John D. Gottsch

Racial Differences in the Cause-Specific Prevalence of Blindness in East Baltimore

BACKGROUND Bilateral blindness unrelated to simple refractive error is twice as prevalent among blacks as among whites, although the difference narrows among the elderly. The reasons for this race- and age-related pattern are uncertain. METHODS AND RESULTS A randomly selected, stratified, multistage cluster sample of 2395 blacks and 2913 whites 40 years of age and older in East Baltimore underwent detailed ophthalmic examinations by a single team. We identified 64 subjects who were blind in both eyes. The leading causes of blindness were unoperated senile cataract (accounting for blindness in 27 of the total of 128 eyes), primary open-angle glaucoma (17 eyes), and age-related macular degeneration (16 eyes). Together, these three disorders accounted for 47 percent of all blindness in this sample. Unoperated cataract accounted for 27 percent of all blindness among blacks, among whom it was four times more common than among whites; whites were almost 50 percent more likely than blacks to have undergone cataract extraction before the age of 80 (P less than 0.002). Primary open-angle glaucoma accounted for 19 percent of all blindness among blacks; it was six times as frequent among blacks as among whites and began 10 years earlier, on average. By contrast, age-related macular degeneration resulting in blindness was limited to whites, among whom it was the leading cause of blindness (prevalence, 2.7 per 1000; 95 percent confidence interval, 1.2 to 5.4); it affected 3 percent of all white subjects 80 years of age or older. CONCLUSIONS The pattern of blindness in urban Baltimore appears to be different among blacks and whites. Whites are far more likely to have age-related macular degeneration, and blacks to have primary open-angle glaucoma. The high rate of unoperated cataracts among younger blacks and among elderly subjects of both races suggests that health services are underused. Half of all blindness in this urban population is probably preventable or reversible.

Risk Factors for Corneal Graft Failure and Rejection in the Collaborative Corneal Transplantation Studies

PURPOSE To evaluate comprehensively the magnitude of suspected risk factors for corneal graft failure from any cause, failure from rejection, and immunologic reaction in patients at high risk for graft failure after corneal transplantation. METHODS The records of the 457 participants in the Collaborative Corneal Transplantation Studies were reviewed. All participants had at least two quadrants of stromal vascularization and/or a history or previous graft rejection. Patients were followed for 2 to 5 years. Characteristics of the patient, study eye, donor, donor-recipient histocompatibility, and surgical procedure were examined for their association with the graft outcomes of failure from any cause, rejection failure, and immunologic reaction. Multivariate survival analysis techniques were used to estimate rates of graft outcome events and to estimate the magnitude of risk factors. RESULTS Many apparent risk factors did not maintain their association with graft outcomes after adjustment for other risk factors. Young recipient age, the number of previous grafts, history of previous anterior segment surgery, preoperative glaucoma, quadrants of anterior synechiae, quadrants of stromal vessels, a primary diagnosis of chemical burn, and blood group ABO incompatibility were among the strongest risk factors identified for graft failure. Donor and corneal preservation characteristics had little influence on graft outcome. CONCLUSIONS Risk of graft failure varies substantially, even within a high-risk population. The number of risk factors present should be considered by the patient and surgeon when contemplating transplantation and planning follow-up.

The Cause-specific Prevalence of Visual Impairment in an Urban Population: The Baltimore Eye Survey

BACKGROUND Whereas population-based data on the causes of bilateral blindness have been reported, little information is available on the distribution of causes of central vision loss less severe than the criteria used to define legal blindness. This visual impairment is responsible for a high proportion of eye care service use and results in important reductions in functional status. METHODS Data from the Baltimore Eye Survey were used to estimate the cause-specific prevalence of visual impairment (best-corrected visual acuity worse than 20/40 but better than 20/200) among black and white residents of east Baltimore who were 40 years of age or older. Eligible subjects underwent a screening examination at a neighborhood location and, for those whose best-corrected visual acuity was less than 20/30, a definitive ophthalmologic examination at the Wilmer Eye Institute. RESULTS The prevalence of visual impairment was 2.7% in whites and 3.3% in blacks; the age-adjusted relative prevalence (B/W) was 1.75 (P = 0.01). The leading causes of visual impaired eyes were cataract (35.8%), age-related macular degeneration (14.2%), diabetic retinopathy (6.6%), glaucoma (4.7%), and other retinal disorders (7.3%). Cataract, diabetic retinopathy, and glaucoma were more common as a cause of visual impairment among blacks, whereas macular degeneration was more frequent among whites. More than 50% of all subjects had the potential for improvement in vision with appropriate surgical intervention. CONCLUSION Visual impairment is a prevalent condition among inner city adults 40 years of age or older. The distribution of causes suggests that improvements in the visual health of the population could be achieved with more effective delivery of efficacious ophthalmologic care.

