Kimberly A. Drenser

Diversity of retinal vascular anomalies in patients with familial exudative vitreoretinopathy.

PURPOSEnTo describe the diversity of clinical findings associated with familial exudative vitreoretinopathy (FEVR) using wide-field angiography and to update the current classification system.nnnDESIGNnRetrospective case series at a single tertiary referral vitreoretinal practice.nnnPARTICIPANTSnA total of 174 eyes of 87 subjects were studied.nnnMETHODSnA retrospective chart review was conducted of patients with a diagnosis of FEVR between January 2011 and January 2013 at a single tertiary care retina practice. Data were collected from patient charts, including sex, gestational age at birth, age at presentation, referring diagnosis, family history, prior ocular surgery, clinical presentation, and diagnostic imaging in each eye. Inclusion criteria included clinical diagnosis of FEVR in patients referred to our clinic for evaluation of decreased vision. Patients were excluded if a diagnosis of FEVR could not be made.nnnMAIN OUTCOME MEASURESnClinical and angiographic findings.nnnRESULTSnA total of 87 subjects met the inclusion criteria for this study. A broad spectrum of previously undescribed clinical and angiographic findings were associated with FEVR on wide-field angiography. These findings can be grossly divided into anatomic and functional changes. Anatomic changes include aberrant circumferential peripheral vessels, venous and arterial tortuosity, late-phase disc leakage, central and peripheral telangiectasias, capillary anomalies, and capillary agenesis. Functional changes include venous-venous shunting, delayed arteriovenous transit, and delayed or absent choroidal perfusion on fluorescein angiography.nnnCONCLUSIONSnFamilial exudative vitreoretinopathy has a wide range of unrecognized or under-recognized clinical and angiographic findings that are easily identified using wide-field fluorescein angiography. These novel findings have led to an update of the original FEVR classification scheme and more complete characterization of early stages of FEVR.

High Prevalence of Peripheral Retinal Vascular Anomalies in Family Members of Patients with Familial Exudative Vitreoretinopathy

OBJECTIVEnTo describe the prevalence and severity of familial exudative vitreoretinopathy (FEVR) in asymptomatic relatives of known symptomatic FEVR patients.nnnDESIGNnUncontrolled and retrospective case series at a single tertiary referral vitreoretinal practice.nnnPARTICIPANTSnA total of 148 eyes of 74 subjects were studied.nnnMETHODSnA retrospective chart review was conducted of patients with a diagnosis of FEVR between January 2011 and January 2013 at a single tertiary care retina practice. Data were collected from patient charts, including sex, gestational age at birth, age at presentation, referring diagnosis, family history, prior ocular surgery, clinical presentation, and diagnostic imaging in each eye. Inclusion criteria included confirmed clinical diagnosis of FEVR in patients referred to our clinic for evaluation of decreased vision. Patients were excluded if a definitive diagnosis of FEVR could not be made.nnnMAIN OUTCOME MEASURESnClinical and angiographic findings.nnnRESULTSnA total of 74 subjects from 17 separate families met the inclusion criteria for this study. There were an average of 4.4 subjects per family included in this study. The cohort was 55% male and included 17 patients and 57 family members who agreed to undergo genotyping, examination, and diagnostic imaging. Forty-three percent of FEVR patients had detectable mutations in FZD4, NDP, or TSPAN12. Only 8% of the cohort reported a positive family history of FEVR in a first-degree relative. Among the index patients, 76% had clinical stage 3, 4, or 5 FEVR and 24% had stage 1 or 2 FEVR. Among the asymptomatic family members screened, 58% demonstrated clinical or angiographic findings consistent with stage 1 or 2 FEVR and 21% demonstrated clinical or angiographic findings consistent with stage 3, 4, or 5 FEVR.nnnCONCLUSIONSnAsymptomatic family members of FEVR patients frequently have early manifestations of FEVR (stage 1 or 2). Early-stage FEVR may progress to more advanced stages, which can result in vision loss. These data support the use of angiographic screening and clinical examination in immediate relatives of patients with symptomatic FEVR.

