Extended optical treatment versus early patching with an intensive patching regimen in children with amblyopia in Europe (EuPatch): a multicentre, randomised controlled trial.

BACKGROUND: Amblyopia, the most common visual impairment of childhood, is a public health concern. An extended period of optical treatment before patching is recommended by the clinical guidelines of several countries. The aim of this study was to compare an intensive patching regimen, with and without extended optical treatment (EOT), in a randomised controlled trial. METHODS: EuPatch was a randomised controlled trial conducted in 30 hospitals in the UK, Greece, Austria, Germany, and Switzerland. Children aged 3-8 years with newly detected, untreated amblyopia (defined as an interocular difference ≥0·30 logarithm of the minimum angle of resolution [logMAR] best corrected visual acuity [BCVA]) due to anisometropia, strabismus, or both were eligible. Participants were randomly assigned (1:1) via a computer-generated sequence to either the EOT group (18 weeks of glasses use before patching) or to the early patching group (3 weeks of glasses use before patching), stratified for type and severity of amblyopia. All participants were initially prescribed an intensive patching regimen (10 h/day, 6 days per week), supplemented with motivational materials. The patching period was up to 24 weeks. Participants, parents or guardians, assessors, and the trial statistician were not masked to treatment allocation. The primary outcome was successful treatment (ie, ≤0·20 logMAR interocular difference in BCVA) after 12 weeks of patching. Two primary analyses were conducted: the main analysis included all participants, including those who dropped out, but excluded those who did not provide outcome data at week 12 and remained on the study; the other analysis imputed this missing data. All eligible and randomly assigned participants were assessed for adverse events. This study is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN51712593) and is no longer recruiting. FINDINGS: Between June 20, 2013, and March 12, 2020, after exclusion of eight participants found ineligible after detailed screening, we randomly assigned 334 participants (170 to the EOT group and 164 to the early patching group), including 188 (56%) boys, 146 (44%) girls, and two (1%) participants whose sex was not recorded. 317 participants (158 in the EOT group and 159 in the early patching group) were analysed for the primary outcome without imputation of missing data (median follow-up time 42 weeks [IQR 42] in the EOT group vs 27 weeks [27] in the early patching group). 24 (14%) of 170 participants in the EOT group and ten (6%) of 164 in the early patching group were excluded or dropped out of the study, mostly due to loss to follow-up and withdrawal of consent; ten (6%) in the EOT group and three (2%) in the early patching group missed the 12 week visit but remained on the study. A higher proportion of participants in the early patching group had successful treatment (107 [67%] of 159) than those in the EOT group (86 [54%] of 158; 13% difference; p=0·019) after 12 weeks of patching. No serious adverse events related to the interventions occurred. INTERPRETATION: The results from this trial indicate that early patching is more effective than EOT for the treatment of most children with amblyopia. Our findings also provide data for the personalisation of amblyopia treatments. FUNDING: Action Medical Research, NIHR Clinical Research Network, and Ulverscroft Foundation.

Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia.

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.

Bacteroides fragilis vertebral osteomyelitis: A rare clinical entity.

Acute pyogenic vertebral osteomyelitis is mainly attributed to haematogenous spread of aerobic bacteria, while anaerobic osteomyelitis results from contiguous spread of polymicrobial infections through breaks in the gut mucosal barrier and involves the vertebral bodies in only about 2%-5%. Herein, we report two cases of vertebral osteomyelitis due to Bacteroides fragilis. It is noteworthy that cases of vertebral osteomyelitis due to Bacteroides fragilis have been attributed to the extension of intra-abdominal or pelvic floor infections. However, in the two cases described, there was no history of a previous medical intervention nor an intestinal or pelvic floor infection. Early recognition of the aetiological agent that causes vertebral osteomyelitis may lead to the timely treatment and therefore, may deter any neurosurgical/orthopaedic interventions.

Quality-adjusted life years in macular oedema due to age-related macular degeneration, diabetes and central retinal vein occlusion: the impact of anti-VEGF agents in a tertiary centre in Greece.

