CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype.

Mutations in CEP290 are the most common cause of Leber congenital amaurosis (LCA), a severe inherited retinal degenerative disease for which there is currently no cure. Autosomal recessive CEP290-associated LCA is a good candidate for gene replacement therapy, and cells derived from affected individuals give researchers the ability to study human disease and therapeutic gene correction in vitro. Here we report the development of lentiviral vectors carrying full-length CEP290 for the purpose of correcting the CEP290 disease-specific phenotype in human cells. A lentiviral vector containing CMV-driven human full-length CEP290 was constructed. Following transduction of patient-specific, iPSC-derived, photoreceptor precursor cells, reverse transcriptase-PCR analysis and western blotting revealed vector-derived expression. As CEP290 is important in ciliogenesis, the ability of fibroblast cultures from CEP290-associated LCA patients to form cilia was investigated. In cultures derived from these patients, fewer cells formed cilia compared with unaffected controls. Cilia that were formed were shorter in patient-derived cells than in cells from unaffected individuals. Importantly, lentiviral delivery of CEP290 rescued the ciliogenesis defect. The successful construction and viral transfer of full-length CEP290 brings us closer to the goal of providing gene- and cell-based therapies for patients affected with this common form of LCA.

Refractive surgery for unilateral high myopia in children.

PURPOSE: To evaluate the safety and efficacy of refractive surgery in children. METHODS: Pediatric patients with unilateral high myopia who were 9 years of age or older were offered refractive surgery to supplement optical correction. The patients and families were informed that the operation may not improve their best-corrected visual acuity. Photorefractive keratectomy (PRK) or laser in situ keratomileusis (LASIK) was performed on the more myopic eye with the use of topical anesthesia. Cycloplegic refraction, stereopsis, motility, and best-corrected visual acuity were measured before the procedure and at 2 months and 20 months after the procedure. All patients had completed amblyopia therapy before surgery. RESULTS: Fourteen eyes of 14 patients aged 9 to 14 years received refractive surgery. Average age at the time of surgery was 11.9 years (+/-1,6). Average corrected preoperative visual acuity was 20/147 (+/-0.065 in decimals). Average preoperative refraction was -7.96 D (+/-2,16) spherical equivalent. Twenty months after refractive surgery, the uncorrected visual acuity averaged 20/129 (+/-0.08 in decimals) and best-corrected vision averaged 20/121 (+/-0.08 in decimals). Average refraction was -0.46 D (+/-0,58) at 2 months and -0.67 D (+/-0,68) D at 20 months. An average myopic shift in refraction of -0.22 D was found in treated eyes during the 20 months of follow-up; this was not statistically significant (P =.69). Three patients had LASIK and 11 patients had PRK. LASIK patients averaged -0.875 D of myopic shift over 20 months of follow-up. Those with PRK averaged -0.025 D. This difference was not statistically significant (P =.10). The vision of 5 of 14 patients improved 1 or 2 lines after refractive surgery. Two patients who had 20/80 vision preoperatively improved to 20/60. No patients lost any lines of vision. Only 4 patients demonstrated stereopsis preoperatively, and all retained stereopsis postoperatively. No patient gained stereopsis. CONCLUSIONS: LASIK and PRK can be performed safely and effectively in children who are cooperative enough to undergo the procedures with topical anesthesia. Refractive surgery does not improve vision in densely amblyopic eyes but may give modest improvement in those that are mildly amblyopic. No significant complications were encountered aside from a myopic shift over time.

Refractive surgery in children.

Refractive surgery techniques, especially those using laser ablation, have revolutionized the treatment of refractive errors. The short-term results have been well studied in adults, but long-term outcomes are not known. No good studies exist to tell us whether the pediatric eye responds the same as the adult eye to these techniques, but there is reason to believe that the pediatric eye will have many differences, both short- and long-term based on other similar surgeries adapted for pediatrics. These techniques have great potential to add to our armamentarium of treatments for frustrating problems such as unilateral high myopia with amblyopia, but they should be used with caution. The patients who are the most attractive to refractive surgeons, namely, teenagers with typical myopia who want to discard their spectacles, are the patients with potentially the most to lose from a procedure with unknown long-term results for a condition easily treated with other modalities. Those who need it most, namely infants and children with high anisometropia who cannot tolerate contact lenses or spectacles, are the least cooperative, the most difficult to treat postoperatively, and the least able to afford expensive treatments not covered by insurance, are therefore the least likely to be offered the procedure, or to have a study designed to evaluate their specific needs and concerns. It behooves ophthalmologists interested in pediatrics to carefully discuss and research the possible indications and theoretical concerns of these powerful techniques in pediatric eyes.

