A. Tim Johnson

Mitomycin C versus 5-Fluorouracil in High-risk Glaucoma Filtering Surgery: Extended Follow-up

Background: With the increased use of a hand-held indirect lens and slit-lamp biomicroscopy for stereoscopic viewing of the optic nerve, the authors believe that an acquired pit of the optic nerve is more common than was recognized previously. This increased recognition has led to the awareness that the central visual field was affected frequently in the presence of such an acquired pit. Methods: The authors retrieved the charts of a series of 97 patients who had an acquired pit of the optic nerve during an 18-month period and retrospectively reviewed the automated visual fields associated with these pits using the Humphrey Visual Field Analyzer Programs 30-2 and 10-2 and looked for involvement of the central visual field. Results: In 81.7% of the acquired pits of the optic nerves, one of the central-most test points (3° from fixation) in the appropriate hemifield on the 30-2 format was depressed severely by Statpac II ( P P = 0.03). Conclusion: The authors showed that the presence of an acquired pit in an optic nerve damaged by glaucoma frequently is associated with a threat to fixation.

Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma

PURPOSE To investigate the association of sequence variations in the optineurin (OPTN) gene in patients with open-angle glaucoma. DESIGN Prospective case control study. METHODS The OPTN gene was screened for sequence variations using a combination of single-strand conformational polymorphism analysis and automated DNA sequencing. A total of 1,299 subjects (1048 glaucoma patients and 251 controls) were screened for variations in the four portions of the gene that had been previously associated with glaucoma. A subset of these subjects (376 patients and 176 controls) was screened for variations in the entire coding sequence. Twenty-four percent of the patients and 35% of the controls were Japanese, whereas the remainder were predominantly Caucasian. Allele frequencies were compared with the Fisher exact test. RESULTS The OPTN sequence variations were not significantly associated with any form of high-tension open-angle glaucoma. One proband with familial normal-tension glaucoma was found to harbor the previously reported Glu50Lys variation. Another previously reported change, Met98Lys, was associated with normal-tension glaucoma in Japanese but not in Caucasian patients. CONCLUSIONS This study provides some additional evidence for the association of the Glu50Lys OPTN sequence variation with familial normal tension glaucoma. However, because familial normal-tension glaucoma is so rare, this change seems to be responsible for less than 0.1% of all open-angle glaucoma. The Arg545Gln variation is likely to be a nondisease-causing polymorphism. The Met98Lys change may be associated with a fraction of normal-tension glaucoma in patients of Japanese ethnicity.

Age-dependent Prevalence of Mutations at the GLC1A Locus in Primary Open-angle Glaucoma

PURPOSE To screen a population with primary open-angle glaucoma for mutations in the gene that encodes the trabecular meshwork inducible glucocorticoid response protein (TIGR), also known as myocilin (MYOC). METHODS Ophthalmologic information was collected for study subjects with primary open-angle glaucoma and their relatives. Mutation screening of 74 primary open-angle glaucoma probands was conducted by sequencing TIGR/MYOC coding sequence and splice sites. RESULTS In 23 families we detected 13 nonsynonymous sequence changes, nine of which appear to be mutations likely to cause or contribute to primary open-angle glaucoma. Two mutations, Arg272Gly and Ile499Ser, and one nonsynonymous sequence variant, Asn57Asp, are novel. We found mutations in nine of 25 juvenile glaucoma probands (36%) and two of 49 adult-onset glaucoma probands (4%). Age classification of families rather than individual probands revealed mutations in three of nine families with strictly juvenile primary open-angle glaucoma (33%), and no mutations in 39 families with strictly adult-onset primary open-angle glaucoma (0%). In families with mixed-onset primary open-angle glaucoma containing both juvenile primary open-angle glaucoma and adult-onset primary open-angle glaucoma cases, we found mutations in eight of 26 families (31%). CONCLUSIONS Our data suggest that Gly252Arg, Arg272Gly, Glu323Lys, Gln368STOP, Pro370Leu, Thr377Met, Val426Phe, Ile477Asn, and Ile499Ser are likely to play roles that cause or contribute to the etiology of autosomal dominant primary open-angle glaucoma. Our finding of more TIGR/MYOC mutations in families with mixed-onset primary open-angle glaucoma than in the families with strictly adult-onset primary open-angle glaucoma implies that the presence of relatives with juvenile primary open-angle glaucoma in a family could be used as a basis for identifying a subset of the population with adult-onset primary open-angle glaucoma with higher prevalence of TIGR/MYOC mutations. To address this issue, and to refine estimations of mutation prevalence in these age-defined subpopulations, prospective study of a larger population ascertained entirely through adult-onset primary open-angle glaucoma probands will be needed.

