Ectopic Ocular Surface Calcification in Patients With Hypophosphatasia Treated With Asfotase Alfa.

PURPOSE: To assess for ectopic ocular calcification in a series of patients with hypophosphatasia (HPP) treated with asfotase alfa, a recombinant tissue-nonspecific alkaline phosphatase. METHODS: This is a retrospective analysis of subjects enrolled at Duke University Medical Center in ENB-009-10 (ClinicalTrials.gov: NCT01163149), a randomized controlled trial of asfotase alfa in adolescents and adults with HPP. Seven patients between the ages of 45 and 66 years diagnosed with HPP based on clinical features and low serum alkaline phosphatase levels were enrolled at our site. Subjects were randomized to receive either daily subcutaneous injections of asfotase alfa or no treatment. After 24 weeks, during the open-label extension phase, all subjects received treatment for at least 4 years. All subjects underwent comprehensive eye examinations at baseline and at 24-week intervals throughout the study to assess for development of ocular calcifications. RESULTS: By week 120, all 7 subjects developed asymptomatic white refractile deposits in the interpalpebral perilimbal conjunctiva. Biopsy of the conjunctival lesions in 2 subjects revealed elastosis with subepithelial calcification. The lesions were nonprogressive and in 5 subjects exhibited some degree of regression. CONCLUSIONS: Asfotase alfa was invariably associated with development of mild focal conjunctival calcification, likely through disinhibition of hydroxyapatite crystal propagation. The calcifications were not symptomatic or vision-threatening and should not preclude enzyme replacement therapy for patients with this rare and often debilitating disease.

Osteogenesis imperfecta and primary open angle glaucoma: genotypic analysis of a new phenotypic association.

PURPOSE: Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by bone fragility. Ocular findings include blue sclera, low ocular rigidity, and thin corneal thickness. However, there are no documented cases linking OI and primary open angle glaucoma (POAG). In this report, we describe three individuals, one isolated case and two from a multiplex family, with OI type I and POAG. METHODS: Available family members with OI and POAG had a complete eye examination, including visual acuity, intraocular pressure (IOP), pachymetry, slit-lamp exam, dilated fundus exam, and visual fields. DNA from blood samples was sequenced and screened for mutations in COL1A1/2 and myocilin (MYOC). RESULTS: All subjects had OI type I. Findings of POAG included elevated IOP, normal gonioscopy, and glaucomatous optic disc cupping and visual field loss. POAG cosegregated with OI in the multiplex family. The multiplex family had a single nucleotide insertion (c.540_541insC) in COL1A1 resulting in a frameshift mutation and a premature termination codon. The sporadic case had a COL1A1 splice acceptor site mutation (c.2452-2A>T or IVS36-2A>T) predicted to result in a premature termination codon due to intron inclusion or a cryptic splice site. None of the glaucoma cases had mutations or sequence changes in MYOC. CONCLUSIONS: We identified two novel mutations in COL1A1 in individuals with OI type I and POAG. Thus, some mutations in COL1A1 may be causative for OI and POAG. Alternatively, susceptibility genes may interact with mutations in COL1A1 to cause POAG.

Artifacts in spectral-domain optical coherence tomography measurements in glaucoma.

