Long-term visual and treatment outcomes of whole-population pre-school visual screening (PSVS) in children: a longitudinal, retrospective, population-based cohort study.

BACKGROUND: This study reports the long-term visual and treatment outcomes in a whole-population, orthoptic-delivered pre-school visual screening (PSVS) programme in Scotland and further examines their associations with socioeconomic backgrounds and home circumstances. METHODS: Retrospective case review was conducted on 430 children who failed PSVS. Outcome measures included best corrected visual acuity (BCVA), severity of amblyopia (mild, moderate and severe), binocular vision (BV) (normal, poor and none), ophthalmic diagnosis and treatment modalities. Parameters at discharge were compared to those at baseline and were measured against the Scottish index of multiple deprivation (SIMD) and Health plan indicator (HPI), which are indices of deprivation and status of home circumstances. RESULTS: The proportion of children with amblyopia reduced from 92.3% (373/404) at baseline to 29.1% (106/364) at discharge (p < 0.001). Eighty percent (291/364) had good BV at discharge compared to 29.2% (118/404) at baseline (p < 0.001). Children from more socioeconomically deprived areas (OR 2.19, 95% CI 1.01-4.30, p = 0.003) or adverse family backgrounds (OR 3.94, 95% CI 1.99-7.74, p = 0.002) were more likely to attend poorly and/or become lost to follow-up. Children from worse home circumstances were five times more likely to have residual amblyopia (OR 5.37, 95% CI 3.29-10.07, p < 0.001) and three times more likely to have poor/no BV (OR 3.41, 95% CI 2.49-4.66, p < 0.001) than those from better home circumstances. CONCLUSIONS: Orthoptic-delivered PSVS is successful at screening and managing amblyopia. Children from homes requiring social care input are less likely to attend and are more likely to have poorer visual outcomes.

The UK Paediatric Ocular Trauma Study 3 (POTS3): clinical features and initial management of injuries.

PURPOSE: Worldwide, as many as 6 million children annually sustain ocular trauma, with up to a quarter of a million children requiring hospitalization. Management of pediatric ocular trauma differs from that in adults, both in terms of initial assessment and acute intervention, with significant variation in practice between different centers. Patterns of healing and long-term outcomes are also very different for children compared to adults. In order to develop effective protocols for management, it is first necessary to understand current trends in presentation and treatment. METHODS: We conducted a prospective, observational study of pediatric ocular trauma presenting to UK-based ophthalmologists over a one-year period; reporting cards were distributed by the British Ophthalmic Surveillance Unit, and clinicians were asked to report cases of acute orbital and ocular trauma in children aged 16 years or less requiring inpatient or day-case admission. A validated, standardized questionnaire was sent to reporting ophthalmologists to collect data on clinical features and initial management of injury. RESULTS: Eighty-six episodes of pediatric ocular trauma were reported. Trauma involving the globe was reported in 66/86 patients (76.7%), of which 40/66 (60.1%) were open-globe. Trauma to the anterior segment was reported in 57/86 (66.3%), and posterior segment in 23/86 patients (26.7%). Twenty-five of 86 (29.1%) patients sustained severe trauma defined as having best-corrected visual acuity worse than 6/60 Snellen (incidence 0.19 per 100,000 population). CONCLUSIONS: There has been no improvement in the incidence or severity of pediatric ocular injury rates over the past 25 years. Eye-care providers must be able to provide the necessary services for assessment and management of severe pediatric ocular trauma in the emergency setting.

The UK Paediatric Ocular Trauma Study 2 (POTS2): demographics and mechanisms of injuries.

PURPOSE: Pediatric ocular trauma is an important cause of visual morbidity worldwide, accounting for up to one-third of all ocular trauma admissions. It has long-term implications for those affected and significant economic consequences for healthcare providers. It has been estimated that 90% of all ocular trauma is preventable. Targeted strategies are required to reduce the incidence and the severity of pediatric ocular trauma; this requires an understanding of the epidemiology and characteristics of these injuries and the children involved. METHODS: Prospective, observational study of pediatric ocular trauma cases presenting to UK-based ophthalmologists over a 1-year period; reporting cards were distributed by the British Ophthalmological Surveillance Unit, and clinicians were asked to report incidents of acute orbital and ocular trauma in children aged ≤16 years requiring inpatient or day-case admission. A validated, standardized questionnaire was sent to reporting ophthalmologists to collect data on the demographics and circumstances of injury. RESULTS: Median age at presentation was 7.7 years, with boys more than twice as likely to be affected than girls (M:F =2.1:1.0). Almost 50% of injuries occurred at home, with 25% occurring in school or nursery. A total of 67% of injuries occurred during play, and 31% involved a sharp implement. CONCLUSION: Pediatric ocular trauma remains an important public health problem. At least three-quarters of all injuries are preventable through measures, including education of children and responsible adults, restricting access to sharp implements, improving adult supervision, and appropriate use of eye protection.