Mitomycin C versus 5-Fluorouracil in High-risk Glaucoma Filtering Surgery

PURPOSE To compare the outcome of filtering surgery in high-risk patients using intraoperative mitomycin C (MMC) versus postoperative 5-fluorouracil (5-FU). METHODS In a randomized clinical trial, the use of postoperative subconjunctival injections of 5-FU in 19 eyes of 19 patients was compared with a single intraoperative application of MMC in 20 eyes of 20 patients. All eyes were at high risk for failure of glaucoma filtering surgery. RESULTS Follow-up ranged from 26 to 38 months (mean, 32.0 months). Three eyes in the MMC-treated group and two eyes in the 5-FU-treated group required subsequent surgery to control the IOP. Excluding these patients, intraocular pressure (IOP) averaged 9.0 +/- 4.9 mmHg in the MMC-treated eyes versus 16.3 +/- 4.6 mmHg in the 5-FU-treated eyes at the patients last visit (P = 0.0003). Of the MMC-treated eyes, 81.3% had IOPs less than or equal to 12 mmHg compared with 26.7% of eyes in the 5-FU group (P = 0.0023). In the MMC-treated group, the average number of medications for IOP control at last visit was 0.5 +/- 0.8 compared with 1.6 +/- 1.3 in the 5-FU-treated group (P = 0.01). Late postoperative complications (those occurring more than 3 months after surgery) were similar for the two groups, with the exception of formation of a Tenon cyst in three of the eyes treated with MMC compared with none of the 5-FU-treated eyes. CONCLUSIONS Eyes treated with MMC have lower IOP on fewer medications than eyes treated with 5-FU. Late postoperative complications are similar with the exception of an increased incidence of Tenon cyst formation in the MMC-treated eyes.

Impact of a structured surgical curriculum on ophthalmic resident cataract surgery complication rates

PURPOSE: To determine whether institution of a structured surgical curriculum for ophthalmology residents decreased the rate of sentinel surgical complications. SETTING: Veterans Affairs Medical Center, Des Moines, Iowa, USA. METHODS: A retrospective review was performed of third‐year ophthalmic resident quality‐assurance surgical outcomes data at a single residency‐training site from 1998 to 2008. The primary outcome measure was defined as a sentinel event; that is, a posterior capsule tear (with or without vitreous loss) or vitreous loss (from any cause) occurring during a resident‐performed case. The study population was divided into 2 groups. Group 1 comprised surgical cases of residents trained before the surgical curriculum change (academic years 1998 to 2003) and Group 2, surgical cases of residents trained with the enhanced curriculum (academic years 2004 to 2008). Data from 1 year (academic year 2003 to 2004) were excluded because the transition to the enhanced curriculum occurred during that period. The data were analyzed and adjusted for surgical experience. RESULTS: In Group 1 (before institution of surgical curriculum), there were 823 cases with 59 sentinel complications. In Group 2 (after institution of surgical curriculum), there were 1009 cases with 38 sentinel complications. There was a statistically significant reduction in the sentinel complication rate, from 7.17% before the curriculum changes to 3.77% with the enhanced curriculum (P = .001, unpaired 2‐tailed t test). CONCLUSION: Implementation of a structured surgical curriculum resulted in a statistically significant reduction in sentinel event complications, even after adjusting for surgical experience.

