Robin L. Gal

Multiple sclerosis risk after optic neuritis: Final optic neuritis treatment trial follow-up

OBJECTIVE To assess the risk of developing multiple sclerosis (MS) after optic neuritis and the factors predictive of high and low risk. DESIGN Subjects in the Optic Neuritis Treatment Trial, who were enrolled between July 1, 1988, and June 30, 1991, were followed up prospectively for 15 years, with the final examination in 2006. SETTING Neurologic and ophthalmologic examinations at 13 clinical sites. PARTICIPANTS Three hundred eighty-nine subjects with acute optic neuritis. MAIN OUTCOME MEASURES Development of MS and neurologic disability assessment. RESULTS The cumulative probability of developing MS by 15 years after onset of optic neuritis was 50% (95% confidence interval, 44%-56%) and strongly related to presence of lesions on a baseline non-contrast-enhanced magnetic resonance imaging (MRI) of the brain. Twenty-five percent of patients with no lesions on baseline brain MRI developed MS during follow-up compared with 72% of patients with 1 or more lesions. After 10 years, the risk of developing MS was very low for patients without baseline lesions but remained substantial for those with lesions. Among patients without lesions on MRI, baseline factors associated with a substantially lower risk for MS included male sex, optic disc swelling, and certain atypical features of optic neuritis. CONCLUSIONS The presence of brain MRI abnormalities at the time of an optic neuritis attack is a strong predictor of the 15-year risk of MS. In the absence of MRI-detected lesions, male sex, optic disc swelling, and atypical clinical features of optic neuritis are associated with a low likelihood of developing MS. This natural history information is important when considering prophylactic treatment for MS at the time of a first acute onset of optic neuritis.

Treatment of Acute Optic Neuritis A Summary of Findings From the Optic Neuritis Treatment Trial

inconclusive because of small sample size. In the 1980s, the Optic Neuritis Treatment Trial was developed to evaluate corticosteroid treatment for optic neuritis. This multicenter randomized clinical trial, supported by the National Eye Institute, was designed to answer the following questions: (1) Does treatment with either oral prednisone or intravenous methylprednisolone followed by oral prednisone improve the visual outcome of acute optic neuritis? (2) Does either treatment speed recovery of vision? and (3) Are the complications of treatment insignificant in relation to the magnitude of the treatment effect? Long-term follow-up of the cohort was performed to investigate the relationship between optic neuritis and the development of multiple sclerosis (MS).

Specular Microscopy Ancillary Study Methods for Donor Endothelial Cell Density Determination of Cornea Donor Study Images

Purpose: To describe reliable methods for determining central corneal endothelial cell density (ECD) in a multicenter eye bank study. Methods: The Specular Microscopy Reading Center utilized a dual-grading procedure and adjudication process to classify image quality and determine ECD for a subset of donor endothelial images obtained in the Specular Microscopy Ancillary Study, which is part of the Cornea Donor Study.1 Two certified readers classified images as analyzable (excellent, good, fair) or unanalyzable and determined the ECD using a variable frame technique. An adjudicator also evaluated the images if quality classifications by the two readers differed by one grade, if any reader found the image unanalyzable, and/or if the ECD determination between the two readers was ≥ 5%. Results: Image quality categorization by the two readers was identical for 441 (64%) of 688 donor images. The ECD differed by < 5% for 442 (69%) of the 645 analyzable images. The ECD determined by the adjudicator was < 5% different than the ECD determined by at least one reader for 193 (95%) of the 203 remaining images. Conclusions: The dual-grading and adjudication procedures produce reliable, reproducible assessments of image quality and ECD. The importance of two independent readings is evident in that image quality ratings differed between the two readers by one grade in 36% of all images and ECD counts differed by ≥5% for 31% of analyzable images.

Clinical profile and early surgical complications in the Cornea Donor Study.

Purpose: The Cornea Donor Study was designed to investigate the safety and efficacy of older donor corneal tissue compared with younger donor tissue in recipient eyes at moderate risk to the graft from progressive endothelial failure. Baseline patient data, including indications for transplant, intraoperative complication rates, and early postoperative complication rates are described herein. Methods: This study was a multicenter prospective, double-masked, controlled clinical trial. Results: Fuchs dystrophy was the most common indication for corneal transplantation (61%). Intraoperative complications occurred in 33 (3%) patients. A persistent epithelial defect was the most commonly reported postoperative complication, occurring in 92 patients (8%). Conclusion: Intraoperative and postoperative complication rates were low. There was no apparent association between donor or recipient age and either intraoperative or early postoperative complication rates.

Visual field profile of optic neuritis: a final follow-up report from the optic neuritis treatment trial from baseline through 15 years.