INTRODUCTION: Neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DME), and macular oedema due to central retinal vein occlusion (CRVO) are leading causes of vision loss, currently managed with anti-vascular endothelial growth factor injections (anti-VEGF). The aim of this study was to calculate QALYs in patients with nAMD, DME, and CRVO treated with anti-VEGF agents (QALYs+) in a Greek tertiary hospital setting and compare them to theoretical QALYs that the patients would have without treatment (QALYs-). MATERIAL AND METHODS: The study included 143 treatment-naive patients with macular oedema due to nAMD (n = 79), DME (n = 57), and CRVO (n = 7), who received anti-VEGF injections as monotherapy according to the Treat-and-Extend (T&E) protocol. The anti-VEGF agents were ranibizumab and aflibercept in equivalent fractions. QALYs where calculated by the formula QALY = Utility Value × Time, where "Time" refers to the follow-up period of the study. For QALYs-, we assumed that visual acuity remained unchanged during this period. RESULTS: Mean follow-up time was 1.3 ± 1.2 years in the nAMD group, 1 ± 1.3 years in the DME group, and 0.5 ± 1 years in the CRVO group. There was no statistically significant difference between QALYs- and QALYs+ in all three ocular pathologies for the study period (p > 0.05 for each of the three statistical tests performed). DISCUSSION/CONCLUSION: Possible explanations for the lack of significant difference between QALYs - and QALYs + in nAMD, DME, and CRVO groups, may be the short time horizon used in this analysis, the inclusion of data from the better-seeing eye (BSE) and the specific socio-economic, geographical and health care characteristics of this rural Greek area.

Scleral buckling surgery for stage 4A and 4B retinopathy of prematurity in critically ill neonates.

PURPOSE: To determine the efficacy of scleral buckling in eyes with stage 4A and 4B retinopathy of prematurity (ROP). METHODS: Seven eyes of five premature infants underwent scleral buckling for stage 4 ROP in zone II. Five eyes had stage 4A ROP, and two eyes had stage 4B ROP. Six eyes had previous diode laser photocoagulation, and one eye had received an intravitreal ranibizumab injection. Scleral buckling was the procedure of choice due to lack of access to specialized pediatric vitrectomy instrumentation. Average age at surgery was 3.4 months. Postoperative anatomic retinal status, visual acuity outcome and refractive error were assessed. RESULTS: The scleral buckle was removed on average 8 months after surgery. Retinal reattachment was achieved in all seven eyes. At final follow-up one eye had macular ectopia and disc dragging, one eye had a macular traction fold and two eyes had optic disc pallor. Average myopic error after buckle removal was -7.5 D. CONCLUSION: Scleral buckling can be performed safely and effectively in 4A and 4B stage ROP in critically ill infants, when access to specialized pediatric vitrectomy instrumentation is limited. This surgical technique may provide adequate relief of vitreoretinal traction with improved visual potential.

Subperiosteal Orbital Hemorrhage: An Unusual Complication During Labor.

ABSTRACT: Subperiosteal orbital hemorrhage in the postpartum period has been rarely reported. The authors herein present a female patient who developed acute-onset vertical diplopia, proptosis, mild retro-orbital pain, and restriction of upgaze immediately after labor. Neuroimaging revealed a subperiosteal hematoma along the right orbital roof. Diplopia, motility limitation, and retro-orbital pain gradually resolved in the following weeks. Subperiosteal orbital hematomas are a rare complication of labor, with only 12 cases reported so far. They result from straining during labor, which increases central and orbital venous pressure by means of the Valsalva-maneuver. In order to evaluate ocular motility and exclude optic nerve compression, an urgent ophthalmological examination is required.

The treatment of amblyopia: current practice and emerging trends.

