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Bansal AK, Madhavan R, Agam Y, Golby A, Madsen JR, Kreiman G. Neural dynamics underlying target detection in the human brain. J Neurosci 2014;34(8):3042-55.Abstract
Sensory signals must be interpreted in the context of goals and tasks. To detect a target in an image, the brain compares input signals and goals to elicit the correct behavior. We examined how target detection modulates visual recognition signals by recording intracranial field potential responses from 776 electrodes in 10 epileptic human subjects. We observed reliable differences in the physiological responses to stimuli when a cued target was present versus absent. Goal-related modulation was particularly strong in the inferior temporal and fusiform gyri, two areas important for object recognition. Target modulation started after 250 ms post stimulus, considerably after the onset of visual recognition signals. While broadband signals exhibited increased or decreased power, gamma frequency power showed predominantly increases during target presence. These observations support models where task goals interact with sensory inputs via top-down signals that influence the highest echelons of visual processing after the onset of selective responses.
Alberti CF, Horowitz T, Bronstad MP, Bowers AR. Visual attention measures predict pedestrian detection in central field loss: a pilot study. PLoS One 2014;9(2):e89381.Abstract
PURPOSE: The ability of visually impaired people to deploy attention effectively to maximize use of their residual vision in dynamic situations is fundamental to safe mobility. We conducted a pilot study to evaluate whether tests of dynamic attention (multiple object tracking; MOT) and static attention (Useful Field of View; UFOV) were predictive of the ability of people with central field loss (CFL) to detect pedestrian hazards in simulated driving. METHODS: 11 people with bilateral CFL (visual acuity 20/30-20/200) and 11 age-similar normally-sighted drivers participated. Dynamic and static attention were evaluated with brief, computer-based MOT and UFOV tasks, respectively. Dependent variables were the log speed threshold for 60% correct identification of targets (MOT) and the increase in the presentation duration for 75% correct identification of a central target when a concurrent peripheral task was added (UFOV divided and selective attention subtests). Participants drove in a simulator and pressed the horn whenever they detected pedestrians that walked or ran toward the road. The dependent variable was the proportion of timely reactions (could have stopped in time to avoid a collision). RESULTS: UFOV and MOT performance of CFL participants was poorer than that of controls, and the proportion of timely reactions was also lower (worse) (84% and 97%, respectively; p = 0.001). For CFL participants, higher proportions of timely reactions correlated significantly with higher (better) MOT speed thresholds (r = 0.73, p = 0.01), with better performance on the UFOV divided and selective attention subtests (r = -0.66 and -0.62, respectively, p<0.04), with better contrast sensitivity scores (r = 0.54, p = 0.08) and smaller scotomas (r = -0.60, p = 0.05). CONCLUSIONS: Our results suggest that brief laboratory-based tests of visual attention may provide useful measures of functional visual ability of individuals with CFL relevant to more complex mobility tasks.
Benaglio P, San Jose PF, Avila-Fernandez A, Ascari G, Harper S, Manes G, Ayuso C, Hamel C, Berson EL, Rivolta C. Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa. Mol Vis 2014;20:843-51.Abstract

PURPOSE: Mutations in genes encoding proteins from the tri-snRNP complex of the spliceosome account for more than 12% of cases of autosomal dominant retinitis pigmentosa (adRP). Although the exact mechanism by which splicing factor defects trigger photoreceptor death is not completely clear, their role in retinitis pigmentosa has been demonstrated by several genetic and functional studies. To test for possible novel associations between splicing factors and adRP, we screened four tri-snRNP splicing factor genes (EFTUD2, PRPF4, NHP2L1, and AAR2) as candidate disease genes. METHODS: We screened up to 303 patients with adRP from Europe and North America who did not carry known RP mutations. Exon-PCR and Sanger methods were used to sequence the NHP2L1 and AAR2 genes, while the sequences of EFTUD2 and PRPF4 were obtained by using long-range PCRs spanning coding and non-coding regions followed by next-generation sequencing. RESULTS: We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified. In one other patient we identified a novel nucleotide substitution in the 5' untranslated region (UTR) of NHP2L1, which did not segregate with the disease in the family. CONCLUSIONS: The absence of clearly pathogenic mutations in the candidate genes screened in our cohort suggests that EFTUD2, PRPF4, NHP2L1, and AAR2 are either not involved in adRP or are associated with the disease in rare instances, at least as observed in this study in patients of European and North American origin.