OBJECTIVE To evaluate visual field abnormalities after an episode of optic neuritis among participants in the Optic Neuritis Treatment Trial. METHODS Three readers independently evaluated 10 443 visual fields from 454 patients and classified visual field abnormalities into 21 different monocular categories representing 3 general types of visual loss: diffuse, localized, and artifactual. Classification frequency was determined and reader agreement was evaluated. The association of visual field abnormality classifications with mean deviation, pattern standard deviation, visual acuity, and foveal threshold was assessed. RESULTS At baseline, diffuse loss accounted for 66.2% of the abnormalities in the affected eyes but only 6.2% of the abnormalities in the fellow eyes. During years 1 through 15, the affected and fellow eyes exhibited predominantly localized loss in the nerve fiber bundle region (partial arcuate, paracentral, and arcuate defects). At year 1, 35.7% of the abnormalities in the affected eyes and 34.4% in the fellow eyes consisted of localized defects. At year 15, 39.5% of abnormalities in the affected eyes and 26.3% in the fellow eyes consisted of localized defects. Foveal threshold was highly correlated with visual acuity and contrast sensitivity in the affected eye at baseline (-0.82 vs 0.79, respectively), 6 months (-0.84 vs 0.81), and 1 year (-0.84 vs 0.79). CONCLUSIONS Diffuse and central loss were more predominant in the affected eye at baseline, and nerve fiber bundle defects (partial arcuate, paracentral, and arcuate) were the most predominant localized abnormalities in both the affected and fellow eyes during the study.

Visual function at baseline and 1 month in acute optic neuritis: Predictors of visual outcome

Objective: To identify cutpoints for visual measures at baseline and 1 month predictive of abnormal 6-month vision that could be used as eligibility criteria in a clinical trial to test potential neuroprotection or myelin repair agents in patients with optic neuritis. To determine whether moderate-to-severe dysfunction in one or more visual measures at baseline or 1 month correlates with having major vision loss at 6 months. Methods: We used the Optic Neuritis Treatment Trial database to evaluate various cutpoints for baseline and 1-month vision levels that predicted abnormal 6-month vision. For selected cutpoints, we computed a 95% CI for positive predictive value and the required sample size if the cutpoint was to be used for clinical trial eligibility. We evaluated whether the degree of visual loss at baseline, 1 month, or change in visual function from baseline to 1 month correlated with 6-month visual acuity, contrast sensitivity, or threshold visual field. Results: The best cutpoints for baseline and 1 month were visual acuity ≤ 20/50, contrast sensitivity < 1.0 log units, and visual field mean deviation ≤ −15 dB. The same levels of visual dysfunction at 1 month, but not at baseline, correlated with having 6-month moderate-to-severe loss for each of these measures (p = 0.01). A trial could require as few as 100 subjects for an outcome variable of one or more abnormal measures. Cutpoints at 1 month were highly predictive of abnormal 6-month vision, but the proportion of patients who would be eligible for a trial would be small. Conclusion: Provided data can be used either for the clinician to counsel patients on expected visual outcome or for designing studies to test therapies that might reduce the amount of permanent optic nerve damage due to optic neuritis in high-risk patients.

Baseline Factors Related to Endothelial Cell Loss Following Penetrating Keratoplasty

OBJECTIVE To identify baseline (donor, recipient, and operative) factors that affect endothelial cell loss following penetrating keratoplasty for a moderate-risk condition (principally Fuchs dystrophy or pseudophakic or aphakic corneal edema). METHODS In a subset (n = 567) of Cornea Donor Study participants, preoperative and postoperative endothelial cell densities (ECDs) were determined by a central reading center. Multivariate regression analyses were performed to examine which baseline factors correlated with ECD over time. RESULTS Larger grafts (P < .001), younger donor age (P < .001), and female donor (P = .004) were significantly associated with higher ECD during follow-up. Median endothelial cell loss at 5 years was 68% for grafts larger than 8.0 to 9.0 mm in diameter, 75% for grafts 7.0 mm to smaller than 8.0 mm in diameter, and 74% for grafts 8.0 mm in diameter. Grafts from female donors experienced a 67% cell loss compared with a 72% cell loss among grafts from male donors. Method of tissue retrieval, donor cause of death, history of diabetes, and time from death to preservation or to surgery were not significantly associated with changes in ECD over time. CONCLUSIONS Following penetrating keratoplasty for endothelial dysfunction conditions, larger donor graft size, younger donor age, and female donor were associated with higher ECD over 5 years. These data warrant exploring the possibility that similar associations may exist following endothelial keratoplasty. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00006411.