PURPOSE: The purpose of this review is to provide an update on current management and recent research for amblyopia treatment. Part I will review patching, atropine penalization, and pharmacological treatments. Part II will focus on perceptual learning, video gaming, and binocular dichoptic approaches. METHODS: A literature search was performed in PubMed, ClinicalTrials.gov , Google Scholar, and reference lists of retrieved articles until December 20, 2018, for all papers containing "amblyopia treatment" or "amblyopia therapy." We have included RCTs, prospective observational studies, prospective and retrospective cohort studies, pilot studies, and review articles. RESULTS: The mainstay of treatment for amblyopia has been based on increasing visual stimulation of the amblyopic eye by occlusion, atropine, or optical penalization of the dominant eye. It has been established that refractive adaptation alone can significantly enhance visual acuity. However, the duration of optical correction varies between studies and the effectiveness of spectacle wear over early beginning of patching is still under investigation. Additionally, by means of occlusion dose monitors, it was found that adherence to occlusion affects the outcome, as a dose-response relationship exists between adherence and visual acuity. Treatment efficiency declines with age; however, recent evidence indicates cortical plasticity beyond the "critical period" and recommends that an attempt at treatment should be offered to all amblyopic children regardless of age, including those in later childhood. Novel approaches targeted to the restoration of binocular functions, such as perceptual learning, video gaming, and dichoptic training, have shown small effects on visual acuity and have failed to demonstrate non-inferiority over standard treatments. CONCLUSIONS: On review, significant evidence for the successful management of amblyopia, with occlusion therapy and atropine, has been found. However, the management of amblyopia remains challenging, mainly due to compliance issues and suboptimal treatment outcomes during occlusion and atropine penalization. Recent studies have found evidence of new ways of treating amblyopia particularly in regard to binocular treatment although these remain under investigation. Further robust clinical trials on these new treatment modalities are still warranted in order to establish their role in treating amblyopia.

Agreement of driving simulator and on-road driving performance in patients with binocular visual field loss.

PURPOSE: On-road testing is considered the standard for assessment of driving performance; however, it lacks standardization. In contrast, driving simulators provide controlled experimental settings in a virtual reality environment. This study compares both testing conditions in patients with binocular visual field defects due to bilateral glaucomatous optic neuropathy or due to retro-chiasmal visual pathway lesions. METHODS: Ten glaucoma patients (PG), ten patients with homonymous visual field defects (PH), and 20 age- and gender-matched ophthalmologically normal control subjects (CG and CH, respectively) participated in a 40-min on-road driving task using a dual brake vehicle. A subset of this sample (8 PG, 8 PH, 8 CG, and 7 CH) underwent a subsequent driving simulator test of similar duration. For both settings, pass/fail rates were assessed by a masked driving instructor. RESULTS: For on-road driving, hemianopia patients (PH) and glaucoma patients (PG) showed worse performance than their controls (CH and CG groups): PH 40%, CH 30%, PG 60%, CG 0%, failure rate. Similar results were obtained for the driving simulator test: PH 50%, CH 29%, PG 38%, CG 0%, failure rate. Twenty-four out of 31 participants (77%) showed concordant results with regard to pass/fail under both test conditions (p > 0.05; McNemar test). CONCLUSIONS: Driving simulator testing leads to results comparable to on-road driving, in terms of pass/fail rates in subjects with binocular (glaucomatous or retro-chiasmal lesion-induced) visual field defects. Driving simulator testing seems to be a well-standardized method, appropriate for assessment of driving performance in individuals with binocular visual field loss.

Case Series: Bilateral Homonymous Visual Field Defects Due to Bilateral Ischemic Strokes.

SIGNIFICANCE: Bilateral strokes are rare and should be considered when patients present with bilateral visual field loss characterized by patterns consistent with right and left-sided homonymous visual field defects. Perimetry, dilated funduscopy, and immediate neuroimaging are mandatory for diagnosis, because patients may present with vague symptoms. These cases reflect the retinotopic features of the striate cortex. PURPOSE: The purposes of this study were to describe the unusual presentation of bilateral homonymous visual field defects in three patients with bilateral ischemic strokes and to discuss the clinical and neuroanatomical correlations. CASE REPORTS: Neuro-ophthalmological examination including perimetry and brain magnetic resonance imaging (MRI) was performed in three patients with bilateral homonymous scotomas. Two of three patients presented with superior altitudinal hemianopia, resulting from right and left homonymous superior quadrantanopia due to bilateral occipital strokes below the calcarine fissure. A 57-year-old man (patient 1) with a history of atrial fibrillation presented with driving difficulties. Perimetry revealed bilateral superior altitudinal hemianopia. Brain MRI demonstrated a subacute right occipital stroke and a chronic left occipital stroke, both inferior to the calcarine fissure. An 83-year-old woman (patient 2) presented with reading disorders. Perimetry showed a left incomplete homonymous hemianopia and a right horizontal wedge-shaped homonymous scotoma. Brain MRI showed a chronic ischemic stroke in the left occipital lobe and acute ischemia in the right thalamus. A 40-year-old man (patient 3) was referred with headache, disorientation, and bilateral blurry vision. Perimetry showed bilateral superior altitudinal hemianopia, and MRI demonstrated acute bilateral occipital ischemia. Patients 1 and 2 suffered sequential bilateral strokes and were not aware of the initial scotoma, whereas patient 3 presented with bilateral concurrent strokes. CONCLUSIONS: Bilateral homonymous visual field defects due to bilateral strokes are rare. Patient history, a careful neuro-ophthalmological examination, and correlation of visual field defect patterns with neuroimaging should prompt the clinician to the presence of this unique entity.