Bujakowska KM, Consugar M, Place E, Harper S, Lena J, Taub DG, White J, Navarro-Gomez D, Weigel DiFranco C, Farkas MH, Gai X, Berson EL, Pierce EA. Targeted exon sequencing in Usher syndrome type I. Invest Ophthalmol Vis Sci 2014;55(12):8488-96.Abstract

PURPOSE: Patients with Usher syndrome type I (USH1) have retinitis pigmentosa, profound congenital hearing loss, and vestibular ataxia. This syndrome is currently thought to be associated with at least six genes, which are encoded by over 180 exons. Here, we present the use of state-of-the-art techniques in the molecular diagnosis of a cohort of 47 USH1 probands. METHODS: The cohort was studied with selective exon capture and next-generation sequencing of currently known inherited retinal degeneration genes, comparative genomic hybridization, and Sanger sequencing of new USH1 exons identified by human retinal transcriptome analysis. RESULTS: With this approach, we were able to genetically solve 14 of the 47 probands by confirming the biallelic inheritance of mutations. We detected two likely pathogenic variants in an additional 19 patients, for whom family members were not available for cosegregation analysis to confirm biallelic inheritance. Ten patients, in addition to primary disease-causing mutations, carried rare likely pathogenic USH1 alleles or variants in other genes associated with deaf-blindness, which may influence disease phenotype. Twenty-one of the identified mutations were novel among the 33 definite or likely solved patients. Here, we also present a clinical description of the studied cohort at their initial visits. CONCLUSIONS: We found a remarkable genetic heterogeneity in the studied USH1 cohort with multiplicity of mutations, of which many were novel. No obvious influence of genotype on phenotype was found, possibly due to small sample sizes of the genotypes under study.