A comparison of grating visual acuity, strabismus, and reoperation outcomes among children with aphakia and pseudophakia after unilateral cataract surgery during the first six months of life.

PURPOSE: The method of correcting aphakia after unilateral cataract extraction during infancy is controversial. Some authorities advocate correction with an intraocular lens (IOL) whereas others advocate correction with a contact lens (CL). We compared grating visual acuity, alignment, and reoperative outcomes in age-matched children treated with these 2 modalities at 5 clinical centers. METHODS: Twenty-five infants born in 1997 or 1998 with a dense unilateral congenital cataract who had cataract surgery coupled with (IOL group, n = 12) or without (CL group, n = 13) primary IOL implantation were enrolled in this study. All patients were prescribed half-time occlusion therapy. In July 1999, their grating visual acuities, ocular alignments, and reoperation rates were assessed. RESULTS: The mean grating visual acuity (LogMAR) for the affected eye was 0.70 +/- 0.32 for the IOL group and 0.87 +/- 0.31 for the CL group (P =.19). The mean interocular difference in grating visual acuity was 0.26 +/- 0.30 for the IOL group and 0.50 +/- 0.28 for the CL group (P =.048). The incidence of strabismus (>10 PD) was 75% in the IOL group compared with 92% in the CL group (P =.24). The incidence of reoperations was 83% in the IOL group compared with 23% in the CL group (P =.003). CONCLUSIONS: Our preliminary data suggest that correcting aphakia after unilateral congenital cataract surgery with primary IOL implantation results in an improved visual outcome but a higher rate of complications requiring reoperation. A randomized clinical trial, the Infant Aphakia Treatment Study, is planned to further study the optimal treatment for aphakia following unilateral cataract extraction during infancy.

Clinical and genetic analysis of a family with X-linked congenital nystagmus (NYS1).

PURPOSE: To describe a family with X-linked congenital nystagmus and identify the genetic interval within which the gene is located. METHODS AND DESIGN: Clinical examination with genotyping of 30 individuals from a multi-generational Caucasian family with congenital nystagmus inherited in an X-linked pattern using markers from Xq26-q27, followed by linkage analysis and sequencing of a candidate gene, solute carrier family 25, member 14 (SLC25A14), in four affected individuals from four families linked to this region. RESULTS: The pattern of inheritance in the family was consistent with X-linkage with incomplete penetrance among carrier females. No affected males had affected sons. Based on the extended pedigree, the estimated penetrance among obligate female carriers (daughters of affected males) was 29% (6 of 21). Visual acuity among 15 affected individuals ranged from 20/20 to 20/70 (median 20/30). Clinical examinations, including electroretinography in two individuals, were otherwise normal except for the presence of nystagmus. Significant LOD scores (theta = 0) were found with markers DXS8057, DXS8044, DXS1047, DXS1062, DXS8072, and DXS8078, placing the gene within a approximately 5 cM interval flanked by DXS9909 and DXS1211 on the long arm of the X chromosome. Sequencing the candidate gene SLC25A14 in four affected individuals from four families linked to this region failed to reveal any mutations. CONCLUSIONS: NYS1 appears to be a common gene for familial congenital idiopathic nystagmus. Linkage analysis of this family further reduces the interval in which NYS1 is located.

Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness.