Population receptive field analysis of the primary visual cortex complements perimetry in patients with homonymous visual field defects.

Injury to the primary visual cortex (V1) typically leads to loss of conscious vision in the corresponding, homonymous region of the contralateral visual hemifield (scotoma). Several studies suggest that V1 is highly plastic after injury to the visual pathways, whereas others have called this conclusion into question. We used functional magnetic resonance imaging (fMRI) to measure area V1 population receptive field (pRF) properties in five patients with partial or complete quadrantic visual field loss as a result of partial V1+ or optic radiation lesions. Comparisons were made with healthy controls deprived of visual stimulation in one quadrant ["artificial scotoma" (AS)]. We observed no large-scale changes in spared-V1 topography as the V1/V2 border remained stable, and pRF eccentricity versus cortical-distance plots were similar to those of controls. Interestingly, three observations suggest limited reorganization: (i) the distribution of pRF centers in spared-V1 was shifted slightly toward the scotoma border in 2 of 5 patients compared with AS controls; (ii) pRF size in spared-V1 was slightly increased in patients near the scotoma border; and (iii) pRF size in the contralesional hemisphere was slightly increased compared with AS controls. Importantly, pRF measurements yield information about the functional properties of spared-V1 cortex not provided by standard perimetry mapping. In three patients, spared-V1 pRF maps overlapped significantly with dense regions of the perimetric scotoma, suggesting that pRF analysis may help identify visual field locations amenable to rehabilitation. Conversely, in the remaining two patients, spared-V1 pRF maps failed to cover sighted locations in the perimetric map, indicating the existence of V1-bypassing pathways able to mediate useful vision.

Retinal development in albinism: a prospective study using optical coherence tomography in infants and young children.

BACKGROUND: Retinal development normally involves migration of the inner retinal layers away from the fovea, migration of the cone photoreceptors into the fovea, and elongation of the photoreceptors over time. This process is arrested prematurely in albinism. However, because retinal development continues at least until the age of 4 years, when development arrests in albinism is uncertain. In this study we outlined the time course of retinal development in children with albinism. METHODS: We studied 44 children with a diagnosis of albinism and 223 control participants. All participants were aged between 0 and 6 years. We obtained 219 mixed cross-sectional and longitudinal optical coherence tomography examinations in the albinism group and compared them with 558 control examinations. Retinal layer segmentation was performed with ImageJ software. Generalised linear mixed regression modelling was used to analyse group differences in retinal development. FINDINGS: In the albinism group, inner retinal layer migration from the fovea was delayed and arrested prematurely, resulting in a significantly thicker central macular thickness than in the control group (p<0·0001). Whereas the central macular thickness increased with age in the control group, in the albinism group it initially decreased with age as a result of continuing regression of the inner retinal layers (p=0·041). The perifoveal retinal thickness was significantly decreased in albinism from a reduction of both inner (p<0·0001) and outer (p<0·0001) retinal layer thicknesses. There was evidence that the photoreceptor layers across the fovea were elongating in albinism, albeit at a reduced rate, compared with the control group. This difference was most apparent for the foveal photoreceptor inner segment (p=0·001). INTERPRETATION: Our findings show that perturbations exist in several aspects of retinal development including the migration and differentiation of the neuronal cells within the retina. We showed continuing regression of the inner retinal layers and elongation of the photoreceptor layers suggesting residual plasticity of the developing albino retina. This finding is important because treatment at the earliest stages of the condition might normalise retinal development and optimise vision. FUNDING: UK Medical Research Council (grant number MR/J004189/1), Ulverscroft Foundation, National Eye Research Centre, Nystagmus Network UK.

Optic Nerve Head Development in Healthy Infants and Children Using Handheld Spectral-Domain Optical Coherence Tomography.

