Category: Peer-reviewed

Ophthalmic Evaluations in Clinical Studies of Fingolimod (FTY720) in Multiple Sclerosis – Corrected Proof

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Purpose:
To report outcomes of ophthalmic evaluations in clinical studies of patients receiving fingolimod (Gilenya; Novartis Pharma AG, Basel, Switzerland) for multiple sclerosis (MS).

Design:
Analysis done on pooled safety data (N = 2615, all studies group) from 3 double-masked, randomized, parallel-group clinical trials (phase 2 core and extension >5 years, and phase 3 FREEDOMS and TRANSFORMS core and extension studies).

Participants:
Patients aged 18 to 55 years (18–60 years in phase 2 study) diagnosed with relapsing-remitting MS were included. Patients with diabetes mellitus or macular edema (ME) at screening were excluded.

Intervention:
Participants received fingolimod (0.5/1.25 mg), placebo, or interferon beta for the respective study durations. Ophthalmic examination included detailed eye history (at screening), visual acuity (VA) assessment, dilated ophthalmoscopy, optical coherence tomography (OCT), and fluorescein angiography (FA).

Main Outcome Measures:
Extensive ophthalmic monitoring was performed for all patients. While being studied, patients with abnormal findings on dilated ophthalmoscopy and OCT compatible with ME were further studied by FA. All locally diagnosed ME cases were centrally reviewed by the retina specialist (M.A.Z.) on the Data and Safety Monitoring Board.

Results:
Among 2615 patients assessed, 19 confirmed ME cases were observed in fingolimod-treated groups (0.5 mg: n = 4, 0.3%; 1.25 mg: n = 15, 1.2%). Most patients (n = 13, 68%) presented with blurred vision, decreased VA, or eye pain. Macular edema was diagnosed within 3 to 4 months of treatment initiation in most cases (n = 13, 68%); 2 patients had late onset (>12 months) ME. Of the 19 patients with ME, 5 (26%), all treated with fingolimod 1.25 mg, had a history of uveitis compared with 26 (1%) in the all studies group. In most cases (n = 16, 84%), ME resolved after discontinuing the study drug. Eleven patients required topical anti-inflammatory medications. No patient had further vision deterioration.

Conclusions:
Fingolimod 0.5 mg is associated with a low incidence of ME in MS studies. Patients with a history of uveitis may be at an increased risk of developing ME. An ophthalmic examination before initiating fingolimod therapy and regular follow-up eye examinations during fingolimod therapy are recommended.

Financial Disclosure(s):
Proprietary or commercial disclosure may be found after the references.

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Inclusion of Genotype with Fundus Phenotype Improves Accuracy of Predicting Choroidal Neovascularization and Geographic Atrophy – Corrected Proof

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Purpose:
The accuracy of predicting conversion from early-stage age-related macular degeneration (AMD) to the advanced stages of choroidal neovascularization (CNV) or geographic atrophy (GA) was evaluated to determine whether inclusion of clinically relevant genetic markers improved accuracy beyond prediction using phenotypic risk factors alone.

Design:
Cohort study.

Participants:
White, non-Hispanic subjects participating in the Age-Related Eye Disease Study (AREDS) sponsored by the National Eye Institute consented to provide a genetic specimen. Of 2415 DNA specimens available, 940 were from disease-free subjects and 1475 were from subjects with early or intermediate AMD.

Methods:
DNA specimens from study subjects were genotyped for 14 single nucleotide polymorphisms (SNPs) in genes shown previously to associate with CNV: ARMS2, CFH, C3, C2, FB, CFHR4, CFHR5, and F13B. Clinical demographics and established disease associations, including age, sex, smoking status, body mass index (BMI), AREDS treatment category, and educational level, were evaluated. Four multivariate logistic models (phenotype; genotype; phenotype + genotype; and phenotype + genotype + demographic + environmental factors) were tested using 2 end points (CNV, GA). Models were fitted using Cox proportional hazards regression to use time-to-disease onset data.

