1 Stickler syndrome. Linkage analysis was carried out using polymorphic markers flanking the COL2A1 gene and the mutation was identified by direct sequencing. The significant retinal abnormality was incarceration of vitreous collagen within glial strands on the inner surface of an atrophic and gliotic detached retina. The incarcerated collagenous layers contained glial cells and extended from the retina to form strands, some of which contributed to a retrolental membrane. Mutation screening detected a C to T mutation in exon 47 that inserted a premature termination codon into the reading frame of the mRNA. Sequence analysis of three of the four affected children confirmed that they were also heterozygous for the base change. The youngest child's DNA was not analysed. The study represents the first evidence of abnormal interactions between pathological vitreous collagen and the inner retina in a patient with type 1 Stickler syndrome with a confirmed mutation in the COL2A1 gene.

High Resolution Ultrasonography in Eyes with Angle-Closure Glaucoma Associated with the Cicatricial Stage of Retinopathy of Prematurity

Angle-closure glaucoma in children at the cicatricial stage of retinopathy of prematurity (ROP) has been thought to be caused by the anterior displacement of the lens-iris diaphragm resulting from contraction of a retrolental fibrous membrane. Other possible mechanisms include pupillary block and ciliary block. Three patients (three eyes) at the cicatricial stage of ROP with angle-closure glaucoma were examined by high-resolution ultrasonography before and after peripheral iridectomy. High-resolution ultrasonography preoperatively showed that the angle was closed. A retrolental fibrous membrane was attached behind the lens. After the iridectomy, ultrasonography showed an open angle, and the intraocular pressure was normal. The angle closure in our three patients was caused mainly by a pupillary block and could be treated by peripheral iridectomy.

Idiopathic Cyclitic Retrolental Membrane in Children

Cyclitic retrolental membranes (CRM) in children are usually associated with chronic uveitis or genetic syndromes. We report two rare cases of idiopathic CRM. Two girls aged 9 and 13 years with visual acuities (VA) of 0.05 underwent lensectomy and anterior vitrectomy with dissection of the central part of the retrolental membrane and intraocular lens (IOL) implantation. The clinical evolution was excellent for the 9 year old girl who recovered 1.0 VA after 2 months. Histological examination revealed a fibroelastic tissue of unknown origin without inflammatory components. The 13 year old girl showed VA of 0.6 within 1 month. However, a recurrent CRM developed with retinal detachment and proliferative vitreoretinopathy (PVR). Vitrectomy, complete excision of the CRM and 360 degrees retinotomy with silicon oil tamponade attached the retina with limited visual recovery. Histology showed fibrovascular tissue with inflammatory components infiltrating the CRM. Idiopathic CRM in children are rare and can be composed of different histological tissues with very different clinical outcomes.

Histopathology and Ultrastructure of Rabbit Retina After Intravitreous Injection of Perfluorohexyloctane (F6H8)

Purpose: To describe changes in rabbit retina after intravitreous injection of perfluorohexyloctane (F6H8). Methods: Intravitreous injections of C3F8 were performed in the right eye of 48 male New Zealand albino rabbits. All 48 eyes were injected with C3F8. The animals were divided in three groups of 18 each. 18 eyes (6 in each group) were used as controls and 30 (10 in each group) were further injected with F6H8. Animals were sacrificed at days 15, 30, and 60 and the eyes processed for light and electron microscopy and immunohistochemistry. Results: Vitreous tracts were observed behind the lens in all groups. Epiretinal and retrolental membranes developed in most of the treated eyes. Light microscopy showed retinal vacuolization in all eyes. No significant ultrastructural changes appeared in any of them. Macrophages were observed in the inner limiting membrane. Conclusions: Ultrastuctural findings can be considered signs of good tolerance to F6H8, though the appearance of epiretinal membranes associated with the presence of macrophagic response suggests we should refrain from using F6H8 until results from clinical trials are available.

Prolactin in eyes of patients with retinopathy of prematurity: implications for vascular regression.

Disruption of the anti-angiogenic environment of the retina leads to neovascular eye diseases, including retinopathy of prematurity (ROP). Prolactin (PRL), the hormone originally associated with milk secretion, is proteolytically processed to 16K-PRL, a fragment with potent antiangiogenic, proapoptotic effects. Whether 16K-PRL is produced in eyes of patients with ROP and promotes the regression of intraocular blood vessels associated with this disease was investigated. PRL was quantified in the aqueous humor, subretinal fluid, and serum from patients with stage 5 ROP and in patients with non-neovascular eye disorders. Intraocular expression of PRL was evaluated by RT-PCR, in situ hybridization, and Western blot analysis. AntiPRL antibodies were injected intravitreously in neonatal rats, and apoptosis of hyaloid vessels determined by TUNEL and ELISA. PRL was elevated in ocular fluids and serum from ROP patients. There was no correlation between PRL in ocular fluids and its level in serum, whereas PRL in aqueous humor and subretinal fluid were significantly correlated. PRL mRNA was expressed in blood vessels and leukocytes within retrolental fibrovascular membranes of ROP patients, and these membranes contained a 16 kDa immunoreactive PRL. The 16K-PRL isoform was more concentrated in subretinal fluid than in serum and was generated from PRL by subretinal fluid proteases. Intravitreous injection of neutralizing antiPRL antibodies inhibited the apoptosis of hyaloid vessels in neonatal rats. 16K-PRL derived from PRL internalized from the circulation or synthesized intraocularly can stimulate apoptosis-induced vascular regression and contribute to the development and progression of ROP.