The UK Paediatric Ocular Trauma Study 1 (POTS1): development of a global standardized protocol for prospective data collection in pediatric ocular trauma.

BACKGROUND: Ocular trauma is an important cause of visual morbidity in children worldwide. Pediatric ocular trauma accounts for up to one third of all ocular trauma admissions, with significant economic implications for health care providers. It is estimated that 90% of all ocular trauma is preventable. Development of strategies to reduce the incidence and severity of pediatric ocular trauma requires an understanding of the epidemiology of these injuries and their characteristics. This will enable appropriate targeting of resources toward prevention and allow effective service planning. At present, there is no standardized methodology for the collection of global cross-sectional data in pediatric ocular trauma, and the ability to undertake detailed epidemiological and health-economic analyses is limited. Furthermore, it is difficult to draw international comparisons in incidence, etiology, and outcomes of pediatric ocular trauma due to the range of published reporting criteria. This study describes two novel questionnaires for standardized data collection in pediatric ocular trauma, which can be adopted across a range of health care settings internationally. METHODS: Two standardized data collection questionnaires have been developed from previously reported templates. The first enables collection of demographic and incident data on serious pediatric ocular trauma requiring hospitalization, and the second enables follow-up outcome data collection. Both the questionnaires are designed to collect primarily categorical data in order to increase ease of completion and facilitate quantitative analysis. These questionnaires enable acquisition of standardized data on the incidence, etiology, and outcomes of pediatric ocular trauma. DISCUSSION: These questionnaires enable collection of standardized data and are designed for global use across all health care settings. Through prospective data collection, epidemiological trends can be determined, allowing health care providers to develop collaborative global preventive strategies. Furthermore, the same questionnaires may be used in future studies to draw comparisons with baseline data, allowing assessment of the efficacy of targeted preventative interventions.

Endonasal versus external dacryocystorhinostomy for nasolacrimal duct obstruction.