Main Outcome Measures:
Brier score (measure of accuracy) was used to identify the model with the lowest prediction error in the training set. The most accurate model was subjected to independent statistical validation, and final model performance was described using area under the receiver operator curve (AUC) or C-statistic.

Results:
The CNV prediction models that combined genotype with phenotype with or without age and smoking revealed superior performance (C-statistic = 0.96) compared with the phenotype model based on the simplified severity scale and the presence of CNV in the nonstudy eye (C-statistic = 0.89; P<0.01). For GA, the model that combined genotype with phenotype demonstrated the highest performance (AUC = 0.94). Smoking status and ARMS2 genotype had less of an impact on the prediction of GA compared with CNV.

Conclusions:
Inclusion of genotype assessment improves CNV prediction beyond that achievable with phenotype alone and may improve patient management. Separate assessments should be used to predict progression to CNV and GA because genetic markers and smoking status do not equally predict both end points.

Financial Disclosure(s):
Proprietary or commercial disclosure may be found after the references.

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Morphologic Characteristics of Optic Nerve Head Drusen on Spectral-Domain Optical Coherence Tomography – Corrected Proof

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Purpose: To evaluate the morphologic characteristics of optic nerve head drusen.Design: Retrospective case series.Methods: Setting: Institutional (Seoul National University Bundang Hospital). Patients: Sixty-one patients with optic nerve head drusen. Observation procedure: Visible and buried optic nerve head drusen were identified using funduscopy, whereas homogenous and nonhomogenous optic nerve head drusen were identified using spectral-domain optical coherence tomography images. Buried optic nerve head drusen were classified according to the size. Main Outcome Measures: Classification of optic nerve head drusen.Results: Of 99 eyes in 61 patients, optic nerve head drusen were buried in 95 eyes and visible in 4 eyes. The patients with visible optic nerve head drusen were older on average than those with buried optic nerve head drusen (53.3 ± 8.6 years vs 13.5 ± 7.1 years; P < .001) and exhibited larger disc diameters (1643 ± 265 μm vs 1287 ± 185 μm; P = .016). All 4 eyes with visible optic nerve head drusen exhibited hyperreflective borders, which were not found in patients with buried optic nerve head drusen. Of 95 eyes with buried optic nerve head drusen, 64 eyes (67%) showed homogenous internal reflectivity, whereas 31 eyes (33%) showed nonhomogenous reflectivity with lobulations. Large optic nerve head drusen were associated with a small optic disc diameter, nonhomogenous internal reflectivity, a partial highly reflective border, intraretinal cysts, and increased temporal retinal nerve fiber layer thickness.Conclusions: Optic nerve head drusen have a diverse spectrum of spectral-domain optical coherence tomography findings associated with patient age and disc size.

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Endothelial Keratoplasty: Prospective, Randomized, Masked Clinical Trial Comparing an Injector With Forceps for Tissue Insertion – Corrected Proof

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Purpose: To compare the complications and outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK) when the tissue is either folded and inserted with a forceps or inserted using a platform injector device without folding.Design: Prospective, randomized, masked clinical trial.Methods: DSAEK was performed in 100 eyes of 79 patients undergoing DSAEK surgery for Fuchs corneal dystrophy. Fifty eyes were randomized to have the donor tissue inserted with Charlie II insertion forceps (Bausch & Lomb Surgical) and 50 eyes were randomized to have the donor tissue inserted with the Neusidl Corneal Inserter (Fischer Surgical Inc). All other steps of the surgical procedure were exactly the same. Surgical problems, postoperative complications, and central endothelial cell density at 6 months were recorded and then measured by a masked observer. The study’s main outcome measures were total central endothelial cell density and percentage of donor endothelial cell loss from before surgery to 6 months after surgery and rate of complications (graft dislocation and primary graft failure).Results: No primary graft failures occurred in either group and only 1 dislocation occurred in the series (Neusidl group). One late failure occurred at 6 months (Neusidl group). There was no difference in the preoperative endothelial cell density between the Neusidl and forceps groups, but there was a higher percentage of cell loss with the Neusidl group (33%) than with the forceps group (25%) at 6 months (P = .017).Conclusions: The Neusidl Corneal Inserter yielded a low immediate complication rate for DSAEK surgery for novice and experienced surgeons. Although still at an acceptable level, short-term endothelial survival was significantly worse after Neusidl tissue insertion than that after forceps tissue insertion.