Posterior chorioretinal atrophy and vitreous phenotype in a family with Stickler syndrome from a mutation in the COL2A1 gene

Purpose To report posterior chorioretinal atrophy (PCRA) and correlate the vitreous phenotype with inheritance of the disease mutation in a family with vitreoretinal dystrophy. Design Prospective observational case series. Methods Twenty-four members of a family with 14 affected individuals were examined, and genetic linkage analysis was performed at the COL2A1, COL11A1, and Wagner disease loci. The vitreous phenotype was prospectively graded as optically empty with retrolenticular membrane, fibrillar, or normal. Ocular ultrasonography and optical coherence tomography (OCT) were performed on selected individuals to study the vitreous structure and vitreoretinal interface. Results The 6-year-old proband had PCRA and optically empty vitreous without systemic features, suggestive of Wagner disease. The family history was negative for systemic disease, except for one cousin with cleft palate. However, when examined, clinical features of the 14 affected subjects included 5 with small chin, 4 with at least submucosal cleft palate, and 9 with a myopic refractive error greater than 5 diopters. Lens opacity or previous cataract extraction was found in 13 family members. All affected individuals in whom the vitreous could be examined had an optically empty vitreous with retrolental membrane. Posterior chorioretinal atrophy was found in eight of the affected subjects. The finding was not limited to highly myopic subjects, nor did all the high myopes have PCRA. Ultrasonography and OCT revealed vitreous adherent to the retina, but without apparent retinal distortion or edema of the macula. Significant linkage was established to the COL2A1 locus; the other loci were excluded. A single nucleotide insertion mutation (c.2012^2013insC) was identified in exon 34, leading to a downstream premature stop codon in the COL2A1 gene. Conclusions Although posterior chorioretinal atrophy and vitreoretinal degeneration have been classically associated with Wagner disease, we demonstrate its presence in a family with typical Stickler syndrome. On the basis of clinical, ultrasonographic, and OCT studies, the etiology of PCRA in this family does not seem to be attributable to vitreomacular traction or myopia. The vitreous findings in this large family confirm reports that mutations in the COL2A1 gene lead to the optically empty vitreous with retrolenticular membrane phenotype.

Persistent hyperplastic tunica vasculosa lentis and persistent hyperplastic primary vitreous in transgenic line TgN3261Rpw.

Persistent hyperplastic tunica vasculosa lentis and persistent hyperplastic primary vitreous are congenital ocular anomalies that can lead to cataract formation. A line of insertional mutant mice, TgN3261Rpw, generated at the Oak Ridge National Laboratory in a large-scale insertional mutagenesis program was found to have a low incidence (8/243; 3.29%) of multiple developmental ocular abnormalities. The ocular abnormalities include persistent hyperplastic primary vitreous, persistent hyperplastic tunica vasculosa lentis, failure of cleavage of the anterior segment, retrolental fibrovascular membrane, posterior polar cataract, and detached retina. This transgenic mouse line provides an ontogenetic model because of the high degree of similarity of this entity in humans, dogs, and mice.

Vascular Endothelial Growth Factor and Hepatocyte Growth Factor Levels Are Differentially Elevated in Patients with Advanced Retinopathy of Prematurity

Although the roles of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in angiogenesis are well described, the putative roles of these factors in retinopathy of prematurity (ROP) remain unknown. We evaluated VEGF and HGF protein levels in subretinal fluid of eyes with ROP, and expression of their corresponding receptors in retrolental membranes associated with stage 5 ROP. We examined subretinal fluid samples from eyes using rhegmatogenous retinal detachment as a control. VEGF and HGF were differentially elevated in eyes with ROP. In Stage 5 ROP (n = 22), the mean VEGF and HGF levels were 14.77 +/- 14.01 ng/ml and 16.56 +/- 9.62 ng/ml, respectively. Interestingly, in patients with active stage 4 ROP, mean VEGF levels were highly elevated (44.16 +/- 18.72 ng/ml), whereas mean HGF levels remained very low (4.77 +/- 2.50 ng/ml). Next, we investigated in vivo expression of VEGF receptor-2 and HGF receptor in retrolental membranes from 16 patients with stage 5 ROP. Both VEGF receptor-2 and HGF receptor proteins were detected mainly in posterior portions of the membrane as well as in vessel walls and along the retinal interface where angiogenesis was active. These findings together suggest that VEGF and HGF play important roles in the pathogenesis of ROP.