During development, visual photoreceptors, bipolar cells and other neurons establish connections within the retina enabling the eye to process visual images over approximately 7 log units of illumination. Within the retina, cells that respond to light increment and light decrement are separated into ON- and OFF-pathways. Hereditary diseases are known to disturb these retinal pathways, causing either progressive degeneration or stationary deficits. Congenital stationary night blindness (CSNB) is a group of stable retinal disorders that are characterized by abnormal night vision. Genetic subtypes of CSNB have been defined and different disease actions have been postulated. The molecular bases have been elucidated in several subtypes, providing a better understanding of the disease mechanisms and developmental retinal neurobiology. Here we have studied 22 families with 'complete' X-linked CSNB (CSNB1; MIM 310500; ref. 4) in which affected males have night blindness, some photopic vision loss and a defect of the ON-pathway. We have found 14 different mutations, including 1 founder mutation in 7 families from the United States, in a novel candidate gene, NYX. NYX, which encodes a glycosylphosphatidyl (GPI)-anchored protein called nyctalopin, is a new and unique member of the small leucine-rich proteoglycan (SLRP) family. The role of other SLRP proteins suggests that mutant nyctalopin disrupts developing retinal interconnections involving the ON-bipolar cells, leading to the visual losses seen in patients with complete CSNB.

Cataract and phthisis bulbi after laser photoablation for threshold retinopathy of prematurity.

PURPOSE: To describe the visual and structural outcome of eyes that developed a dense cataract after laser photoablation for threshold retinopathy of prematurity. METHODS: A retrospective review of eight consecutive infants who developed dense cataract(s) after bilateral laser photoablation for threshold retinopathy of prematurity. Of the 10 eyes with cataract, five eyes were treated with a diode laser and five with an argon laser. The stage and zone of the retinopathy of prematurity, number of burns applied, time of onset of the cataract, clinical findings at the time of cataract surgery, and the course after cataract surgery were reviewed. RESULTS: Six eyes had zone 1 disease and four had zone 2 disease. The mean number of burns applied per eye was 2532 +/- 856 (range, 1400 to 4500). A cataract was diagnosed a median of 3 [corrected] weeks (range, 1 to 28 weeks) after laser photoablation. Nine of the 10 cataracts were sufficiently dense to preclude a view of the fundus. All 10 eyes had clinical signs suggestive of an inflammatory or ischemic process that included one or more of the following findings: corneal edema, pupillary membrane, iris atrophy, depigmentation of ciliary processes, pigment on the anterior lens surface, posterior synechiae, hyphema, and shallow anterior chamber. Nine eyes underwent cataract surgery. Five of the 10 eyes had retinal detachment ranging in severity from stage 4A to stage 5 at the time of cataract surgery. Nine of the 10 eyes progressed to phthisis bulbi and no light perception. CONCLUSIONS: A dense cataract developing in the eye of an infant after laser photoablation for threshold retinopathy of prematurity is associated with a poor visual prognosis. The constellation of associated clinical findings appears to be most consistent with anterior segment ischemia.

Avoidance and treatment of retinopathy of prematurity.

Retinopathy of prematurity is a blinding eye disease of premature infants. It is increasing in incidence as more babies of lower birth weights survive. Although in the 1940s and 1950s the major predisposing factor was high oxygen exposure, the main risk factor now is birth weight less than 1,000 g. Retinopathy of prematurity can be classified into several distinct stages, which progress in a typical manner. Once the stage of threshold is reached, the eye has a 50% chance of becoming blind. At this stage, laser peripheral retinal photo ablation or peripheral cryo ablation may cause the neovascularization to regress and preserve vision. The treatment is not effective in all cases, however, and a large number of children continue to become blind each year because of this devastating disease. New microsurgical techniques such as lens-sparing vitrectomy and modified scleral buckle for tiny eyes have improved the outcome for some children. Prevention is the best hope to eradicate blindness caused by this disorder, and manipulations of the metabolic and neonatal intensive care unit environment are currently being studied.

Heterochromia after pediatric cataract surgery.

PURPOSE: Changes in iris color have been noted anecdotally after cataract surgery in infants, but they have not been studied systematically. The mechanism for these iris color changes has not previously been reported in the biomedical literature. METHODS: Photographs were taken of both eyes of 15 children and 11 rhesus monkeys who had undergone unilateral cataract surgery. Masked examiners reviewed the photographs and compared the iris color of the eyes that were operated on with the eyes that were not operated on. Between 4 and 6 weeks postoperatively, the level of prostaglandin F(2alpha) in the aqueous humor (n = 4) and vitreous humor (n = 2) was measured in both the operated and nonoperated eyes of 4 monkeys that had undergone a neonatal lensectomy during the first 5 days of life. RESULTS: Thirteen of 15 children had a darker iris color in the operated eye in relation to the nonoperated (control) eye. Four of 11 monkeys had a uniformly darker iris in the operated eye; the other 7 monkeys had regional darkening or patches of darker iris in the eye that was operated on. The prostaglandin F(2alpha) levels in neonatal monkeys were higher in the aqueous humor and in the vitreous humor of the operated eye in relation to the nonoperated eye. CONCLUSION: In some children, cataract surgery is associated with a darkening of the iris color in the operated eye. We speculate that this darkening results from an exuberant prostaglandin release stimulated by the cataract surgery and may occur through the same or a similar mechanism by which latanoprost causes the darkening of iris color.