Clinical Phenotype of Juvenile-onset Primary Open-angle Glaucoma Linked to Chromosome 1q*

PURPOSE Recent reports have suggested that a gene responsible for juvenile-onset primary open-angle glaucoma exists on the long arm of chromosome 1 (1q). This report describes a previously unpublished family (UM:JG3) in which juvenile-onset glaucoma is segregating in an autosomal dominant manner. The clinical features in this family were compared with those seen in other pedigrees with this condition. Linkage analysis was performed to evaluate whether a glaucoma-causing gene in UM:JG3 is linked to genetic markers on chromosome 1q. METHODS Affected family members, their siblings, children, and spouses were examined to identify the presence of glaucoma. Linkage studies were performed using short tandem repeat polymorphisms from chromosome 1q. Results of these studies were compared with those found for other families in which juvenile-onset primary open-angle glaucoma is linked genetically to the same chromosome 1q region. RESULTS The UM:JG3 family includes 22 affected individuals over five generations, including 12 still living. The average age at diagnosis for living affected individuals was 26 years. An association between myopia and glaucoma was observed in this family, but the glaucoma was not associated with iris processes or other structural anomalies. The clinical course of disease and response to treatment were similar to other families with this disease. The disease phenotype in this family is linked to markers on chromosome 1q with a maximum lod score of 3.52 at a recombination fraction of 0.00 for marker D1S433. Haplotype analysis suggests the gene responsible for glaucoma in this family is located in an 8-cM region between markers D1S445 and D1S218. CONCLUSIONS The glaucoma in UM:JG3 is linked to markers on chromosome 1q, with a candidate interval smaller than that in previous reports. In individuals with juvenile-onset open-angle glaucoma linked to chromosome 1q, the phenotype can range from mild ocular hypertension to blindness, resulting from marked elevations in intraocular pressure, with age at diagnosis ranging from 6 to 62 years. However, most affected individuals display a characteristic phenotype that includes onset in the first three decades of life, unusually high intraocular pressures, and the need for surgical therapy to prevent loss of vision. Whether differences in expression among families is due to allelic heterogeneity remains to be determined.

Effects of Jogging Exercise on Patients with the Pigmentary Dispersion Syndrome and Pigmentary Glaucoma

BACKGROUND Exercise-induced anterior chamber pigment dispersion with intraocular pressure (IOP) elevation has been reported in patients with the pigmentary dispersion syndrome. Marked pigment dispersion with or without elevation of IOP could predispose these patients to visual field loss. The authors designed this study to evaluate the effects of jogging exercise on anterior chamber pigment and IOP in a group of patients with the pigmentary dispersion syndrome or pigmentary glaucoma. METHODS Fourteen subjects with the pigmentary dispersion syndrome, 10 subjects with pigmentary glaucoma, and 10 control subjects underwent a 45-minute protocol of jogging exercise. Anterior chamber pigment was graded and IOP was measured before and up to 3 hours after completion of the exercise protocol. RESULTS Eyes of experimental subjects were significantly more likely to develop exercise-induced pigment dispersion than were eyes of control subjects. In experimental subjects, eyes treated with pilocarpine at the time of the study were significantly less likely to develop exercise-induced pigment dispersion than eyes not treated with pilocarpine. In two experimental subjects, pre-exercise treatment with pilocarpine appeared to inhibit exercise-induced pigment dispersion. CONCLUSIONS The authors do not believe that all patients with the pigmentary dispersion syndrome or pigmentary glaucoma need to avoid exercise. However, for patients with these disorders who regularly engage in jogging or more strenuous or more jarring types of exercise, they suggest an evaluation before and after the type of exercise in question. If marked exercise-induced pigment dispersion occurs, pilocarpine therapy may be an alternative to avoidance of the exercise.

The Pathology of Posterior Amorphous Corneal Dystrophy

The youngest affected member of a family with a five-generation history of posterior amorphous corneal dystrophy underwent penetrating keratoplasty. The corneal button was studied by light and electron microscopy, representing the first pathologic description of this condition. Light microscopy demonstrated fracturing of the most posterior collagen layers of the stroma and focal attenuation of endothelial cells. Electron microscopy showed the collagen fibers in the most posterior stromal lamellae to be disorganized. Descemets layer was interrupted by a band of collagen fibers resembling stroma, and there was loss of endothelial cells. These findings suggest a developmental abnormality in the formation of the posterior stroma and Descemets membrane in posterior amorphous corneal dystrophy.