Kloek CE, Borboli-Gerogiannis S, Chang K, Kuperwaser M, Newman LR, Lane AM, Loewenstein JI. A broadly applicable surgical teaching method: evaluation of a stepwise introduction to cataract surgery. J Surg Educ 2014;71(2):169-75.Abstract
OBJECTIVE: Although cataract surgery is one of the most commonly performed surgeries in the country, it is a microsurgical procedure that is difficult to learn and to teach. This study aims to assess the effectiveness of a new method for introducing postgraduate year (PGY)-3 ophthalmology residents to cataract surgery. SETTING: Hospital-based ophthalmology residency program. DESIGN: Retrospective cohort study. PARTICIPANTS: PGY-3 and PGY-4 residents of the Harvard Medical School Ophthalmology Residency from graduating years 2010 to 2012. RESULTS: In July 2009, a new method of teaching PGY-3 ophthalmology residents cataract surgery was introduced, which was termed "the stepwise introduction to cataract surgery." This curriculum aimed to train residents to perform steps of cataract surgery by deliberately practicing each of the steps of surgery under a structured curriculum with faculty feedback. Assessment methods included surveys administered to the PGY-4 residents who graduated before the implementation of these measures (n = 7), the residents who participated in the first and second years of the new curriculum (n = 16), faculty who teach PGY-4 residents cataract surgery (n = 8), and review of resident Accreditation Council for Graduate Medical Education surgical logs. Resident survey response rate was 100%. Residents who participated in the new curriculum performed more of each step of cataract surgery in the operating room, spent more time practicing each step of cataract surgery on a cataract surgery simulator during the PGY-3 year, and performed more primary cataract surgeries during the PGY-3 year than those who did not. Faculty survey response rate was 63%. Faculty noted an increase in resident preparedness following implementation of the new curriculum. There was no statistical difference between the precurriculum and postcurriculum groups in the percentage turnover of cataracts for the first 2 cataract surgery rotations of the PGY-4 year of training. CONCLUSIONS: The introduction of cataract surgery to PGY-3 residents in an organized, stepwise manner improved resident preparedness for the PGY-4 year of residency. This surgical teaching method can be easily applied to other surgical specialties.
Yonekawa Y, Hacker HD, Lehman RE, Beal CJ, Veldman PB, Vyas NM, Shah AS, Wu D, Eliott D, Gardiner MF, Kuperwaser MC, Rosa RH, Ramsey JE, Miller JW, Mazzoli RA, Lawrence MG, Arroyo JG. Ocular blast injuries in mass-casualty incidents: the marathon bombing in Boston, Massachusetts, and the fertilizer plant explosion in West, Texas. Ophthalmology 2014;121(9):1670-6.e1.Abstract
PURPOSE: To report the ocular injuries sustained by survivors of the April 15, 2013, Boston Marathon bombing and the April 17, 2013, fertilizer plant explosion in West, Texas. DESIGN: Multicenter, cross-sectional, retrospective, comparative case series. PARTICIPANTS: Seventy-two eyes of 36 patients treated at 12 institutions were included in the study. METHODS: Ocular and systemic trauma data were collected from medical records. MAIN OUTCOME MEASURES: Types and severity of ocular and systemic trauma and associations with mechanisms of injury. RESULTS: In the Boston cohort, 164 of 264 casualties were transported to level 1 trauma centers, and 22 (13.4%) required ophthalmology consultations. In the West cohort, 218 of 263 total casualties were transported to participating centers, of which 14 (6.4%) required ophthalmology consultations. Boston had significantly shorter mean distances to treating facilities (1.6 miles vs. 53.6 miles; P = 0.004). Overall, rigid eye shields were more likely not to have been provided than to have been provided on the scene (P<0.001). Isolated upper body and facial wounds were more common in West largely because of shattered windows (75.0% vs. 13.6%; P = 0.001), resulting in more open-globe injuries (42.9% vs. 4.5%; P = 0.008). Patients in Boston sustained more lower extremity injuries because of the ground-level bomb. Overall, 27.8% of consultations were called from emergency rooms, whereas the rest occurred afterward. Challenges in logistics and communications were identified. CONCLUSIONS: Ocular injuries are common and potentially blinding in mass-casualty incidents. Systemic and ocular polytrauma is the rule in terrorism, whereas isolated ocular injuries are more common in other calamities. Key lessons learned included educating the public to stay away from windows during disasters, promoting use of rigid eye shields by first responders, the importance of reliable communications, deepening the ophthalmology call algorithm, the significance of visual incapacitation resulting from loss of spectacles, improving the rate of early detection of ocular injuries in emergency departments, and integrating ophthalmology services into trauma teams as well as maintaining a voice in hospital-wide and community-based disaster planning.
Yang S, MacKinnon S, Dagi LR, Hunter DG. Superior rectus transposition vs medial rectus recession for treatment of esotropic Duane syndrome. JAMA Ophthalmol 2014;132(6):669-75.Abstract
