Paul R. Lichter

Interim clinical outcomes in the collaborative initial glaucoma treatment study comparing initial treatment randomized to medications or surgery

PURPOSE To report interim outcome data, using all available follow-up through 5 years after treatment initiation, in the Collaborative Initial Glaucoma Treatment Study (CIGTS). DESIGN Randomized clinical trial. PARTICIPANTS Six hundred seven newly diagnosed glaucoma patients. METHODS In a randomized clinical trial, 607 patients with newly diagnosed open-angle glaucoma were initially treated with either medication or trabeculectomy (with or without 5-fluorouracil). After treatment onset and early follow-up, patients were evaluated clinically at 6-month intervals. In addition, quality of life telephone interviews were conducted at similar frequency to the clinical visits. Patients in both arms of CIGTS were treated aggressively in an effort to reduce intraocular pressure (IOP) to a level at or below a predetermined target pressure specific for each individual eye. Visual field (VF) scores were analyzed by time-specific comparisons and by repeated measures models. MAIN OUTCOME MEASURES VF loss was the primary outcome variable in CIGTS. Secondary outcomes of visual acuity (VA), IOP, and cataract were also studied. RESULTS On the basis of completed follow-up through 4 years and partially completed through 5 years, VF loss did not differ significantly by initial treatment. Over the entire period of follow-up, surgical patients had a greater risk of substantial VA loss compared with medical patients. However, by 4 years after treatment, the average VA in the two groups was about equal. Over the course of follow-up, IOP in the medicine group has averaged 17 to 18 mmHg, whereas that in the surgery group averaged 14 to 15 mmHg. The rate of cataract requiring removal was greater in the surgically treated group. CONCLUSIONS Both initial medical or initial surgical therapy result in about the same VF outcome after up to 5 years of follow-up. VA loss was greater in the surgery group, but the differences between groups seem to be converging as follow-up continues. When aggressive treatment aimed at substantial reduction in IOP from baseline is used, loss of VF can be seen to be minimal in general. Because 4 to 5 years of follow-up in a chronic disease is not adequate to draw treatment conclusions, these interim CIGTS outcomes do not support altering current treatment approaches to open-angle glaucoma.

Intraoperative Mitomycin versus Postoperative 5-Fluorouracil in High-risk Glaucoma Filtering Surgery

In a randomized clinical trial, the authors compared the use of postoperative subconjunctival injections of 5-fluorouracil (5-FU) in 19 eyes with a single intraoperative application of subconjunctival mitomycin (MMC) at the filtering site in 20 eyes at high risk for failure of glaucoma filtering surgery. Six months after surgery, intraocular pressures averaged 10.9 +/- 5.3 mmHg (mean +/- standard deviation) in the MMC-treated eyes versus 14.2 +/- 5.5 mmHg in the 5-FU-treated eyes (P = 0.08) and were less than or equal to 12 mmHg in 60.0% of MMC-treated eyes and 21.1% of 5-FU-treated eyes (P = 0.03). Mitomycin-treated eyes were receiving an average of 0.3 +/- 0.5 medications for intraocular pressure control, and 5-FU-treated eyes were receiving an average of 1.1 +/- 1.1 medications (P = 0.01). Drug-induced corneal epithelial defects were seen in nine 5-FU-treated eyes and in no MMC-treated eyes (P = 0.0004). These results suggest that intraoperative MMC may be a viable alternative to postoperative 5-FU, with lower overall intraocular pressures, decreased dependence on postoperative ocular antihypertensive medications, and decreased corneal toxicity.