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Surgical Management of Rhegmatogenous Retinal Detachment: A Meta-Analysis of Randomized Controlled Trials – Corrected Proof

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Purpose:
To examine possible differences in clinical outcomes between pars plana vitrectomy (PPV) and scleral buckling (SB) for uncomplicated rhegmatogenous retinal detachment (RRD).

Design:
Meta-analysis.

Participants:
Adult patients with uncomplicated RRD from previously reported randomized controlled trials of PPV and SB.

Methods:
A comprehensive literature search using the Cochrane Collaboration methodology to identify randomized controlled trials comparing PPV with SB for uncomplicated RRD.

Main Outcome Measures:
Analysis was divided into phakic and pseudophakic/aphakic patients. Primary outcome parameters included proportion of primary reattachment and difference of means of best-corrected visual acuity (BCVA) at 6 months or more between the PPV and SB groups. Secondary outcome parameters included the proportion of secondary reattachment and complications between the PPV and SB groups.

Results:
Seven studies were identified and analyzed for comparing PPV (636 eyes) with SB (670 eyes) for uncomplicated RRD. In the phakic group, there were no significant differences in the proportion of primary reattachments (odds ratio [OR], 1.00; 95% confidence interval [CI], 0.69–1.46) or secondary reattachments (OR, 0.99; 95% CI, 0.34–2.87) between the PPV and SB groups. Meta-analysis showed a statistically significant difference in the logarithm of the minimum angle of resolution (logMAR) BCVA at 6 months between the PPV-treated and SB-treated phakic eyes (mean deviation, 0.14; 95% CI, 0.06–0.21; P<0.0004). In the pseudophakic/aphakic group, there were no significant differences in the proportion of primary reattachments (OR, 1.46; 95% CI, 0.79–2.71) or logMAR BCVA at 6 months between the PPV and SB groups (mean deviation, −0.03; 95% CI, −0.10 to 0.04). A statistically significant difference was noted in the proportion of secondary reattachments (OR, 2.08; 95% CI, 1.08–4.03; P = 0.03) between the PPV and SB groups in pseudophakic/aphakic eyes. Meta-analysis showed a statistically significant rate of cataract progression in the PPV group (OR, 4.11; 95% CI, 2.70–6.25; P<0.00001).

Conclusions:
There were no significant differences in the proportions of primary reattachment in the PPV and SB groups in phakic eyes. The SB-treated phakic eyes had better postoperative BCVA at 6 months or more. This is most likely related to higher rates of cataract progression in PPV-treated phakic eyes. There were no significant differences in proportions of primary reattachment and postoperative BCVA at 6 months or more in pseudophakic/aphakic eyes.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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Anatomic and Visual Outcomes of Descemetopexy in Post-Cataract Surgery Descemet’s Membrane Detachment – Corrected Proof

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Objective:
To study the anatomic and visual outcomes of descemetopexy in Descemet’s membrane detachment (DMD) after cataract surgery.

Design:
Retrospective case series.

Participants:
Clinical notes of 60 patients who underwent DMD after cataract surgery between 2007 and 2011.

Methods:
Descemetopexy was performed with air or 14% isoexpansile perfluoropropane (C3F8).

Main Outcome Measures:
Anatomical (reattachment rates) and functional results (best-corrected visual acuity) were studied. Secondary outcome measures were assessment of surgical complications and association of various factors with final visual outcome.