IMPORTANCE: Superior rectus transposition (SRT) with or without medial rectus recession (MRc) has been introduced as an alternative to MRc alone for treatment of esotropic Duane syndrome; however, the effectiveness of these procedures has not been compared previously. OBJECTIVE: To compare the safety and efficacy of MRc and SRT in treatment of Duane syndrome. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of all patients with esotropic Duane syndrome who underwent surgical treatment from January 1, 2006, through December 31, 2012, in a multispecialty, hospital-based pediatric ophthalmology/adult strabismus practice at Boston Children's Hospital. Patients in the SRT group underwent SRT with or without MRc; those in the non-SRT group underwent unilateral or bilateral MRc. EXPOSURES: Surgical treatment of esotropic Duane syndrome. MAIN OUTCOMES AND MEASURES: Binocular alignment, ocular ductions, head position, stereopsis, and fundus torsion were recorded before surgery and at the 2-month and final postoperative visits. We also evaluated postoperative drift. RESULTS: The medical record review identified 36 patients who underwent 37 procedures, including 19 in the SRT group (13 SRT + MRc and 6 SRT alone) and 18 in the non-SRT group (11 unilateral MRc and 7 bilateral medial rectus resession). Mean MRc was smaller when performed with SRT (3.3 vs 5.3 mm; P = .004). Although the initial deviation was larger in the SRT group, both groups had a similar improvement in esotropia and head turn. Abduction improved by at least 1 unit in 15 of 19 patients in the SRT group (79%) vs 5 of 18 in the non-SRT group (28%). In 24 patients followed up for more than 6 months, mean esotropia decreased from 8.2 to 6.1 prism diopters (Δ) in the SRT group (n = 12) but increased from 7.2 to 10.9Δ in the non-SRT group (n = 12). CONCLUSIONS AND RELEVANCE: The combination of SRT and MRc was more effective than MRc or bilateral medial rectus resession at improving abduction while allowing for a smaller recession to align the eyes and eliminate a compensatory head posture. Although any surgery on the vertical rectus muscles should in theory increase the risk for vertical or torsional complications, to date this theory has not been borne out in our patients. Patients treated with SRT appear to have a reduced likelihood of long-term undercorrection. We therefore recommend SRT with adjustable MRc for treatment of Duane syndrome in patients with larger amounts of esotropia.
Wan MJ, Adebona O, Benson LA, Gorman MP, Heidary G. Visual outcomes in pediatric optic neuritis. Am J Ophthalmol 2014;158(3):503-7.e2.Abstract
PURPOSE: To describe the visual outcomes of a large cohort of pediatric patients presenting to a tertiary care pediatric hospital with first-episode optic neuritis. DESIGN: Retrospective, observational cohort study. METHODS: In a tertiary care pediatric hospital, patients with first-episode optic neuritis and at least 3 months of follow-up over a 10-year period were assessed and followed-up in the ophthalmology department. The main outcome measures were visual acuity at 3 months and 1 year of follow-up, with analysis of risk factors for poor visual outcomes and the time course of visual recovery. RESULTS: Of the 59 pediatric patients with first-episode optic neuritis, 46 had at least 3 months of follow-up and 36 had at least 1 year of follow-up. The mean age was 12.6 years old; 72% were female, 41% had bilateral involvement, 52% had or developed an underlying diagnosis (39% multiple sclerosis, 7% acute disseminated encephalomyelitis, 7% neuromyelitis optica), and 91% received treatment (85% steroids, 7% multimodal). At 1 year, 81% were at least 20/20 and 89% were at least 20/40. A poor visual outcome at 1 year (<20/40) was associated with vision of <20/20 at 3 months (P = 0.041). Other clinical characteristics, including visual acuity at presentation, sex, bilateral involvement, optic nerve edema, and underlying diagnoses were not significantly associated with poor visual outcomes. CONCLUSIONS: In this cohort of pediatric patients with optic neuritis, the majority of patients regained normal visual acuity at 1 year, regardless of baseline clinical characteristics.
Ribeiro AG, Rodrigues RAM, Guerreiro AM, Regatieri CVS. A teleophthalmology system for the diagnosis of ocular urgency in remote areas of Brazil. Arq Bras Oftalmol 2014;77(4):214-8.Abstract
PURPOSES: To validate a teleophthalmology mobile system aimed at improving and providing eye urgency screenings in remote and poor area settings in Brazil. The system enables one or more ophthalmologists to remotely examine a patient's condition and submit a decision describing the gravity of the case. If necessary, the patient can be forwarded to a hospital for further consultation. METHODS: A cellphone (Nexus One model, with a 5 megapixel camera) was used to collect data and pictures from 100 randomly selected patients at the Ophthalmology Emergency Room located at the General Hospital of the Federal University of São Paulo (UNIFESP). Data was then sent remotely to an online recording system to be reviewed by an ophthalmologist who provided feedback regarding the state of ocular urgency. RESULTS were then compared to the gold standard diagnosis provided at the hospital. RESULTS: The diagnosis of urgency was given by two ophthalmologists: one in the hospital (gold standard) and one remotely. When we compared both diagnoses we obtained results of 81.94% specificity, 92.85% sensitivity, and 85% accuracy, with a negative predictive value of 96.72%. This work also included a processing time analysis, resulting in an average time of 8.6 min per patient for remote consultations. CONCLUSIONS: This study is the first that has used only a cellphone for diagnosing the urgency of ocular cases. Based on our results, the system can provide a reliable distinction between urgent and non-urgent situations and can offer a viable alternative for the servicing of underprivileged areas. In screening techniques, the most important outcome is to identify urgent cases with a high level of sensitivity and predictive negative value. Thus, our results demonstrate that this tool is robust and we suggest that a major study aimed to verify its efficiency in resource-poor areas should be initiated.
Srinivasan PP, Kim LA, Mettu PS, Cousins SW, Comer GM, Izatt JA, Farsiu S. Fully automated detection of diabetic macular edema and dry age-related macular degeneration from optical coherence tomography images. Biomed Opt Express 2014;5(10):3568-77.Abstract