BLEB RELATED ENDOPHTHALMITIS AFTER TRABECULECTOMY WITH MITOMYCIN C

PURPOSE To determine whether filtering blebs resulting from adjunctive use of mitomycin C (MMC) leads to an increased risk of endophthalmitis. METHODS The authors retrospectively reviewed the records of 232 consecutive trabeculectomies performed at the W. K. Kellogg Eye Center with adjunctive use of MMC from May 1990 through June 1993. Data obtained from the records included patient age, sex, race, type of glaucoma, site of filtration surgery, concentration and duration of exposure to MMC, presence of early or late bleb leakage, and the occurrence of endophthalmitis. RESULTS Three patients were lost to follow-up less than 1 month after surgery. A total of 229 eyes of 192 patients (11 women and 82 men) were included in the study. Mean follow-up of patients remaining free of infection was 18.5 +/- 10.8 months (range, 1-44 months). The overall incidence of bleb-related endophthalmitis was 2.6%. Endophthalmitis developed in 8% of patients (4 or 50) in whom an inferior approach was used and in 1.1% (2 or 179) in whom a superior approach was used (P = 0.02, Fishers exact test). The estimated odds ratio for the development of endophthalmitis after trabeculectomy with adjunctive MMC for inferior versus superior filtration sites was 7.7. CONCLUSION Short-term follow-up of trabeculectomies performed with adjunctive use of MMC demonstrates an overall incidence of endophthalmitis comparable to filtrationprocedures performed with 5-fluorouracil or without antifibrotic agents. However, inferior trabeculectomy performed with adjunctive MMC carries a significantly increased risk of bleb-related endophthalmitis compared with filters performed superiorly.

Visual Field Progression in the Collaborative Initial Glaucoma Treatment Study: The Impact of Treatment and Other Baseline Factors

PURPOSE To evaluate factors associated with visual field (VF) progression, using all available follow-up through 9 years after treatment initiation, in the Collaborative Initial Glaucoma Treatment Study (CIGTS). DESIGN Longitudinal follow-up of participants enrolled in a randomized clinical trial. PARTICIPANTS Six hundred seven newly diagnosed glaucoma patients. METHODS In a randomized clinical trial, 607 subjects with newly diagnosed open-angle glaucoma initially were treated with either medication or trabeculectomy. After treatment initiation and early follow-up, subjects were evaluated clinically at 6-month intervals. Study participants in both arms of the CIGTS were treated aggressively in an effort to reduce intraocular pressure (IOP) to a level at or below a predetermined, eye-specific target pressure. Visual field progression was analyzed using repeated measures models. MAIN OUTCOME MEASURES Visual field progression, measured by Humphrey 24-2 full-threshold testing and assessed by the change in the mean deviation (MD), and an indicator of substantial worsening of the VF (MD decrease of > or =3 dB from baseline), assessed at each follow-up visit. RESULTS Follow-up indicated minimal change from baseline in each initial treatment groups average MD. However, at the 8-year follow-up examination, substantial worsening (> or =3 dB) of MD from baseline was found in 21.3% and 25.5% of the initial surgery and initial medicine groups, respectively. The effect of initial treatment on subsequent VF loss was modified by time (P<0.0001), baseline MD (P = 0.03), and diabetes (P = 0.01). Initial surgery led to less VF progression than initial medicine in subjects with advanced VF loss at baseline, whereas subjects with diabetes had more VF loss over time if treated initially with surgery. CONCLUSIONS The CIGTS intervention protocol led to a lowering of IOP that persisted over time in both treatment groups. Progression in VF loss was seen in a subset, increasing to more than 20% of the subjects. The findings regarding initial surgery being beneficial for subjects with more advanced VF loss at presentation, but detrimental for patients with diabetes, are noteworthy and warrant independent confirmation. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

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.

Prognostic Factors in the Uveitis of Juvenile Rheumatoid Arthritis

Risk factors for significant visual loss were investigated in 51 patients with iridocyclitis associated with juvenile rheumatoid arthritis (JRA). Average follow-up was 12.7 years. Of 89 eyes with uveitis, 22% had visual loss to 20/200 or worse, 46% had cataracts, 30% had band keratopathy, and 27% had glaucoma. Severity of visual loss and complications correlated with the degree of inflammation found on initial ocular examination. Of 58 eyes that were initially normal or had signs of mild inflammation (cells, flare, keratitic precipitates), 3% had final vision of 20/200 or worse, 28% had cataracts, 5% had band keratopathy, and 17% had glaucoma. Of 31 eyes with posterior synechiae on initial examination, 58% had final vision of 20/200 or worse, 81% had cataracts, 77% had band keratopathy, and 45% had glaucoma. When arthritis clearly preceded uveitis, 6% of patients had a poor visual outcome compared to 67% of patients whose initial manifestation of JRA was uveitis. Systemic corticosteroid administration used primarily for arthritis correlated with cataract formation.