Effect of donor and recipient factors on corneal graft rejection

Purpose: To assess the relationship between donor and recipient factors and corneal allograft rejection in eyes that underwent penetrating keratoplasty in the Cornea Donor Study. Methods: Overall, 1090 subjects undergoing corneal transplantation for a moderate risk condition (principally Fuchs dystrophy or pseudophakic corneal edema) were followed for up to 5 years. Associations of baseline recipient and donor factors with the occurrence of a probable or definite rejection event were assessed in univariate and multivariate proportional hazards models. Results: Eyes with pseudophakic or aphakic corneal edema (n = 369) were more likely to experience a rejection event than eyes with Fuchs dystrophy (n = 676) [34% ± 6% vs. 22% ± 4%; hazard ratio = 1.56; 95% confidence interval (CI), 1.21–2.03]. Among eyes with Fuchs dystrophy, a higher probability of a rejection event was observed in phakic posttransplant eyes compared with those that underwent cataract extraction with or without intraocular lens implantation during penetrating keratoplasty (29% vs. 19%; hazard ratio = 0.54; 95% CI, 0.36–0.82). Female recipients had a higher probability of a rejection event than male recipients (29% vs. 21%; hazard ratio = 1.42; 95% CI, 1.08–1.87) after controlling for the effect of preoperative diagnosis and lens status. Donor age and donor recipient ABO compatibility were not associated with rejection. Conclusions: There was a substantially higher graft rejection rate in eyes with pseudophakic or aphakic corneal edema compared to that in eyes with Fuchs dystrophy. Female recipients were more likely to have a rejection event than male recipients. Graft rejection was not associated with donor age.

The Effect of ABO Blood Incompatibility on Corneal Transplant Failure in Conditions with Low Risk of Graft Rejection

PURPOSE To determine whether corneal graft survival over a 5-year follow-up period was affected by ABO blood type compatibility in participants in the Cornea Donor Study undergoing corneal transplantation principally for Fuchs dystrophy or pseudophakic corneal edema, conditions at low-risk for graft rejection. DESIGN Multi-center prospective, double-masked, clinical trial. METHODS ABO blood group compatibility was determined for 1,002 donors and recipients. During a 5-year follow-up period, episodes of graft rejection were documented, and graft failures were classified as to whether or not they were attributable to immunologic rejection. Endothelial cell density was determined by a central reading center for a subset of subjects. RESULTS ABO donor-recipient incompatibility was not associated with graft failure attributable to any cause including graft failure because of rejection, or with the occurrence of a rejection episode. The 5-year cumulative incidence of graft failure attributable to rejection was 32 (6%) for recipients with ABO recipient-donor compatibility and 12 (4%) for those with ABO incompatibility (hazard ratio, 0.65; 95% confidence interval, 0.33 to 1.25; P = .20). The 5-year incidence for a definite rejection episode, irrespective of whether graft failure ultimately occurred, was 64 (12%) for ABO compatible compared with 25 (8%) for ABO incompatible cases (P = .09). Among clear grafts at 5 years, percent loss of endothelial cells was similar in ABO compatible and incompatible cases. CONCLUSIONS In patients undergoing penetrating keratoplasty for Fuchs dystrophy or pseudophakic corneal edema, ABO matching is not indicated since ABO incompatibility does not increase the risk of transplant failure attributable to graft rejection.

Cornea preservation time study: methods and potential impact on the cornea donor pool in the United States.

Purpose: The aim of this study was to describe the aims, methods, donor and recipient cohort characteristics, and potential impact of the Cornea Preservation Time Study (CPTS). Methods: The CPTS is a randomized clinical trial conducted at 40 clinical sites (70 surgeons) designed to assess the effect of donor cornea preservation time (PT) on graft survival 3 years after Descemet stripping automated endothelial keratoplasty (DSAEK). Eyes undergoing surgery for Fuchs endothelial corneal dystrophy or pseudophakic/aphakic corneal edema were randomized to receive donor corneas stored ⩽7 days or 8 to 14 days. Donor and patient characteristics, tissue preparation and surgical parameters, recipient and donor corneal stroma clarity, central corneal thickness, intraocular pressure, complications, and a reading center-determined central endothelial cell density were collected. Surveys were conducted to evaluate pre-CPTS PT practices. Results: The 1330 CPTS donors were: 49% >60 years old, 27% diabetic, had a median eye bank–determined screening endothelial cell density of 2688 cells/mm2, and 74% eye bank prepared for DSAEK. A total of 1090 recipients (1330 eyes including 240 bilateral cases) had: median age of 70 years, were 60% female, 90% white, 18% diabetic, 52% phakic, and 94% had Fuchs endothelial corneal dystrophy. Before the CPTS, 19 eye banks provided PT data on 20,852 corneas domestically placed for DSAEK in 2010 to 2011; 96% were preserved ⩽7 days. Of 305 American Academy of Ophthalmology members responding to a pre-CPTS survey, 233 (76%) set their maximum PT preference at 8 days or less. Conclusions: The CPTS will increase understanding of factors related to DSAEK success and, if noninferiority of longer PT is shown, will have great potential to extend the available pool of endothelial keratoplasty donors. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01537393.