Identification of a Recurrent Missense Mutation in the Norrie Disease Gene Associated with a Simplex Case of Exudative Vitreoretinopathy

Disorders such as Norrie disease, X-linked familial exudative vitreoretinopathy, retinopathy of prematurity and X-linked primary vitreoretinal dysplasia have very similar clinical manifestations. They exhibit retinal fold, retinal detachment, retinal traction and the formation of retrolental fibrovascular membrane. In order to identify carriers for these disorders and provide precise genetic counseling of the relatives, a molecular genetic analysis will be helpful. This report describes the results of Norrie disease gene analysis in simplex cases of exudative vitreoretinopathy. The identification of a recurrent mutation in the Norrie disease gene in a simplex case of exudative vitreoretinopathy further strengthens the notion that Norrie disease and exudative vitreoretinopathy are allelic disorders.

Histopathological and immunohistochemical findings associated with a null mutation in the Norrie disease gene

Purpose: To determine the clinical, histopathological, and immunohistochemical ocular changes associated with a null mutation in the Norrie disease protein (NDP) gene. Methods: Tissue from a six-month-old boy with bilateral retrolental membranes and retinal detachment was obtained during vitreoretinal surgery. Histological sections were stained immunohistochemically with specific antibodies. No eye diseases with severe visual impairment or blindness were reported in the parents and their families. The NDP gene was analyzed by standard molecular genetic methods. Results: A severe reduction in the number of retinal ganglion cells and a largely disarranged and hypoplastic inner nuclear layer were visible in the tissue specimen. Areas of the tissue with advanced pathology displayed massive fibrovascular proliferation in the vitreous cavity. Shrinkage and traction resulted in folding and detachment of the outer retina. Immunohistochemical reactivity for MIB1 antigen demonstrated many proliferating cells in the vitreous, but no proliferative activity in the neuroretina. Retinal neurons showed a high grade of differentiation and expressed uniformly neuron-specific enolase and synaptophysin. A 1-base pair insertion (544/545insA) in the NDP gene was found in the affected boy. This mutation predicts a ‘functional null-allele’ due to a shift in the reading frame and, thus, a premature termination of mRNA translation after 55 instead of 133 amino acids. Conclusions: Loss of function of the NDP gene causes marked hypoplasia of the inner retinal cell layers and fibrovascular proliferation in the vitreous cavity, leading to retinal folding and detachment. The NDP therefore seems to play a critical role in terminal differentiation of the inner retinal cell layers and establishment and maintaining of anti-proliferative cellular interactions in the vitreous.

Intravenous cefazolin in penetrating eye injuries. Treatment of experimental posttraumatic endophthalmitis.

The use of intravenous antibiotics as prophylaxis in penetrating eye injuries is strictly empiric and not based on scientific data supporting their use. To determine the efficacy of prophylactic intravenous cefazolin in penetrating eye injuries, a rabbit model of posttraumatic endophthalmitis was developed. Forty rabbits received penetrating eye injuries followed immediately by an intravitreal inoculum of live Staphylococcus epidermidis. The rabbits then were randomly divided into four groups: group 1 received three doses of intravenous cefazolin; group 2 received six doses, and group 3 received nine doses; group 4 received no treatment and served as controls. All control rabbits developed 4+ vitreitis; rabbits receiving three doses of the antibiotic developed 2+ vitreitis, and those receiving six or nine doses of cefazolin showed no vitreous inflammation (P < or = 0.0001). Histologic examination of control eyes showed an exuberant reaction with formation of retrolental membranes, vitreous abscess, and retinal detachment. Eyes treated with nine doses of cefazolin were devoid of inflammatory cells. These findings suggest that intravenous cefazolin is effective in preventing the development of posttraumatic endophthalmitis in a rabbit model.

Evaluation of Eyes with Advanced Stages of Retinopathy of Prematurity Using Standard Echography

The authors evaluated 36 patients (72 eyes) who had either Stage 4 or Stage 5 retinopathy of prematurity (ROP) with standardized A-scan and B-scan echography. The eyes were evaluated for vitreous opacities, retrolental membranes, and retinal detachments. Stage 5 retinal detachments were present in 94% (68 of 72) of the eyes with 65% (47 of 72) having a wide anterior and narrow posterior configuration. Anterior retinal loops were noted in 36% of the eyes. Subretinal opacities were present in 47% of the eyes. Choroidal thickening and intraocular calcium were noted in 22% and 14% of eyes, respectively. The axial eye length was measured and adjusted for the differences in chronological and gestational age and compared with data from normal eyes. This showed that eyes with ROP were much smaller. The standardized A-scan was helpful in confirming the diagnosis of retinal detachment, evaluating the peripheral retina, and examining the subretinal space. The combination of A-scan and B-scan echography is helpful in predicting anatomic findings in patients with ROP undergoing surgery.