PURPOSE: To determine feasibility of optic nerve head (ONH) imaging and to characterize ONH development in full-term infants without sedation using handheld spectral-domain optical coherence tomography (SD OCT). DESIGN: Prospective cross-sectional study. PARTICIPANTS: Three hundred fifty-two children aged between 1 day and 13 years. METHODS: All participants were imaged using handheld SD OCT without sedation during a single scan session. The percentage of successful scans was calculated. Interexaminer reproducibility and differences between right and left eyes were assessed using intraclass correlation coefficients (ICCs). Images were analyzed using ImageJ software. The developmental trajectories over time for ONH parameters were calculated using fractional polynomial modelling. MAIN OUTCOME MEASURES: Disc and cup diameter (expressed as distance in micrometers and visual angle in degrees), cup depth, Bruch's membrane opening-minimum rim width (BMO-MRW), retinal thickness, and retinal nerve fiber layer (RNFL; 1700 µm and 6° from the disc center). RESULTS: On average, 70% of participants were imaged successfully. Interexaminer reliability was excellent (ICC, >0.89) for diametric and retinal thickness parameters. Right and left eyes were similar for diametric measurements (ICC, >0.79), but more variable for nasal BMO-MRW, RNFL, and retinal thickness. The mean disc and cup diameter increase by 30% and 40%, respectively, between birth and 13 years of age when expressed as a distance measure, but remained constant (at 5°-5.5° and 2°, respectively) when expressed as a visual angle with reference to the eye nodal point. The peripapillary temporal RNFL demonstrated a marked initial decrease of nearly 35% between birth and approximately 18 months of age. This was followed by a slow increase up to 12 years of age when measured at 1700 µm from the disc center, although there was little change when measured at 6° from the disc center. CONCLUSIONS: We demonstrated feasibility of handheld SD OCT imaging of the ONH in full-term infants and children without anaesthesia or sedation. This is the first in vivo handheld SD OCT study to describe the development of ONH parameters during the critical early years of visual maturation. Our results provide a normative database for use in routine practice and further studies of ONH pathologic features.

Macular morphology in patients with optic nerve head drusen and optic disc edema.

PURPOSE: In this study we investigated macular morphology, including individual retinal layers, in patients with optic nerve head drusen (ONHD) and optic disc edema (ODE) compared with healthy participants, using high-resolution spectral domain optical coherence tomography (OCT). DESIGN: Prospective, cross-sectional, observational study. PARTICIPANTS: A total of 67 patients with ONHD, 36 patients with ODE, and 57 healthy participants. METHODS: High-resolution spectral domain OCT (Copernicus [OPTOPOL Technology S.A., Zawiercie, Poland] 3-µm resolution, 7 × 7 × 2-mm volumetric scans) was used to image macula morphology. Average retinal nerve fiber layer (RNFL) thickness was measured using a semiautomated method with manual correction of the internal limiting membrane, RNFL, and retinal pigment epithelium (RPE). Retinal and RNFL thicknesses were measured and analyzed in 3 circular zones (Early Treatment Diabetic Retinopathy Study protocol). Individual retinal layers at the macula were quantified by analyzing tomograms using ImageJ (http://rsbweb.nih.gov/ij/; Accessed June 1, 2013). MAIN OUTCOME MEASURES: Average retinal and individual retinal layer thickness in patients with ODE or ONHD, and healthy controls. RESULTS: Patients with ONHD had thicker retinae in the inner annulus compared with patients with ODE and controls (significant in the temporal segment compared with those with ODE [P = 0.013] and in the superior segment compared with controls [P = 0.05]). Patients with ONHD had a significantly thinner inner plexiform layer (IPL) (P = 0.02), nerve fiber layer (P = 0.05), and RPE (P = 0.0001), and thicker ganglion cell layer (P = 0.003) and outer plexiform layer (OPL) (P < 0.001) compared with controls. Patients with ODE demonstrated the thickest retina and RNFL in the outer annulus (significant in the inferior segment compared with controls, P = 0.02 for both) with significant thickening in the IPL (P = 0.004), OPL (P < 0.003), and outer segment layer (P ≤ 0.02), and severe ganglion cell loss (P = 0.004) and RPE (P = 0.0001) thinning compared with healthy volunteers. CONCLUSIONS: Our study shows that optic nerve diseases are associated with selective changes in different retinal layers in patients with ODE and ONHD. These findings may be of diagnostic value and could be taken into consideration in assessing patients and studying the pathogenesis of these conditions.