IMPORTANCE Spectral-domain optical coherence tomography (SD-OCT) has an integral role in the diagnosis and treatment of glaucoma. Understanding the types of artifacts commonly seen in the imaging of patients being evaluated for glaucoma will help physicians better implement these data in the care of patients. OBJECTIVES To determine the frequency and distribution of SD-OCT imaging artifacts in patients being evaluated for glaucoma and to provide examples of common artifacts. DESIGN, SETTING, AND PARTICIPANTS A retrospective cross-sectional study design was used to examine SD-OCT images (using Spectralis SD-OCT) of 277 consecutive patients who had a diagnosis of glaucoma of any stage or had suspected glaucoma. Retinal nerve fiber layer (RNFL) and macular thickness scans were included. For each scan, the final printout and the source images that generated the final printout were examined. If present, artifacts were classified as evident on the final printout or not and were categorized as to the primary source of the artifact (eg, ocular pathologic features or technician errors). Examples of common artifacts are provided. MAIN OUTCOMES AND MEASURES The presence of imaging artifacts. RESULTS In 277 consecutive patients, 131 macular thickness scans were obtained, and 277 RNFL scans were obtained. Of the macular thickness scans, 37 (28.2%; 95% CI, 20.8%-36.1%) had imaging artifacts. Six of these artifacts were not obvious on the final printout. Of the RNFL scans, 55 (19.9%; 95% CI, 15.2%-24.6%) contained artifacts. Seven of these artifacts were not evident on the final printout. The most common cause of artifacts for macular thickness and RNFL scans was ocular pathologic features, primarily the presence of an epiretinal membrane. CONCLUSIONS AND RELEVANCE It is likely that SD-OCT-related imaging artifacts occur in 15.2% to 36.1% of scans obtained in patients being evaluated for glaucoma. Some of these artifacts may not be evident on the final printout. Physicians should be alert to the possibility of artifacts, particularly in patients with ocular pathologic features such as an epiretinal membrane.

Patient and family attitudes about an eye donation registry for research.

PURPOSE: There is a shortage of human eye tissue available for scientists, and it is unknown how willing ophthalmic patients are to donate their eyes for research. Therefore, we assessed eye patient and family member attitudes regarding the establishment of an eye donation registry for research purposes. MATERIALS AND METHODS: Surveys were distributed to consecutive patients attending the clinics of an academic ophthalmology practice over a period of 8 days. This survey consisted of questions about demographic information of the participant, attitudes regarding eye donation and attitudes regarding a registry for research-specific eye donation. An additional nested survey was administered to family members who accompanied survey participants. RESULTS: A total of 207 patients and 76 accompanying family members returned their respective surveys. Of the patients, 55% indicated that they would consider joining a proposed eye donation registry for research, 30% were undecided and 15% would not consider joining (n = 193). Over 95% of family members indicated that they would support their relative's decision to enroll in the registry (n = 74). Of the potential donors, 41% indicated they would most prefer to learn about the registry from their eye doctor and 37% from a pamphlet (n = 180). CONCLUSIONS: A majority of patients with eye disease and their family members support the idea of establishing an advance-directive eye donation registry for research. This registry for research donors could be incorporated into the current eye donation registry. Such an addendum would bridge the current disconnect between ophthalmic patients who want to donate their eyes for research on their disease (and are ineligible to donate for corneal transplantation) and scientists who need more human eye tissue for experimentation.

Genome-wide linkage scan for primary open angle glaucoma: influences of ancestry and age at diagnosis.

Primary open-angle glaucoma (POAG) is the most common form of glaucoma and one of the leading causes of vision loss worldwide. The genetic etiology of POAG is complex and poorly understood. The purpose of this work is to identify genomic regions of interest linked to POAG. This study is the largest genetic linkage study of POAG performed to date: genomic DNA samples from 786 subjects (538 Caucasian ancestry, 248 African ancestry) were genotyped using either the Illumina GoldenGate Linkage 4 Panel or the Illumina Infinium Human Linkage-12 Panel. A total of 5233 SNPs was analyzed in 134 multiplex POAG families (89 Caucasian ancestry, 45 African ancestry). Parametric and non-parametric linkage analyses were performed on the overall dataset and within race-specific datasets (Caucasian ancestry and African ancestry). Ordered subset analysis was used to stratify the data on the basis of age of glaucoma diagnosis. Novel linkage regions were identified on chromosomes 1 and 20, and two previously described loci-GLC1D on chromosome 8 and GLC1I on chromosome 15--were replicated. These data will prove valuable in the context of interpreting results from genome-wide association studies for POAG.