We present a novel fully automated algorithm for the detection of retinal diseases via optical coherence tomography (OCT) imaging. Our algorithm utilizes multiscale histograms of oriented gradient descriptors as feature vectors of a support vector machine based classifier. The spectral domain OCT data sets used for cross-validation consisted of volumetric scans acquired from 45 subjects: 15 normal subjects, 15 patients with dry age-related macular degeneration (AMD), and 15 patients with diabetic macular edema (DME). Our classifier correctly identified 100% of cases with AMD, 100% cases with DME, and 86.67% cases of normal subjects. This algorithm is a potentially impactful tool for the remote diagnosis of ophthalmic diseases.

Kwon MY, Lu Z-L, Miller A, Kazlas M, Hunter DG, Bex PJ. Assessing binocular interaction in amblyopia and its clinical feasibility. PLoS One 2014;9(6):e100156.Abstract
PURPOSE: To measure binocular interaction in amblyopes using a rapid and patient-friendly computer-based method, and to test the feasibility of the assessment in the clinic. METHODS: Binocular interaction was assessed in subjects with strabismic amblyopia (n = 7), anisometropic amblyopia (n = 6), strabismus without amblyopia (n = 15) and normal vision (n = 40). Binocular interaction was measured with a dichoptic phase matching task in which subjects matched the position of a binocular probe to the cyclopean perceived phase of a dichoptic pair of gratings whose contrast ratios were systematically varied. The resulting effective contrast ratio of the weak eye was taken as an indicator of interocular imbalance. Testing was performed in an ophthalmology clinic under 8 mins. We examined the relationships between our binocular interaction measure and standard clinical measures indicating abnormal binocularity such as interocular acuity difference and stereoacuity. The test-retest reliability of the testing method was also evaluated. RESULTS: Compared to normally-sighted controls, amblyopes exhibited significantly reduced effective contrast (∼20%) of the weak eye, suggesting a higher contrast requirement for the amblyopic eye compared to the fellow eye. We found that the effective contrast ratio of the weak eye covaried with standard clincal measures of binocular vision. Our results showed that there was a high correlation between the 1st and 2nd measurements (r = 0.94, p<0.001) but without any significant bias between the two. CONCLUSIONS: Our findings demonstrate that abnormal binocular interaction can be reliably captured by measuring the effective contrast ratio of the weak eye and quantitative assessment of binocular interaction is a quick and simple test that can be performed in the clinic. We believe that reliable and timely assessment of deficits in a binocular interaction may improve detection and treatment of amblyopia.
Sun JK, Lin MM, Lammer J, Prager S, Sarangi R, Silva PS, Aiello LP. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema. JAMA Ophthalmol 2014;132(11):1309-16.Abstract