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.

The Collaborative Initial Glaucoma treatment study: Interim quality of life findings after Initial medical or surgical treatment of Glaucoma

OBJECTIVE To present interim quality of life (QOL) findings in the Collaborative Initial Glaucoma Treatment Study (CIGTS) using all available follow-up through 5 years from treatment initiation. DESIGN Randomized controlled clinical trial. PARTICIPANTS Six hundred seven newly diagnosed patients with open-angle glaucoma from 14 clinical centers. INTERVENTION Patients were randomly assigned to either initial medical therapy or initial trabeculectomy. After treatment initiation and early follow-up, patients received clinical and QOL evaluations at 6-month intervals. QOL assessments were administered by telephone at a centralized interviewing center. MAIN OUTCOME MEASURES The CIGTS collected comprehensive QOL information that included both generic and vision-specific QOL measures. This article focuses on initial treatment group differences related to symptom reporting, as measured by a Symptom and Health Problem Checklist, and changes in daily visual functioning, as measured by the Visual Activities Questionnaire (VAQ). RESULTS Across both treatment groups, there was an overall decline in the percent of participants reporting symptoms over time. Of 43 possible symptoms, 12 symptoms were reported with greater frequency by the surgically treated group and 7 symptoms more frequently by the medically-treated group. The surgical patients reported more total Symptom Impact Glaucoma (P = 0.005) and, in particular, more bother related to local eye symptoms. Very few treatment group differences were noted in visual functioning, although surgical patients reported more problems with activities related to their visual acuity (P = 0.024). The percentage of patients across treatment groups reporting worry about blindness was 50% at baseline but declined to approximately 25% over time. CONCLUSIONS Overall, the QOL impact reported by the two treatment groups as measured by instruments used in this study is remarkably similar, with relatively few significant study group differences observed after up to 5 years of follow-up in the CIGTS. When significant differences in visual function have been detected using the VAQ, they are consistent with the clinical outcomes. To date, the most persistent QOL finding is the increased impact of local eye symptoms reported by the surgical group compared with the medical group. Although no changes are recommended in the treatment of newly diagnosed glaucoma patients at the time of this interim report, further follow-up will allow for more definitive answers to the QOL impact of these two treatment approaches.

Mutations in TCF8 Cause Posterior Polymorphous Corneal Dystrophy and Ectopic Expression of COL4A3 by Corneal Endothelial Cells

Posterior polymorphous corneal dystrophy (PPCD, also known as PPMD) is a rare disease involving metaplasia and overgrowth of corneal endothelial cells. In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern, produce an aberrant basement membrane, and, sometimes, spread over the iris and nearby structures in a way that increases the risk for glaucoma. We previously mapped PPCD to a region (PPCD3) on chromosome 10 containing the gene that encodes the two-handed zinc-finger homeodomain transcription factor TCF8. Here, we report a heterozygous frameshift mutation in TCF8 that segregates with PPCD in the family used to map PPCD3 and four different heterozygous nonsense and frameshift mutations in TCF8 in four other PPCD probands. Family reports of inguinal hernia, hydrocele, and possible bone anomalies in affected individuals suggest that individuals with TCF8 mutations should be examined for nonocular anomalies. We detect transcripts of all three identified PPCD genes (VSX1, COL8A2, and TCF8) in the cornea. We show presence of a complex (core plus secondary) binding site for TCF8 in the promoter of Alport syndrome gene COL4A3, which encodes collagen type IV alpha 3, and we present immunohistochemical evidence of ectopic expression of COL4A3 in corneal endothelium of the proband of the original PPCD3 family. Identification of TCF8 as the PPCD3 gene provides a valuable tool for the study of critical gene regulation events in PPCD pathology and suggests a possible role for TCF8 mutations in altered structure and function of cells lining body cavities other than the anterior chamber of the eye. Thus, this study has identified TCF8 as the gene responsible for approximately half of the cases of PPCD, has implicated TCF8 mutations in developmental abnormalities outside the eye, and has presented the TCF8 regulatory target, COL4A3, as a key, shared molecular component of two different diseases, PPCD and Alport syndrome.