Evaluation of the ICare rebound tonometer as a home intraocular pressure monitoring device.

PURPOSE: (a) To investigate whether the ICare rebound tonometer can provide accurate measurements of intraocular pressure (IOP) in the hands of an inexperienced user compared with ICare measurements and Goldmann tonometry by a trained technician and (b) to assess the intrauser reproducibility of IOP measurements and the learning curve among patients using the ICare rebound tonometer. METHODS: A trained technician used the ICare rebound tonometer to measure the IOP of the right eye of 100 glaucoma patients. The technician then instructed each patient on use of the ICare tonometer. Each patient then measured his/her own pressure using the ICare tonometer. Finally, a different technician, who was masked to both of the earlier readings, measured IOP by Goldmann applanation tonometry. Thirty patients repeated the ICare measurement 3 times (once every 5 min) 20 minutes after the initial IOP measurement. RESULTS: Of the 100 patients, 82 of patient ICare and the technician ICare readings were within 3 mm Hg of each other, and 75 of the patient ICare and Goldmann applanation tonometry measurements were within 3 mm Hg of each other. Intraclass correlations between self-administered ICare measurements 1 and 2, 1 and 3, and 2 and 3 were 0.69, 0.71 and 0.81, respectively. CONCLUSION: In this study, the ICare rebound tonometer was accurate and reliable in the hands of patients. Patients can easily learn to self-administer this test, possibly allowing for home monitoring of IOP.

Myocilin and optineurin coding variants in Hispanics of Mexican descent with POAG.

Coding variants in both myocilin (MYOC) and optineurin (OPTN) are reported risk factors for primary open-angle glaucoma (POAG) in many populations. This study investigated the contribution of MYOC and OPTN coding variants in Hispanics of Mexican descent with and without POAG. We conducted a case-control study of unrelated POAG cases and nonglaucomatous controls in a population of Hispanics of Mexican descent. Ascertainment criteria for POAG included the presence of glaucomatous optic neuropathy with associated visual field loss and the absence of secondary causes of glaucoma. Controls had normal optic nerves, visual fields and intraocular pressure. All coding exons of MYOC and OPTN were sequenced. The data set consisted of 88 POAG cases and 93 controls. A novel nonsynonymous coding variant (R7H) in the first exon of MYOC was identified. Other identified variants in MYOC and OPTN have been previously described and do not seem to contribute to POAG risk. This is the first comprehensive study of MYOC and OPTN in Hispanics of Mexican descent with POAG. Neither MYOC nor OPTN sequence variants seem to have a major role in the etiology of POAG in this population.

Glaucoma patients' trust in the physician.

Objectives. To describe glaucoma patients' trust in the physician and to test the hypothesis that increased interpersonal trust is associated with increased medication adherence. Methods. One hundred ninety-five subjects with open-angle glaucoma seen by multiple glaucoma subspecialists participated in a cross-sectional patient survey and concomitant chart review which included a test of health literacy and the Trust in Physician Scale (TPS), a scale from 1-100, with 100 indicating greatest trust. Charts were reviewed for visual acuity and visual field results. Subjects' pharmacies were contacted to ascertain medication refill rates over the preceding six months. Results. TPS scores ranged from 57.5 to 100, 78.7 +/- 8.4 (mean +/- SD,) median 75.0. When age, race, gender, baseline visual acuity and visual field status, education level, and literacy status were considered, only race was associated with TPS. Caucasians expressed slightly higher levels of trust (n = 108; TPS 80.1 +/- 8.2) than non-Caucasians, (n = 87 (82 Africans Americans); TPS 77.1 +/- 8.4; P = .012). TPS score was not associated with refill rates (P = .190). Conclusions. Trust in physician is generally high in this group of glaucoma patients but varies slightly by race. Trust in physician was not associated with glaucoma medication adherence in this tertiary care population.