Probable Exclusion of GLC1A as a Candidate Glaucoma Gene in a Family with Middle-age-onset Primary Open-angle Glaucoma

PURPOSE To determine whether an adult-onset variety of primary open-angle glaucoma in family UM:POAG1 is linked to the previously mapped GLC1A juvenile-onset primary open-angle glaucoma locus on chromosome 1q or whether linkage can be excluded. METHODS Microsatellite repeat markers from the 9 cM D1S196 to D1S218 interval containing the GLC1A gene were amplified by polymerase chain reaction from DNA samples collected from 11 members of one sibship in family UM:POAG1. Haplotype analysis was carried out, including calculation of the probability that the observed data would have been obtained if the underlying cause of primary open-angle glaucoma in this family were a defect in a gene located in the tested interval. Linkage analysis was carried out under an autosomal dominant model for GLC1A glaucoma. RESULTS In family UM:POAG1, primary open-angle glaucoma was diagnosed in six surviving and one deceased member of a sibship of 13 individuals during the fifth or sixth decade of life. Glaucoma in this family has a later average age at diagnosis and significantly less elevation in intraocular pressure than GLC1A glaucoma so far described. Haplotype analysis, using a population prevalence up to 0.9%, shows that it is unlikely that the reported data would have been observed if primary open-angle glaucoma in this pedigree were due to the GLC1A locus on chromosome 1q21-q31. Linkage analysis under the juvenile glaucoma autosomal dominant model allowed exclusion of linkage across the entire GLC1A genetic inclusion interval, with a maximum lod score in the interval of -3.28. CONCLUSION The most likely interpretation of these observations is that a defect in the GLC1A glaucoma gene is not responsible for adult-onset primary open-angle glaucoma in family UM:POAG1. This suggests the existence of at least two primary open-angle glaucoma genes, the previously reported GLC1A gene on chromosome 1q and another gene located elsewhere in the genome. Diagnosis of UM:POAG1 glaucoma between 42 and 57 years of age also raises questions regarding the relation of the glaucoma present in this family to the common later-age-onset form of the disease.

Cataracts and corticosteroids in granulocyte donors

I n this issue of TRANSFUSION, the third of three studies investigating a possible link between repeated doses of adrenal corticosteroids and posterior subcapsular cataracts (PSCs) in granulocyte (neutrophil) donors is reported. Unfortunately, the overall findings of the three studies are neither in complete agreement nor are definitive, in terms of risk to healthy donors. Moreover, recommendations from the three studies are inconsistent as to how best to obtain informed consent for granulocyte donation. Accordingly, it is worthwhile to critically assess the findings of all three studies and to offer our suggestions as how to manage and counsel granulocyte donors. To collect the largest number of neutrophils for granulocyte transfusion therapy, it is mandatory to stimulate donors before leukapheresis with a combination of granulocyte–colony-stimulating factor (G-CSF) and corticosteroids (generally, dexamethasone)—although some blood centers prefer to avoid G-CSF, because it is not approved by the Federal Food and Drug Administration for this purpose, and to use corticosteroids alone. For decades, granulocyte donors have been given corticosteroids within several hours before each leukapheresis procedure, generally as a single oral dose of 8 mg of dexamethasone or as divided oral doses of up to 60 mg of prednisone. Although repeat granulocyte donors receive multiple individual doses of corticosteroids, sometimes extending over the course of several years, it has been widely assumed that the brief and interrupted doses would not lead to PSCs—a well-known complication of long-term corticosteroid therapy. The initial study from Iowa was prompted when a granulocyte donor reported to the Medical Director of the DeGowin Blood Center that his ophthalmologist had told him that he needed surgery for cataracts caused by the prednisone that he had received over the years as a granulocyte donor. Although an earlier editorial reviewed the available data about the possible relationship between corticosteroids and PSCs in granulocyte donors and offered guidance regarding informed consent for repeat granulocyte donation, information at that time was fairly sparse and in disagreement. Now that a third article has completed the “trilogy” and has provided some additional information, it is worthwhile to critically reassess the findings and to offer practice guidelines. ANALYSIS OF THE THREE STUDIES