David C. Musch

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.

Descemet's Stripping Endothelial Keratoplasty: Safety and Outcomes

OBJECTIVE To review the published literature on safety and outcomes of Descemets stripping endothelial keratoplasty (DSEK) for the surgical treatment of endothelial diseases of the cornea. DESIGN Peer-reviewed literature searches were conducted in PubMed and the Cochrane Library with the most recent search in February 2009. The searches yielded 2118 citations in English-language journals. The abstracts of these articles were reviewed and 131 articles were selected for possible clinical relevance, of which 34 were determined to be relevant to the assessment objectives. RESULTS The most common complications from DSEK among reviewed reports included posterior graft dislocations (mean, 14%; range, 0%-82%), followed by endothelial graft rejection (mean, 10%; range, 0%-45%), primary graft failure (mean, 5%; range, 0%-29%), and iatrogenic glaucoma (mean, 3%; range, 0%-15%). Average endothelial cell loss as measured by specular microscopy ranged from 25% to 54%, with an average cell loss of 37% at 6 months, and from 24% to 61%, with an average cell loss of 42% at 12 months. The average best-corrected Snellen visual acuity (mean, 9 months; range, 3-21 months) ranged from 20/34 to 20/66. A review of postoperative refractive results found induced hyperopia ranging from 0.7 to 1.5 diopters (D; mean, 1.1 D), with minimal induced astigmatism ranging from -0.4 to 0.6 D and a mean refractive shift of 0.11 D. A review of graft survival found that clear grafts at 1 year ranged from 55% to 100% (mean, 94%). CONCLUSIONS The evidence reviewed is supportive of DSEK being a safe and effective treatment for endothelial diseases of the cornea. In terms of surgical risks, complication rates, graft survival (clarity), visual acuity, and endothelial cell loss, DSEK appears similar to penetrating keratoplasty (PK). It seems to be superior to PK in terms of earlier visual recovery, refractive stability, postoperative refractive outcomes, wound and suture-related complications, and intraoperative and late suprachoroidal hemorrhage risk. The most common complications of DSEK do not appear to be detrimental to the ultimate vision recovery in most cases. Long-term endothelial cell survival and the risk of late endothelial rejection are beyond the scope of this assessment. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

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.

Deep Anterior Lamellar Keratoplasty as an Alternative to Penetrating Keratoplasty: A Report by the American Academy of Ophthalmology

OBJECTIVE To review the published literature on deep anterior lamellar keratoplasty (DALK) to compare DALK with penetrating keratoplasty (PK) for the outcomes of best spectacle-corrected visual acuity (BSCVA), refractive error, immune graft rejection, and graft survival. METHODS Searches of the peer-reviewed literature were conducted in the PubMed and the Cochrane Library databases. The searches were limited to citations starting in 1997, and the most recent search was in May 2009. The searches yielded 1024 citations in English-language journals. The abstracts of these articles were reviewed, and 162 articles were selected for possible clinical relevance, of which 55 were determined to be relevant to the assessment objective. RESULTS Eleven DALK/PK comparative studies (level II and level III evidence) were identified that compared the results of DALK and PK procedures directly; they included 481 DALK eyes and 501 PK eyes. Of those studies reporting vision and refractive data, there was no significant difference in BSCVA between the 2 groups in 9 of the studies. There was no significant difference in spheroequivalent refraction in 6 of the studies, nor was there a significant difference in postoperative astigmatism in 9 of the studies, although the range of astigmatism was often large for both groups. Endothelial cell density (ECD) stabilized within 6 months after surgery in DALK eyes. Endothelial cell density values were higher in the DALK groups in all studies at study completion, and, in general, the ECD differences between DALK and PK groups were significant at all time points at 6 months or longer after surgery for all of the studies reporting data. CONCLUSIONS On the basis of level II evidence in 1 study and level III evidence in 10 studies, DALK is equivalent to PK for the outcome measure of BSCVA, particularly if the surgical technique yields minimal residual host stromal thickness. There is no advantage to DALK for refractive error outcomes. Although improved graft survival in DALK has yet to be demonstrated, postoperative data indicate that DALK is superior to PK for preservation of ECD. Endothelial immune graft rejection cannot occur after DALK, which may simplify long-term management of DALK eyes compared with PK eyes. As an extraocular procedure, DALK has important theoretic safety advantages, and it is a good option for visual rehabilitation of corneal disease in patients whose endothelium is not compromised.

Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant

BACKGROUND Sustained-release, intraocular implants that deliver ganciclovir are an alternative method for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS). METHODS We conducted a randomized study of 188 patients with AIDS and newly diagnosed cytomegalovirus retinitis. The patients were randomly assigned to treatment with an implant delivering 1 microg of ganciclovir per hour, an implant delivering 2 microg of ganciclovir per hour, or intravenous ganciclovir. The primary outcome we studied was progression of cytomegalovirus retinitis. RESULTS The median time to progression of retinitis was 221 days with the 1-microg-per-hour implant (75 eyes), 191 days with the 2-microg-per-hour implant (71 eyes), and 71 days with ganciclovir administered intravenously (76 eyes; P<0.001). The risk of progression of retinitis was almost three times as great among patients treated with intravenous ganciclovir as among those treated with a ganciclovir implant (risk ratio, 2.8; P<0.001). However, the risk of disease in the initially uninvolved eye was lower with intravenous ganciclovir than with a ganciclovir implant (risk ratio, 0.5; P=0.19). Patients treated with intravenous ganciclovir were also less likely to have extraocular cytomegalovirus infections (0, vs. 10.3 percent in the two implant groups; P=0.04). CONCLUSIONS For the treatment of cytomegalovirus retinitis, the sustained-release ganciclovir implant is more effective than intravenous ganciclovir, but patients treated with a ganciclovir implant alone remain at greater risk for the development of cytomegalovirus disease outside of the treated eye.

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.

Brain biopsy in primary angiitis of the central nervous system

Article abstract To determine the yield of brain biopsy and the predictive value of clinical features and ancillary studies, we retrospectively analyzed hospital chart data from 61 consecutive patients suspected of having primary angiitis of the CNS (PACNS). Biopsies disclosed PACNS in 22 (36%), alternative diagnoses in 24 (39%), and no diagnosis in 15 (25%). Clinical indicators and angiography were not useful predictors of PACNS. Brain biopsy should be the primary diagnostic tool in this setting because of the poor reliability of other indicators and because of the high yield of alternative diagnoses requiring different management.

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.