Ultrastructural Study of Norrie's Disease

We studied the clinicopathologic and ultrastructural features of a full-term infant with Norrie's disease. The infant had bilateral retrolental fibrous vascular masses and retinal detachment with no other apparent physical abnormalities and no family history of ocular defects. A vitrectomy and a membrane peeling were attempted, and specimens of the retina, the retrolental membrane, and a vascularized epiretinal peripheral mass were examined by light and electron microscopy. The retrolental membrane was composed of layered collagenous tissue and contained structures resembling blood vessels. Inner and outer neuroblastic layers were identified in the retinal tissue, but no vessels were present. In the epiretinal mass, portions of retina and cortical vitreous were seen along with primitive vascular structures. The histologic appearance of these specimens suggests that the major pathologic event of Norrie's disease occurs in the retina in the third to fourth gestational month. We believe the subsequent ocular abnormalities found in this patient were secondary to this early retinal malformation and did not represent a progressive ocular disorder.

Cryotherapy in Infants With Retinopathy of Prematurity

To the Editor.— In the Multicentre Trial of Cryotherapy for Retinopathy of Prematurity (ROP), the avascular peripheral retina was treated in one of the impaired eyes with threshold ROP. 1 An outcome was an eye that had a fold of retina through the macula or partial to complete retrolental membrane (grade III through V retrolental fibroplasia). 2 Twenty-two percent of the treated eyes had unfavorable results, compared with 43% of the untreated eyes. Not yet reported is the fact that some of the favorable eyes with grade II retrolental fibroplasia and grade III retrolental fibroplasia not through the macula will be visually disabled (acuity Drs Phelps and Phelps 3 present a complex process for determining treatment of one or both eyes.

Retinopathy of Prematurity: The Association of a Persistent Hyaloid Artery

In a review of 160 cases of retinopathy of prematurity (ROP), 14 patients were found to have an associated persistent hyaloid vascular system. The following four different manifestations of a persistent hyaloid system were identified: (1) hyaloid artery anastomosed to peripheral neovascularization (1 case); (2) hyaloid artery present with attached retina (3 cases); (3) fibrousappearing stalk with detached retina (3 cases); and (4) massive persistent hyaloid vascular system (7 cases). In some cases, the hyaloid artery was only an associated finding and unrelated to ROP. In other cases, the hyaloid artery appeared to be an integral component of the retrolental membrane. Recognition of a massive persistent hyaloid artery has important prognostic value because the vessels are adherent to the retina and the retrolental membrane complicating surgical repair. The role of the associated hyaloid artery in ROP is described.

Experimental intravitreal proliferation and neovascularization in the cynomolgus monkey

An experimental model for intravitreal cellular proliferation was produced by injection of carbon microparticles into the vitreous of nine cynomolgus monkeys. Eighteen eyes were studied following enucleations 10 weeks after the injections. Histological examinations showed retinal folds or detachments in 16 eyes, while 6 of those had total detachments. Eight eyes contained transvitreal fibrovascular strands, passing from the optic disk to a "cyclitic" retrolental membrane. The strands and membranes were composed mainly of infiltrates of macrophages, inflammatory cells, fibroblasts, newly formed vessels and van Gieson-staining collagen. Epiretinal proliferation of glial cells also occurred. These experiments indicate that a primarily phagocytic cellular invasion into the vitreous is capable of stimulating further cellular migration and growth and for inducing fibrovascular proliferations.

In Situ Actin Distribution in Excised Retrolental Membranes in Retinopathy of Prematurity

Actin, an intracellular contractile protein, is associated with cell movements in both muscle and nonmuscle tissues. Using the fluorescent derivative of the mushroom toxin, phallacidin, which specifically binds to polymerized (filamentous) actin, we demonstrated the distribution of actin in retrolental membranes excised during open-sky vitrectomy from six infants with leukokoria due to retrolental fibroplasia. Actin was detected in ubiquitous linear bundles, which is consistent with the existence of contractile forces. Actin was also concentrated in the cortical cytoplasm of cells, thus outlining the plasma membranes. Transmission electron microscopy has identified many of these cells to be myofibroblastlike in appearance. Myofibroblasts are known to contract like smooth-muscle cells and have been reported as the putative causal factor in the contraction of scars and transvitreal membranes.