Distribution of WDR36 DNA sequence variants in patients with primary open-angle glaucoma.

PURPOSE: To determine the distribution of WDR36 sequence variants in a cohort of patients with primary open-angle glaucoma (POAG) in the United States. METHODS: All of the 23 coding exons and flanking introns of the WDR36 gene were sequenced in 118 probands from families with at least two members affected by POAG, 6 probands from juvenile-onset POAG families, and 108 control individuals. RESULTS: Thirty-two WDR36 sequence variants were found in this population of patients with POAG. Nonsynonymous single-nucleotide polymorphisms (SNPs), including those previously described as "disease-causing" and "disease susceptibility," were found in 17% of POAG patients and 4% of control subjects. Although the distribution of WDR36 variants in the pedigrees did not show consistent segregation with the disease, the WDR36 sequence variants were found more frequently in patients with more severe disease. CONCLUSIONS: The results of this study suggest that abnormalities in WDR36 alone are not sufficient to cause POAG. The association of WDR36 sequence variants with more severe disease in affected individuals suggests that defects in the WDR36 gene can contribute to POAG and that WDR36 may be a glaucoma modifier gene.

Early adult-onset POAG linked to 15q11-13 using ordered subset analysis.

PURPOSE: Primary open-angle glaucoma (POAG) is a complex inherited disorder. It has been demonstrated in other complex disorders that phenotypic heterogeneity may be the result of genetic heterogeneity and that stratification analysis can be used to increase the power of detection. Ordered subset analysis (OSA) is a recently described method that utilizes the variability of phenotypic traits to determine underlying genetic heterogeneity. METHODS: Eighty-six multiplex families with POAG were clinically ascertained for genetic analysis. Age at diagnosis (AAD) was used as a surrogate for age of onset in affected family members. Nine genetic markers within the 15q11-13 interval on chromosome 15 were used for OSA analysis. RESULTS: An 11-cM linkage interval with a peak LOD score of 3.24 centered at the GABRB3 locus (P = 0.013 by permutation test) was identified in a subset of 15 families, which represents 17% of the total dataset (15/86 families). The mean AAD for the affected OSA families was 44.1 +/- 9.1 years (SD). The mean AAD for the complementary group was 61.3 +/- 10.4 years. African-American and white families were well represented in the OSA subset. CONCLUSIONS: Linkage was identified for POAG to an 11-cM region on chromosome 15, designated GLC1I. This result provides further evidence that AAD and other phenotypic traits can be used as stratification variables to identify genes in complex disorders such as POAG and suggests that the 15q11-13 locus is one of the largest genetic contributors to POAG identified to date.

Patient expectations regarding eye care: focus group results.

BACKGROUND: Increasing emphasis on patient-centered care and other recent developments should make patient expectations increasingly important in ophthalmology. Motivated by the pivotal role of patient expectations in quality-of-care assessments and by the limited knowledge about patients' expectations regarding eye care, we initiated a pilot study using focus groups to determine a relevant set of concerns that patients express as expectations. METHODS: A total of 6 focus groups were conducted with patients at Duke University Eye Center (Durham, NC). Focus groups ranged in size from 4 to 10 people. The average group size was 6. RESULTS: Content analysis of transcripts from the 6 focus groups yielded 22 areas of expectations for eye care, which were classified into 5 categories: communication, interpersonal manner, physician's skill, logistics, and other. The 6 areas that appeared to be of greatest importance to focus group participants were the following: (1) honesty, (2) information about diagnosis and prognosis, (3) explanation in clear language, (4) ophthalmologist's experience and reputation, (5) empathy, and (6) listening and addressing concerns. CONCLUSIONS: In general, ophthalmology patients in the focus groups emphasized expectations related to communication and interpersonal manner. In contrast to previous studies with primary care patients, however, ophthalmology patients expressed few expectations for technical interventions, such as medication prescriptions, physical examination, or diagnostic testing.