Posterior chamber intraocular lens implantation in the absence of posterior capsular support.

Because of the high incidence and great variety of complications associated with anterior chamber intraocular lenses, we have developed a technique for the implantation of a posterior chamber intraocular lens in the absence of posterior capsular support. The posterior chamber IOL is placed in the ciliary sulcus by suturing the superior haptic to the iris and the inferior haptic to the sclera at the ciliary sulcus. We have used this technique successfully in both complicated extracapsular surgery and secondary intraocular lens implantation.

Missense Mutations in TCF8 Cause Late-Onset Fuchs Corneal Dystrophy and Interact with FCD4 on Chromosome 9p

Fuchs corneal dystrophy (FCD) is a degenerative genetic disorder of the corneal endothelium that represents one of the most common causes of corneal transplantation in the United States. Despite its high prevalence (4% over the age of 40), the underlying genetic basis of FCD is largely unknown. Here we report missense mutations in TCF8, a transcription factor whose haploinsufficiency causes posterior polymorphous corneal dystrophy (PPCD), in a cohort of late-onset FCD patients. In contrast to PPCD-causing mutations, all of which are null, FCD-associated mutations encode rare missense changes suggested to cause loss of function by an in vivo complementation assay. Importantly, segregation of a recurring p.Q840P mutation in a large, multigenerational FCD pedigree showed this allele to be sufficient but not necessary for pathogenesis. Execution of a genome-wide scan conditioned for the presence of the 840P allele identified an additional late-onset FCD locus on chromosome 9p, whereas haplotype analysis indicated that the presence of the TCF8 allele and the disease haplotype on 9p leads to a severe FCD manifestation with poor prognosis. Our data suggest that PPCD and FCD are allelic variants of the same disease continuum and that genetic interaction between genes that cause corneal dystrophies can modulate the expressivity of the phenotype.

Combined phacoemulsification, intraocular lens implantation, and vitrectomy for eyes with coexisting cataract and vitreoretinal pathology ☆

PURPOSE To report the preoperative, intraoperative, and postoperative outcomes of combining phacoemulsification and posterior chamber intraocular lens (IOL) implantation with pars plana vitrectomy in eyes with significant cataract and coexisting vitreoretinal pathology. DESIGN Retrospective, consecutive, interventional case series. METHODS Charts of patients undergoing combined procedures at the Wilmer Ophthalmologic Institute between March 1995 and May 2000 were reviewed. RESULTS In all, 122 eyes of 111 patients were identified. Patient ages ranged from 27 to 89 years (mean 65). Forty-three eyes had diabetic retinopathy; 11 had undergone vitrectomy previously. Macular pathology (hole, membrane, choridal neovascularization) was present in 69 eyes. The most common indications for surgery were diabetic vitreous hemorrhage, macular hole, epiretinal membrane, and retinal detachment. In all cases, phacoemulsification and IOL implantation were performed before vitreoretinal surgery. Preoperative vision ranged from 20/30 to light perception and postoperative vision ranged from 20/20 to no light perception. In 105 patients vision improved, in 7 there was no change, and in 10 vision decreased. Postoperative complications included opacification of the posterior capsule, increased intraocular pressure, corneal epithelial defects, vitreous hemorrhage, retinal detachment and iris capture by the IOL. CONCLUSIONS Combined surgery is a reasonable alternative in selected patients. Techniques that may simplify surgery and reduce complications include: careful, limited, curvilinear capsulorhexis; in-the-bag placement of IOLs; use of IOLs with larger optics; suturing of cataract wounds before vitrectomy; use of miotics and avoidance of long-acting dilating drops in patients with intravitreal gas; and use of wide-field viewing systems.