Expert Diagnosis of Plus Disease in Retinopathy of Prematurity From Computer-Based Image Analysis

IMPORTANCEnPublished definitions of plus disease in retinopathy of prematurity (ROP) reference arterial tortuosity and venous dilation within the posterior pole based on a standard published photograph. One possible explanation for limited interexpert reliability for a diagnosis of plus disease is that experts deviate from the published definitions.nnnOBJECTIVEnTo identify vascular features used by experts for diagnosis of plus disease through quantitative image analysis.nnnDESIGN, SETTING, AND PARTICIPANTSnA computer-based image analysis system (Imaging and Informatics in ROP [i-ROP]) was developed using a set of 77 digital fundus images, and the system was designed to classify images compared with a reference standard diagnosis (RSD). System performance was analyzed as a function of the field of view (circular crops with a radius of 1-6 disc diameters) and vessel subtype (arteries only, veins only, or all vessels). Routine ROP screening was conducted from June 29, 2011, to October 14, 2014, in neonatal intensive care units at 8 academic institutions, with a subset of 73 images independently classified by 11 ROP experts for validation. The RSD was compared with the majority diagnosis of experts.nnnMAIN OUTCOMES AND MEASURESnThe primary outcome measure was the percentage of accuracy of the i-ROP system classification of plus disease, with the RSD as a function of the field of view and vessel type. Secondary outcome measures included the accuracy of the 11 experts compared with the RSD.nnnRESULTSnAccuracy of plus disease diagnosis by the i-ROP computer-based system was highest (95%; 95% CI, 94%-95%) when it incorporated vascular tortuosity from both arteries and veins and with the widest field of view (6-disc diameter radius). Accuracy was 90% or less when using only arterial tortuosity and 85% or less using a 2- to 3-disc diameter view similar to the standard published photograph. Diagnostic accuracy of the i-ROP system (95%) was comparable to that of 11 expert physicians (mean 87%, range 79%-99%).nnnCONCLUSIONS AND RELEVANCEnExperts in ROP appear to consider findings from beyond the posterior retina when diagnosing plus disease and consider tortuosity of both arteries and veins, in contrast with published definitions. It is feasible for a computer-based image analysis system to perform comparably with ROP experts, using manually segmented images.

Evaluation of Screening for Retinopathy of Prematurity by ROPtool or a Lay Reader.

PURPOSEnTo determine if (1) tortuosity assessment by a computer program (ROPtool, developed at the University of North Carolina, Chapel Hill, and Duke University, and licensed by FocusROP) that traces retinal blood vessels and (2) assessment by a lay reader are comparable with assessment by a panel of 3 retinopathy of prematurity (ROP) experts for remote clinical grading of vascular abnormalities such as plus disease.nnnDESIGNnValidity and reliability analysis of diagnostic tools.nnnPARTICIPANTSnThree hundred thirty-five fundus images of prematurely born infants.nnnMETHODSnThree hundred thirty-five fundus images of prematurely born infants were obtained by neonatal intensive care unit nurses. A panel of 3 ROP experts graded 84 images showing vascular dilatation, tortuosity, or both and 251 images showing no evidence of vascular abnormalities. These images were sent electronically to an experienced lay reader who independently graded them for vascular abnormalities. The images also were analyzed using the ROPtool, which assigns a numerical value to the level of vascular abnormality and tortuosity present in each of 4 quadrants or sectors. The ROPtool measurements of vascular abnormalities were graded and compared with expert panel grades with a receiver operating characteristic (ROC) curve. Grades between human readers were cross-tabulated. The area under the ROC curve was calculated for the ROPtool, and sensitivity and specificity were computed for the lay reader.nnnMAIN OUTCOME MEASURESnMeasurements of vascular abnormalities by ROPtool and grading of vascular abnormalities by 3 ROP experts and 1 experienced lay reader.nnnRESULTSnThe ROC curve for ROPtools tortuosity assessment had an area under the ROC curve of 0.917. Using a threshold value of 4.97 for the second most tortuous quadrant, ROPtools sensitivity was 91% and its specificity was 82%. Lay reader sensitivity and specificity were 99% and 73%, respectively, and had high reliability (κ, 0.87) in repeated measurements.nnnCONCLUSIONSnROPtool had very good accuracy for detection of vascular abnormalities suggestive of plus disease when compared with expert physician graders. The lay readers results showed excellent sensitivity andxa0good specificity when compared with those of the expert graders. These options for remote reading of images to detect vascular abnormalities deserve consideration in the quest to use telemedicine with remotexa0reading for efficient delivery of high-quality care and to detect infants requiring bedside examination.