Results:
The mean age of the patients was 64.3±8.3 years, and the male:female ratio was 21:39. At 1 month, the mean logarithm of the minimum angle of resolution (logMAR) interval visual acuity (IVA) improved from 1.27±0.8 to 0.42±0.49 (P < 0.001). Five patients (8.3%) obtained 20/20 vision, and 37 of 60 patients (61.6%) achieved IVA of ≥20/40. Ninety-five percent (57/60) of patients had successful reattachment of the Descemet’s membrane (DM) after the intervention. Multiple linear regression analysis showed that patients with a cataract score of 5 (estimate = 0.38; P=0.014), with a cataract score of 4 with compromised visibility due to a corneal opacity (estimate = 0.45; P=0.039), and prolonged duration between cataract surgery and descemetopexy (estimate = 0.012; P=0.007) were associated with a significantly poorer final visual outcome. No association of final visual outcome was observed with age; sex; eye treated; cataract scores 2, 3, and 4; preoperative visual acuity; and involvement of the visual axis (P > 0.5). The eyes in which air was used for descemetopexy (estimate = −0.2; P=0.009) had statistically significantly better final visual outcomes. Three patients (5%) had treatment failures and required subsequent endothelial transplantation. Pupillary block was observed in the early postoperative period in 7 patients (11.66%) in whom C3F8 had been used and was not seen with air (P=0.02).

Conclusions:
This study suggests that DMD after cataract surgery can be treated effectively and good visual outcomes can be expected if the patient is treated in time with anterior chamber injection of gas. Air has advantages of better efficacy than C3F8 without the risk of pupillary block and thus should be preferred.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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Association of Retinal Sensitivity to Integrity of Photoreceptor Inner/Outer Segment Junction in Patients with Diabetic Macular Edema – Corrected Proof

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Purpose:
To evaluate the relationship between retinal sensitivity and the photoreceptor inner segment/outer segment (IS/OS) layer status in patients with diabetic macular edema (DME).

Design:
Cross-sectional study.

Participants:
Twenty-five adult patients (37 eyes) diagnosed with DME and managed at the Wilmer Eye Institute, Johns Hopkins University (Baltimore, MD).

Methods:
We obtained simultaneous fundus microperimetry (MP) and optical coherence tomography (OCT) of patients with DME using a combined MP/OCT system. The device recorded retinal sensitivity and retinal thickness on a 3-dimensional tomography map, and we performed a point-by-point analysis of the IS/OS layer integrity at every MP point. We also reviewed OCT scans to determine the type of DME, cystoid macular edema, or diffuse macular edema (absence of any cysts). In addition, fixation stability and fixation location were analyzed.

Main Outcome Measures:
Retinal point sensitivity measured by MP.

Results:
Twenty-five patients (37 eyes: 29 male and 8 female; mean age, 64.16 years) with DME were enrolled. Fixation was centric in 30 eyes (81%), paracentric in 3 eyes (8%), and eccentric in 4 eyes (11%). Twenty-seven eyes had cystoid macular edema, and 10 eyes had diffuse macular edema. Mean central subfield thickness was 325 μm. We analyzed a total of 1036 individual MP points. Mean point sensitivity was 10.51 dB. A total of 793 points (76.5%) had IS/OS layer present, and 243 points (23.5%) had IS/OS layer disrupted. A mixed linear model, constructed to adjust for potential confounders and account for dependence between retinal points, revealed that the absence of the IS/OS junction was significantly associated with a 3.28-dB decrease in retinal point sensitivity (P<0.001).

Conclusions:
This novel index study demonstrates that disruption of the IS/OS junction is correlated with a significant decrease in point sensitivity in eyes with DME. Further studies are indicated to confirm and validate this relationship.

Financial Disclosure(s):
Proprietary or commercial disclosure may be found after the references.