The Efficacy and Safety of Combined Trabeculectomy Cataract Extraction, and Intraocular Lens Implantation

The safety and efficacy of combined trabeculectomy, extracapsular cataract extraction (ECCE), and posterior chamber intraocular lens (PC IOL) implantation were evaluated by retrospectively analyzing 108 consecutive operations. Postoperatively, 89% of eyes achieved 20/40 or better visual acuity when preoperative macular and optic nerve diseases were excluded. Mean follow-up was 16.8 months. Intraocular pressure (IOP) control (less than or equal to 21 mmHg) was achieved in 92% of eyes; 57% required no medications. Capsulotomy (20%) and transient hyphema (15%) occurred significantly more often (P less than 0.001) than in a comparison group. These results suggest that the combined procedure gives excellent visual rehabilitation and IOP control in the majority of patients included in this analysis.

Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophya

Homozygous mutations in the Borate Cotransporter SLC4A11 cause two early‐onset corneal dystrophies: congenital hereditary endothelial dystrophy (CHED) and Harboyan syndrome. More recently, four sporadic patients with late‐onset Fuchs corneal dystrophy (FCD), a common age‐related disorder, were also reported to harbor heterozygous mutations at this locus. We therefore tested the hypothesis that SLC4A11 contributes to FCD and asked whether mutations in SLC4A11 are responsible for familial cases of late‐onset FCD. We sequenced SLC4A11 in 192 sporadic and small nuclear late‐onset FCD families and found seven heterozygous missense novel variations that were absent from ethnically matched controls. Familial data available for one of these mutations showed segregation under a dominant model in a three‐generational family. In silico analyses suggested that most of these substitutions are intolerant, whereas biochemical studies of the mutant protein indicated that these alleles impact the localization and/or posttranslational modification of the protein. These results suggest that heterozygous mutations in SLC4A11 are modest contributors to the pathogenesis of adult FCD, suggesting a causality continuum between FCD and CHED. Taken together with a recent model between FCD and yet another early onset corneal dystrophy, PPCD, our data suggest a shared pathomechanism and genetic overlap across several corneal dystrophies. Hum Mutat 31:1–8, 2010.

Mutations in LOXHD1, a recessive-deafness locus, cause dominant late-onset Fuchs corneal dystrophy.

Fuchs corneal dystrophy (FCD) is a genetic disorder of the corneal endothelium and is the most common cause of corneal transplantation in the United States. Previously, we mapped a late-onset FCD locus, FCD2, on chromosome 18q. Here, we present next-generation sequencing of all coding exons in the FCD2 critical interval in a multigenerational pedigree in which FCD segregates as an autosomal-dominant trait. We identified a missense change in LOXHD1, a gene causing progressive hearing loss in humans, as the sole variant capable of explaining the phenotype in this pedigree. We observed LOXHD1 mRNA in cultured human corneal endothelial cells, whereas antibody staining of both human and mouse corneas showed staining in the corneal epithelium and endothelium. Corneal sections of the original proband were stained for LOXHD1 and demonstrated a distinct increase in antibody punctate staining in the endothelium and Descemet membrane; punctate staining was absent from both normal corneas and FCD corneas negative for causal LOXHD1 mutations. Subsequent interrogation of a cohort of >200 sporadic affected individuals identified another 15 heterozygous missense mutations that were absent from >800 control chromosomes. Furthermore, in silico analyses predicted that these mutations reside on the surface of the protein and are likely to affect the proteins interface and protein-protein interactions. Finally, expression of the familial LOXHD1 mutant allele as well as two sporadic mutations in cells revealed prominent cytoplasmic aggregates reminiscent of the corneal phenotype. All together, our data implicate rare alleles in LOXHD1 in the pathogenesis of FCD and highlight how different mutations in the same locus can potentially produce diverse phenotypes.

A Single-Base Substitution in the Seed Region of miR-184 Causes EDICT Syndrome

PURPOSE To investigate the cause of the syndrome characterized by endothelial dystrophy, iris hypoplasia, congenital cataract, and stromal thinning (EDICT). METHODS Previously a multigenerational family was reported that comprised 10 individuals affected by syndromal anterior segment dysgenesis. Blood samples were re-collected from eight affected and two unaffected individuals, and genomic DNA was extracted. A total of 24 candidate genes and 4 microRNAs residing within the critical interval were sequenced bidirectionally. In silico analyses were performed to examine the effect of the causal variant on the stability of the pre-microRNA structure. RESULTS Bidirectional sequencing identified the single-base substitution +57C>T in miR-184. This variation segregated with the disease phenotype and was absent in the 1000 Genomes project, 1130 control chromosomes, and 28 nonhuman vertebrates. CONCLUSIONS The single-base-pair substitution in the seed region of miR-184 is responsible for the disease phenotype observed in EDICT syndrome.