Familial Exudative Vitreoretinopathy: Spectral-Domain Optical Coherence Tomography of the Vitreoretinal Interface, Retina, and Choroid

PURPOSEnThe in vivo microstructural features of familial exudative vitreoretinopathy (FEVR) have not been well described. We present new anatomic features of FEVR with functional and genetic correlations.nnnDESIGNnConsecutive, retrospective, observational case series.nnnPARTICIPANTSnPatients with FEVR treated from 2009 to 2014.nnnMETHODSnWe identified 346 patients with FEVR. Those imaged with spectral-domain optical coherence tomography (SD OCT) with or without enhanced depth imaging (EDI) were included, and images were correlated with best-corrected visual acuity (BCVA), widefield angiography, fundus autofluorescence (AF), and wnt signaling pathway mutations.nnnMAIN OUTCOME MEASURESnExploratory SD OCT findings and BCVA.nnnRESULTSnA total of 225 imaging sessions were acquired in 74 eyes from 41 patients. Mean age was 19.0 years. Sixty-seven eyes (91%) had interpretable images, of which 50 (75%) had anomalous microstructural findings; all eyes with FEVR severity of stage 2 or greater had abnormalities. A broad spectrum of features were identified: various forms of posterior hyaloidal organization, vitreomacular traction (VMT), vitreopapillary traction, vitreo-fold traction, vitreo-laser scar adhesion, diminished foveal contour, persistent fetal foveal architecture, cystoid macular edema (CME), intraretinal exudates and subretinal lipid aggregation, dry or edematous radial folds, and disruption of the ellipsoid zone. Mean foveal, central macular, and choroidal thicknesses were 305±145 μm, 337±160 μm, and 216±64 μm, respectively. In stages 1 to 2, greater foveal and central macular thicknesses (Rho=0.493, 0.544, respectively; both P<0.001) correlated with poorer BCVA, but not choroidal thickness (Rho=0.032; P=0.868). Posterior hyaloidal organization (P<0.001), VMT (P<0.001), CME (P<0.001), exudation (P<0.001), and disruption of the ellipsoid zone (P<0.001) were associated with poorer BCVA. Disruption of the ellipsoid zone (β=0.699; P<0.001) and posterior hyaloidal organization (β=0.289; P=0.011) retained significance in multivariate modeling (R2=0.627; P<0.001). Spectral-domain OCT detected all cases of angiographic edema and areas of outer retinal dysfunction that were hypoautofluorescent on AF. Microstructural-genetic associations were not identified.nnnCONCLUSIONSnSpectral-domain OCT imaging identified microstructural anomalies in the majority of patients with FEVR.

Frizzled-4 Variations Associated with Retinopathy and Intrauterine Growth Retardation: A Potential Marker for Prematurity and Retinopathy.

PURPOSEnTo present the association between mutations affecting the Wnt-signaling receptor protein (FZD4), inherited vitreoretinopathies, and retinopathy of prematurity (ROP).nnnDESIGNnRetrospective analysis of prospective samples at a tertiary referral center.nnnPARTICIPANTSnPatients referred to our practice for management of a variety of pediatric vitreoretinopathies were offered participation in an ophthalmic biobank (421 participants with vitreoretinopathies were included in this study). Full-term healthy infants (n = 98) were recruited to the study as controls.nnnMETHODSnPatients with various vitreoretinopathies were prospectively enrolled in an ophthalmic biobank, approved by the Human Investigation Committee at William Beaumont Hospital. Retrospective genetic analysis of the FZD4 gene was performed (Sanger sequencing). Participants with a diagnosis of familial exudative vitreoretinopathy (FEVR), Norrie disease, Coats disease, bilateral persistent fetal vasculature, and ROP were reviewed for the presence of a FZD4 variant. Data retrieval included status of retinopathy (including staging when possible), gestational age (GA), birth weight (BW) (when available), and family and birth histories.nnnMAIN OUTCOME MEASURESnThe association of FZD4 variants with the presence of vitreoretinopathy.nnnRESULTSnThe sequence variation p.[P33S(;)P168S] is the most prevalent FZD4 variant and is statistically significant for ROP and FEVR (P = 4.6E-04 and P = 2.4E-03, respectively) compared with full-term newborns (P = 1.7E-01). In addition, infants expressing the sequence variation tended to have significantly lower BWs for respective GA (P = 0.04). This suggests that the FZD4 p.[P33S(;)P168S] variant may be a risk factor for retinopathy and restricted intrauterine growth.nnnCONCLUSIONSnTesting for FZD4 gene mutations is useful in patients with suspected FEVR and ROP. The relatively high prevalence of the p.[P33S(;)P168S] variant in ROP and intrauterine growth restriction suggests that it also may be a marker for increased risk of developing ROP and preterm birth.