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Myopia-Related Fundus Changes in Singapore Adults With High Myopia – Corrected Proof

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Purpose: To examine the pattern of myopia-related macular and optic disc changes in Singapore adults with high myopia (spherical equivalent ≤−6.00 diopters).Design: Asian adults with high myopia from 3 population-based surveys.Methods: Adults 40 years and older (n = 359) with high myopia were pooled from 3 population-based surveys in Singapore Asians: (1) the Singapore Prospective Study Program (SP2, n = 184); (2) the Singapore Malay Eye Study (SiMES, n = 98); and (3) the Singapore Indian Eye Study (SINDI, n = 77). All study participants underwent standardized refraction and fundus photography, and SiMES and SINDI subjects also completed ocular biometry measurements. Myopia-related macular (posterior staphyloma, lacquer cracks, Fuchs spot, myopic chorioretinal atrophy, and myopic choroidal neovascularization) and optic disc (optic nerve head tilt, optic disc dimensions, and peripapillary atrophy) changes were evaluated.Results: The most common myopia-related macular finding in adults with high myopia was staphyloma (23%), followed by chorioretinal atrophy (19.3%). There were few cases of lacquer crack (n = 6, 1.8%), T-sign (n = 6, 1.8%), retinal hemorrhage (n = 3, 0.9%), active myopic choroidal neovascularization (n = 3, 0.9%), and no case of Fuchs spot. The most common disc finding associated with high myopia was peripapillary atrophy (81.2%), followed by disc tilt (57.4%). Staphyloma and chorioretinal atrophy increased in prevalence with increasing age, increasing myopic refractive error, and increasing axial length (all P < .001). Ethnicity comparisons demonstrated the highest proportion of staphyloma (P = .04) among Malays, the highest proportion of peripapillary atrophy (P = .01) and disc tilt (P < .001) among Chinese, and the largest cup-to-disc ratio (P < .001) among Indians.Conclusions: Staphyloma and chorioretinal atrophy lesions were the most common fundus findings among Asian adults with high myopia. In this population, tilted discs and peripapillary atrophy were also common, while choroidal neovascularization and Fuchs spot were rare. In contrast with Singapore teenagers, in whom tilted disc and peripapillary atrophy were common while staphyloma and chorioretinal atrophy were rare, pathologic myopia appears to be dependent on the duration of disease and, thus, age of the individual.

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A Longitudinal Study of Stargardt Disease: Clinical and Electrophysiologic Assessment, Progression, and Genotype Correlations – Corrected Proof

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Purpose: To investigate the clinical and electrophysiologic natural history of Stargardt disease and correlate with the genotype.Design: Cohort study of 59 patients.Methods: Clinical history, examination, and electrophysiologic assessment were undertaken in a longitudinal survey. Patients were classified into 3 groups based on electrophysiologic findings, as previously published: Group 1 had dysfunction confined to the macula; Group 2 had macular and generalized cone system dysfunction; and Group 3 had macular and both generalized cone and rod system dysfunction. At baseline, there were 27 patients in Group 1, 17 in Group 2, and 15 in Group 3. Amplitude reduction of >50% in the relevant electroretinogram (ERG) component or a peak time shift of >3 ms for the 30 Hz flicker ERG or bright flash a-wave was considered clinically significant ERG deterioration. Molecular screening of ABCA4 was undertaken.Results: The mean age at baseline was 31.7 years, with the mean follow-up interval being 10.5 years. A total of 22% of patients from Group 1 showed ERG group transition during follow-up, with 11% progressing to Group 2 and 11% to Group 3. Forty-seven percent of patients in Group 2 progressed to Group 3. There was clinically significant ERG deterioration in 54% of all subjects: 22% of Group 1, 65% of Group 2, and 100% of Group 3. At least 1 disease-causing ABCA4 variant was identified in 47 patients.Conclusions: All patients with initial rod ERG involvement demonstrated clinically significant electrophysiologic deterioration; only 20% of patients with normal full-field ERGs at baseline showed clinically significant progression. Such data assist counseling by providing more accurate prognostic information and are also highly relevant in the design, patient selection, and monitoring of potential therapeutic interventions.