Unilateral retinal hemorrhages in documented cases of child abuse.

PURPOSE: To describe the occurrence of unilateral retinal hemorrhages in four cases of documented child abuse, including a case in which retinal hemorrhages were an incidental finding on routine examination. METHODS: Case reports. RESULTS: Three children, 5 to 17 months of age, with suspected child abuse had fundus examinations with a dilated pupil as part of their evaluation. An additional child, 6 months of age, received fundus examination with a dilated pupil as part of follow-up for regressed retinopathy of prematurity. Each of the four children had extensive retinal or preretinal hemorrhages in one eye only. Three of the four had ecchymoses on the ipsilateral face or neck. Two had evidence of bone fractures on skeletal surveys. All four had neuroimaging that documented cerebral hemorrhage or infarct. In all four cases an adult caretaker was found responsible for shaking, choking, or squeezing the child. One child died. Two had resolution of retinal hemorrhage, whereas one required vitrectomy. All three had at least partial recovery of vision in the affected eye after amblyopia treatment. CONCLUSION: In cases of documented child abuse, unilateral retinal or preretinal hemorrhages may be present. Ophthalmologists should recognize that unilateral retinal or preretinal hemorrhages may be associated with child abuse.

Anterior hyaloid face opacification after pediatric Nd:YAG laser capsulotomy.

PURPOSE: The purpose of this study was to examine the clarity of the visual axis after Nd:YAG laser capsulotomy following cataract extraction and primary intraocular lens implantation in a pediatric population. METHODS: A retrospective review was performed of all cases of cataract extraction and primary intraocular lens implantation over a period of 5 years. A group of children who had been treated by primary surgical posterior capsulotomy and anterior vitrectomy (Group 1) was used as the "gold standard," with whom the children treated with Nd:YAG laser capsulotomy (Group 2) were compared. The groups were studied for the incidence of opacification of the visual axis after the primary procedure. RESULTS: Data on 78 eyes were reviewed, and 56 eyes met inclusion criteria. Of these, 33 eyes were treated with primary posterior capsulotomy and anterior vitrectomy (Group 1) and 23 eyes were treated with Nd:YAG laser capsulotomy (Group 2). One eye (3%) of Group 1 experienced postoperative visual axis reopacification. Thirteen (57%) of 23 eyes in Group 2 experienced reopacification, requiring retreatment. Four eyes (17%) treated with Nd:YAG laser required a third treatment. CONCLUSIONS: In our series, 57% of patients treated with Nd:YAG laser capsulotomy experienced reopacification across the anterior hyaloid face. With the removal of the anterior vitreous at the time of cataract extraction, the scaffolding for cell migration is removed and reopacification of the visual axis is rarely seen. For patients in whom slit-lamp capsulotomy is not possible, especially if there is no Nd:YAG laser available for use in the operating room or when loss to follow-up may be an issue, primary posterior capsulotomy and anterior vitrectomy should be strongly considered.

Strabismus and mitochondrial defects in chronic progressive external ophthalmoplegia.

PURPOSE: To describe the results of strabismus surgery on three patients with chronic progressive external ophthalmoplegia, a group of rare disorders characterized by ptosis and slowly progressive ophthalmoparesis that has been shown to result from defects in mitochondrial DNA. METHODS: Strabismus surgery using the adjustable suture technique was performed in three patients with strabismus and chronic progressive external ophthalmoplegia confirmed by clinical, biochemical, histopathologic, and genetic criteria. All three patients had mitochondrial DNA deletions. Two patients were exotropic; one patient was esotropic. RESULTS: Rectus muscle recessions were initially unsuccessful in correcting strabismus in one patient, although a subsequent procedure employing rectus muscle resections was successful in alleviating a significant head turn and improved ocular alignment. In the two other patients, a single procedure consisting of rectus muscle recessions combined with large rectus muscle resections successfully achieved good postoperative alignment. The amount of surgery performed in these three patients exceeded that predicted in standard strabismus tables. CONCLUSIONS: The myopathic process that results in chronic progressive external ophthalmoplegia renders rectus muscle recessions less effective compared with resections for correcting the associated strabismus seen in these patients. Rectus muscle resections therefore should be an integral procedure in the surgical management of the strabismus associated with chronic progressive external ophthalmoplegia.