Plus Disease in Retinopathy of Prematurity: Improving Diagnosis by Ranking Disease Severity and Using Quantitative Image Analysis.

PURPOSEnTo determine expert agreement on relative retinopathy of prematurity (ROP) disease severity and whether computer-based image analysis can model relative disease severity, and to propose consideration of a more continuous severity score for ROP.nnnDESIGNnWe developed 2 databases of clinical images of varying disease severity (100 images and 34 images) as part of the Imaging and Informatics in ROP (i-ROP) cohort study and recruited expert physician, nonexpert physician, and nonphysician graders to classify and perform pairwise comparisons on both databases.nnnPARTICIPANTSnSix participating expert ROP clinician-scientists, each with a minimum of 10 years of clinical ROP experience and 5 ROP publications, and 5 image graders (3 physicians and 2 nonphysician graders) who analyzed images that were obtained during routine ROP screening in neonatal intensive care units.nnnMETHODSnImages in both databases were ranked by average disease classification (classification ranking), by pairwise comparison using the Elo rating method (comparison ranking), and by correlation with the i-ROP computer-based image analysis system.nnnMAIN OUTCOME MEASURESnInterexpert agreement (weighted κ statistic) compared with the correlation coefficient (CC) between experts on pairwise comparisons and correlation between expert rankings and computer-based image analysis modeling.nnnRESULTSnThere was variable interexpert agreement on diagnostic classification of disease (plus, preplus, or normal) among the 6 experts (mean weighted κ, 0.27; range, 0.06-0.63), but good correlation between experts on comparison ranking of disease severity (mean CC, 0.84; range, 0.74-0.93) on the set of 34 images. Comparison ranking provided a severity ranking that was in good agreement with ranking obtained by classification ranking (CC, 0.92). Comparison ranking on the larger dataset by both expert and nonexpert graders demonstrated good correlation (mean CC, 0.97; range, 0.95-0.98). The i-ROP system was able to model this continuous severity with good correlation (CC, 0.86).nnnCONCLUSIONSnExperts diagnose plus disease on a continuum, with poor absolute agreement on classification but good relative agreement on disease severity. These results suggest that the use of pairwise rankings and a continuous severity score, such as that provided by the i-ROP system, may improve agreement on disease severity in the future.

Plus Disease in Retinopathy of Prematurity: A Continuous Spectrum of Vascular Abnormality as a Basis of Diagnostic Variability.

PURPOSEnTo identify patterns of interexpert discrepancy in plus disease diagnosis in retinopathy of prematurity (ROP).nnnDESIGNnWe developed 2 datasets of clinical images as part of the Imaging and Informatics in ROP study and determined a consensus reference standard diagnosis (RSD) for each image based on 3 independent image graders and the clinical examination results. We recruited 8 expert ROP clinicians to classify these images and compared the distribution of classifications between experts and the RSD.nnnPARTICIPANTSnEight participating experts with more than 10 years of clinical ROP experience and more than 5 peer-reviewed ROP publications who analyzed images obtained during routine ROP screening in neonatal intensive care units.nnnMETHODSnExpert classification of images of plus disease in ROP.nnnMAIN OUTCOME MEASURESnInterexpert agreement (weighted κ statistic) and agreement and bias on ordinal classification between experts (analysis of variance [ANOVA]) and the RSD (percent agreement).nnnRESULTSnThere was variable interexpert agreement on diagnostic classifications between the 8 experts and the RSD (weighted κ, 0-0.75; mean, 0.30). The RSD agreement ranged from 80% to 94% for the dataset of 100 images and from 29% to 79% for the dataset of 34 images. However, when images were ranked in order of disease severity (by average expert classification), the pattern of expert classification revealed a consistent systematic bias for each expert consistent with unique cut points for the diagnosis of plus disease and preplus disease. The 2-way ANOVA model suggested a highly significant effect of both image and user on the average score (dataset A: P < 0.05 and adjusted R2xa0= 0.82; and dataset B: P < 0.05 and adjusted R2xa0=xa00.6615).nnnCONCLUSIONSnThere is wide variability in the classification of plus disease by ROP experts, which occurs because experts have different cut points for the amounts of vascular abnormality required for presence of plus and preplus disease. This has important implications for research, teaching, and patient care for ROP and suggests that a continuous ROP plus disease severity score may reflect more accurately the behavior of expert ROP clinicians and may better standardize classification in the future.