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Displacement of the Retina and Its Recovery After Vitrectomy in Idiopathic Epiretinal Membrane – Corrected Proof

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Objective: To study the displacement of the retina and its change after vitrectomy in idiopathic epiretinal membrane (ERM).Design: Prospective, interventional case series.Methods: Fifty-six eyes of 53 consecutive patients with ERM underwent vitrectomy with ERM removal and internal limiting membrane peeling. Fundus autofluorescence (FAF) imaging was examined before and at 1, 3, 6, and 12 months after vitrectomy. Main outcome measures were the proportion of eyes with retinal displacement for ERM detected by FAF imaging and the recovery rate of retinal displacement after vitrectomy.Results: Before surgery, FAF photography demonstrated hyperautofluorescent lines within the vascular arcade in 37 (66.1%) of the 56 eyes. The lines seemed to be consistent with the location of the retinal vessels before their displacement. These hyperautofluorescent lines appeared significantly more frequently among patients in whom the disease duration was 3 years or less. In 23 (62.2%) of these 37 eyes, within the first postoperative month, the hyperautofluorescent lines disappeared. The disappearance of the hyperautofluorescent line was thought to be the result of the return of the retinal vessel to its original position. Greater visual improvements (logarithm of the minimal angle of resolution, ≥0.3) were statistically significantly obtained in patients in whom the hyperautofluorescent lines had become indistinct at 1 month after surgery (P < .05).Conclusions: Hyperautofluorescent lines indicating retinal displacement were found by FAF in 66.1% of patients before surgery for ERM. In addition, retinal displacement was significantly more common among patients who had experienced subjective symptoms for 3 years or less. Fundus autofluorescence is useful for predicting postoperative visual acuity improvement.

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Retention of the Boston Keratoprosthesis Type 1: Multicenter Study Results – Corrected Proof

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Objective:
To report the retention rate of the Boston keratoprosthesis type 1 and to identify risk factors for keratoprosthesis loss.

Design:
Cohort study.

Participants:
A total of 300 eyes of 300 patients who underwent implantation of the Boston keratoprosthesis type I device between January 2003 and July 2008 by 19 surgeons at 18 medical centers.

Methods:
Forms reporting preoperative, intraoperative, and postoperative parameters were prospectively collected and subsequently analyzed at a central data collection site.

Main Outcome Measures:
Keratoprosthesis retention.

Results:
A total cumulative number of 422 life-years of device implantation are included in this analysis. The average duration of follow-up was 17.1±14.8 months, with a range of 1 week to >6.1 years. Ninety-three percent of the 300 Boston keratoprosthesis implants were retained at their last follow-up, corresponding to a retention time of 396 patient-years or 1.42 years/keratoprosthesis. The probability of retention after 1 year and 2 years was 94% and 89%, respectively. During the study period, 21 (7%) eyes failed to retain the device; the reasons for keratoprosthesis loss include sterile keratolysis (9), fungal infections (8), dense retroprosthetic membranes (3), and bacterial endophthalmitis (1). Multivariate analysis demonstrated 3 independent risk factors for keratoprosthesis loss: autoimmune cause (hazard ratio [HR], 11.94; 95% confidence interval [CI], 3.31–43.11), ocular surface exposure requiring a concomitant tarsorrhaphy (HR, 3.43; 95% CI, 1.05–11.22), and number of prior failed penetrating keratoplasties (HR, 1.64; 95% CI, 1.18–2.28).

Conclusions:
The Boston keratoprosthesis type 1 seems to be a viable option for eyes that are not candidates for penetrating keratoplasty (PK). Ocular surface disease due to an autoimmune cause demonstrated the lowest retention rate.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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