IMPORTANCE: Biomarkers that predict future visual acuity (VA) in eyes with baseline diabetic macular edema (DME) would substantively improve risk assessment, management decisions, and selection of eyes for clinical studies targeting DME. OBJECTIVE: To determine whether baseline or early change in the novel spectral domain-optical coherence tomography (SD-OCT) parameter disorganization of the retinal inner layers (DRIL) is predictive of VA in eyes with center-involved DME. DESIGN, SETTING, AND PARTICIPANTS: At a tertiary care referral center for diabetic eye disease, a retrospective, longitudinal cohort study obtained demographics, VA, and SD-OCT images from baseline, 4-month, and 8-month visits in 96 participants (120 eyes) with diabetes mellitus and baseline center-involved DME (SD-OCT central subfield thickness, ≥ 320 µm for men and ≥ 305 µm for women). Exclusion criteria included substantial media opacity, cataract surgery within 6 months, and nondiabetic retinal pathology affecting VA. On SD-OCT, the 1-mm-wide retinal area centered on the fovea was evaluated by masked graders for DRIL extent, cysts, hyperreflective foci, microaneurysms, cone outer segment tip visibility, and external limiting membrane or photoreceptor disruption and reflectivity. MAIN OUTCOMES AND MEASURES: Visual acuity and SD-OCT-derived retinal morphology. RESULTS: Greater DRIL extent at baseline correlated with worse baseline VA (point estimate, 0.04; 95% CI, 0.02-0.05 per 100 µm; P < .001). An increase in DRIL during 4 months was associated with VA worsening at 8 months (point estimate, 0.03; 95% CI, 0.02-0.05 per 100 µm; P < .001). A multivariate model that included a 4-month change in VA, DRIL, and external limiting membrane disruption was predictive of an 8-month VA change (r = 0.80). Each approximately 300-µm DRIL increase during 4 months predicted a 1-line, 8-month VA decline. When DRIL increased at least 250 µm at 4 months, no eyes had VA improvement of at least 1 line at 8 months. When DRIL decreased at least 250 µm at 4 months, no eyes had VA decline of at least 1 line at 8 months, and 77.7% had VA improvement of at least 1 line. CONCLUSIONS AND RELEVANCE: Disorganization of the retinal inner layers in the 1-mm foveal area is associated with VA, and change in DRIL predicts future change in VA. Early change in DRIL prospectively identifies eyes with a high likelihood of subsequent VA improvement or decline. Therefore, DRIL warrants further study as a robust, readily obtained, and noninvasive biomarker of future VA response in eyes with DME.

Wiecek E, Lashkari K, Dakin S, Bex PJ. Novel Quantitative Assessment of Metamorphopsia in Maculopathy. Invest Ophthalmol Vis Sci 2014;Abstract

Purpose: Patients with macular disease often report experiencing metamorphopsia (visual distortion). Although typically measured with Amsler charts, more objective and quantitative assessments of perceived distortion are desirable to effectively monitor the presence, progression and remediation of visual impairment. Methods: Participants with binocular (n = 33) and monocular (n= 50) maculopathy across seven disease groups, and control participants (n = 10) with no identifiable retinal disease completed a modified Amsler Grid assessment (presented on a computer screen with eye tracking to ensure fixation compliance) and two novel objective measures of metamorphopsia in the central five degrees of visual field. 81% (67/83) of participants completed a task requiring them to configure eight dots in the shape of a square, and 64% (32/50) of participants experiencing monocular distortion completed a spatial alignment task using dichoptic stimuli. 10 controls completed all tasks. Results: Horizontal and vertical distortion magnitudes were calculated for each of the three assessments. Distortion magnitudes were significantly higher in patients than controls in all assessments. There was no significant difference in magnitude of distortion across different macular diseases. Among patients, there were no significant correlations between overall magnitude of distortion among any of the three measures and no significant correlations in localized measures of distortion. Conclusions: Three alternative quantifications of monocular spatial distortion in the central visual field generated uncorrelated estimates of visual distortion. It is therefore unlikely that metamorphopsia is caused solely by displacement of photoreceptors in the retina, but instead involves additional top-down information, knowledge about the scene, and perhaps, cortical reorganization.

Salcone EM, Hamdy S, Melki S, Hunter DG. Scleral perforations during routine traction test in a patient with osteogenesis imperfecta. J AAPOS 2014;18(6):610-2.Abstract

Osteogenesis imperfecta comprises a rare group of genetic disorders caused by abnormal collagen that results in increased bone fragility and other sequelae. We describe a 37-year-old woman with osteogenesis imperfecta in whom two full-thickness scleral perforations were created by adjacent teeth of 0.5 mm forceps during traction testing while undergoing routine strabismus surgery. This case reviews the ocular findings of osteogenesis imperfecta and highlights the potential risk of ocular surgical complications in these patients.

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