Long-term outcomes on lens clarity after lens-sparing vitrectomy for retinopathy of prematurity.

OBJECTIVEnTo describe the long-term effect of lens-sparing vitrectomy surgery for advanced retinopathy of prematurity (ROP) on lens clarity.nnnDESIGNnRetrospective case series at a single tertiary referral pediatric vitreoretinal practice.nnnPARTICIPANTSnFour hundred ninety-six eyes from 351 patients were included.nnnMETHODSnA retrospective chart review was conducted of patients with diagnosis of ROP stage 4A, 4B, and 5 who underwent lens-sparing vitrectomy (LSV) between 1992 and 2013. Data were collected from patient charts, including gender, date of birth, gestational age at birth, birthweight, stage of ROP at presentation, initial treatment (laser or cryotherapy), date of LSV, date of lensectomy (if performed), lens status at time of lensectomy, date of last visit, lens status at last visit, subsequent retinal surgeries, and retinal attachment status at last visit. Patients were excluded if any surgery had been performed at an outside institution before referral, or if a scleral buckle had been placed. Eyes with a concurrent anatomic abnormality, such as coloboma or microcornea, or a known family history of familial exudative vitreoretinopathy (FEVR), were also excluded.nnnMAIN OUTCOME MEASURESnRetinal reattachment after LSV, lensectomy after LSV, lens opacity at the time of lensectomy, and lens clarity at last follow-up.nnnRESULTSnFour hundred ninety-six eyes from 351 patients met inclusion criteria for this study. The reattachment rate after a single LSV surgery was 82.1% for stage 4A, 69.5% for stage 4B, and 42.6% for stage 5. Subsequent retinal surgeries were required in 19.8% of eyes, with 88.7% of them including a lensectomy. Among eyes requiring lensectomy, 75% occurred within the first year after LSV surgery. Lens opacities were present in 26.6% of eyes at the time of lensectomy. Of all eyes in this series, 5.9% required lensectomy because of lens opacity.nnnCONCLUSIONSnThis study demonstrates that lens clarity is observed in most eyes after LSV surgery for advanced ROP for the patients childhood. Within the first decade of life, if necessary, lensectomy after LSV occurred mostly within 1 year following LSV.

Genetic Evaluation to Establish the Diagnosis of X-Linked Familial Exudative Vitreoretinopathy

Purpose: To determine the usefulness of genetic analysis for confirming the diagnosis of X-linked familial exudative vitreoretinopathy (FEVR) and verifying the mode of inheritance. Methods: Twenty-seven consecutive patients diagnosed with FEVR were enrolled for genetic analysis. All patients underwent dilated fundus examination. A complete birth, medical, and family history was obtained at the time of examination. Patients were categorized by gender and family history in an effort to identify X-linked FEVR. Participants provided a blood sample for analysis and were evaluated for a mutation in the Norries disease gene (NDP) by direct sequencing. Results: Of the 27 enrolled patients, four male patients had a pedigree consistent with X-linked inheritance and 12 male patients had little or no family history. Two of these 16 patients were found to have a missense mutation in the NDP gene. Conclusions: We found genetic testing of NDP to be helpful in confirming the diagnosis of X-linked FEVR in male patients, especially when limited family history was available. As genetic diagnostics improve, we feel that confirming diagnoses and informing patients better through genetic evaluation and consultation will become more useful in the clinical practice of ophthalmology.