Balloon dilatation for treatment of resistant nasolacrimal duct obstruction.

PURPOSE: Our purpose was to report our experience with balloon catheter dilatation for resistant nasolacrimal duct obstruction. METHODS: Patients enrolled had symptoms of nasolacrimal duct obstruction and (1) had failed previous probing or (2) were more than 2 years old. Balloon dilatation was performed with a LacriCATH lacrimal catheter (Atrion Medical Products, Birmingham, Ala.). A subset of patients had Silastic silicone rubber (Dow Corning, Midland, Mich.) intubation after balloon dilatation. Success was determined by clinical examination a minimum of 6 weeks later. RESULTS: Twenty-one lacrimal systems of 12 patients were treated (age range 4 months to 7 years). Of the patient subset treated with a LacriCATH lacrimal catheter alone, 9 of 18 systems demonstrated complete resolution of symptoms. Three of the 12 patients underwent balloon dilatation intraoperatively after attempts at Silastic silicone rubber intubation were unsuccessful. In two of these patients, who were younger, Silastic silicone rubber tubes passed easily after balloon treatment; however, in an older patient, age 5 years, intubation still could not be accomplished. CONCLUSION: Common clinical strategy for treatment of resistant nasolacrimal obstruction includes repeat probing, intubation of the nasolacrimal system with Silastic silicone rubber tubes, or dacryocystorhinostomy. Balloon catheter dilatation is an alternative or adjunct to consider. Factors that may affect the success of treatment include the age of the patient, the complexity of the nasolacrimal anatomy, and use of adjunctive systemic antibiotics and steroids.

Optic nerve hypoplasia: absence of posterior pituitary bright signal on magnetic resonance imaging correlates with diabetes insipidus.

PURPOSE: Magnetic resonance imaging has been used to examine children with optic nerve hypoplasia for pituitary abnormalities who may be at risk for anterior pituitary hormonal deficiencies. We correlated the sellar and optic pathway anatomic findings on magnetic resonance imaging in children with optic nerve hypoplasia with findings from their endocrinologic and ophthalmologic examinations to determine whether magnetic resonance imaging findings predict anterior and posterior pituitary dysfunction. METHODS: A retrospective review identified five children with optic nerve hypoplasia and endocrinopathy who also underwent high resolution volumetric magnetic resonance imaging. RESULTS: All children had severe bilateral optic nerve hypoplasia and anterior pituitary hormone deficiencies. Three children had no recognizable intrasellar or ectopic posterior pituitary bright spot on magnetic resonance imaging; all had clinical evidence of diabetes insipidus. Two patients with a recognizable but ectopic posterior pituitary did not have diabetes insipidus. CONCLUSION: Children with optic nerve hypoplasia and no recognizable posterior lobe of the pituitary gland on magnetic resonance imaging are at risk for both anterior and posterior pituitary dysfunction, whereas those with a posterior lobe on magnetic resonance imaging appear to have intact posterior pituitary function.

Infantile cataracts.

Cataracts are one of the most treatable causes of visual impairment during infancy. Recent epidemiological studies have shown that they have a prevalence of 1.2 to 6.0 cases per 10,000 infants. The morphology of infantile cataracts can be helpful in establishing their etiology and prognosis. Early surgery and optical correction have resulted in an improved outcome for infants with either unilateral or bilateral cataracts. While contact lenses continue to be the standard means of optically correcting an infant's eyes after cataract surgery, intraocular lenses are gaining in popularity as an alternative means of optically correcting these eyes. Post-operative complications occur more commonly after infantile than adult cataract surgery and many of these complications do not develop until years later. As a result, it is critical that children be followed closely on a long term basis after infantile cataract surgery.