BACKGROUND: A dacryocystorhinostomy (DCR) procedure aims to restore drainage of tears by bypassing a blockage in the nasolacrimal duct, through the creation of a bony ostium that allows communication between the lacrimal sac and the nasal cavity. It can be performed using endonasal or external approaches. The comparative success rates of these two approaches have not yet been established and this review aims to evaluate the relevant up-to-date research. OBJECTIVES: The primary aim of this review is to compare the success rates of endonasal DCR with that of external DCR. The secondary aim is to compare the complication rates between the two procedures. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2016, Issue 8), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to 22 August 2016), Embase (January 1980 to 22 August 2016), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to 22 August 2016), Web of Science Conference Proceedings Citation Index- Science (CPCI-S) (January 1990 to 22 August 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 22 August 2016. We requested or examined relevant conference proceedings for appropriate trials. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing endonasal and external DCRs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility and extracted data on reported outcomes. We attempted to contact investigators to clarify the methodological quality of the studies. We graded the certainty of the evidence using GRADE. MAIN RESULTS: We included two trials in this review. One trial from Finland compared laser-assisted endonasal DCR with external DCR, and one trial from India compared mechanical endonasal DCR (using punch forceps) with external DCR. The trials were poorly reported and it was difficult to judge the extent to which bias had been avoided.Anatomic success was defined as the demonstration of a patent lacrimal passage on syringing, or endoscopic visualisation of fluorescein dye at the nasal opening of the anastomoses after a period of at least six months following surgery. Subjective success was defined as the resolution of symptoms of watering following surgery after a period of at least six months. Both included trials used anatomic patency demonstrated by irrigation as a measure of anatomic success. Different effects were seen in these two trials (I2 = 76%). People receiving laser-assisted endonasal DCR were less likely to have a successful operation compared with external DCR (63% versus 91%; risk ratio (RR) 0.69, 95% confidence intervals (CI) 0.52 to 0.92; 64 participants). There was little or no difference in success comparing mechanical endonasal DCR and external DCR (90% in both groups; RR 1.00, CI 0.81 to 1.23; 40 participants). We judged this evidence on success to be very low-certainty, downgrading for risk of bias, imprecision and inconsistency. The trial from Finland also assessed subjective improvement in symptoms following surgery. Resolution of symptoms of watering in outdoor conditions was reported by 84% of the participants in the external DCR group and 59% of those in the laser-assisted endonasal DCR group (RR 0.70, CI 0.51 to 0.97; 64 participants, low-certainty evidence).There were no cases of intraoperative bleeding in any participant in the trial that compared laser-assisted endonasal DCR to external DCR. This was in contrast to the trial comparing mechanical endonasal DCR to external DCR in which 45% of participants in both groups experienced intraoperative bleeding (RR 1.00, 95% CI 0.50 to 1.98; 40 participants). We judged this evidence on intraoperative bleeding to be very low-certainty, downgrading for risk of bias, imprecision and inconsistency.There were only two cases of postoperative bleeding, both in the external DCR group (RR 0.33, 95% CI 0.04 to 3.10; participants = 104; studies = 2). There were only two cases of wound infection/gaping, again both in the external DCR group (RR 0.20, CI 0.01 to 3.92; participants = 40; studies = 1). We judged this evidence on complications to be very low-certainty, downgrading one level for risk of bias and two levels for imprecision due to the very low number of cases. AUTHORS' CONCLUSIONS: There is uncertainty as to the relative effects of endonasal and external DCR. Differences in effect seen in the two trials included in this review may be due to variations in the endonasal technique, but may also be due to other differences between the trials. Future larger RCTs are required to further assess the success and complication rates of endonasal and external DCR. Different techniques of endonasal DCR should also be assessed, as the choice of endonasal technique can influence the outcome. Strict outcome criteria should be adopted to assess functional and anatomical outcomes with a minimal follow-up of six months.

Management of patients with Graves' orbitopathy: initial assessment, management outside specialised centres and referral pathways.

Graves' orbitopathy (GO) is uncommon, but responsible for considerable morbidity. A coordinated approach between healthcare professionals is required in order to meet the needs of patients. Early diagnosis can be achieved by a simple clinical assessment. Low-cost effective interventions can be initiated by generalists, which may improve outcomes. Moderate-to-severe GO should be referred to specialised centres. Recommendations for clinical diagnosis, initial management and referral pathways are highlighted.

Diagnosis of Graves' orbitopathy (DiaGO): results of a pilot study to assess the utility of an office tool for practicing endocrinologists.

CONTEXT: In active Graves' orbitopathy (GO), treatment can improve the final cosmetic and visual outcome. Diagnostic delay results in significant morbidity and increases patient dissatisfaction. However, it can be challenging for endocrinologists to recognize GO and decide who should be referred for ophthalmic care. OBJECTIVE: DiaGO, a clinical assessment tool, was developed for use in patients with Graves' disease (GD). The tool is designed to alert clinicians to the possibility of GO and prompt early ophthalmic assessment. DESIGN AND SETTING: A 20-point assessment tool was devised and tested on 104 GD patients: 27 "positive controls" with GO and 77 people with GD attending endocrine clinics over 17 months. Those scoring positively in endocrine clinics were referred for ophthalmic assessment. Both the appropriateness of the referral and subsequent treatment were assessed. RESULTS: Eighty-eight of the 104 patients (85%) were female (mean age, 48.5 y; range, 18-76 y). All 27 "controls" scored positively. Of the 77 people evaluated with GD, 27 (35%) scored above the threshold for referral and GO was confirmed in 24/26 (92%) who attended for specialist ophthalmic assessment. Twelve of these 24 (50%) were offered specific treatment following ophthalmology review. CONCLUSIONS: The timely diagnosis of GO is important because early intervention in active disease can improve prognosis. DiaGO alerts clinicians to the possibility of GO and prompts referral to specialist ophthalmic care. It is quick and easy to use and does not require specialist ophthalmic skills. Overall, half of those referred after use of DiaGO were offered specific treatment, suggesting its use might significantly improve the management of patients.

siRNA silencing of the mutant keratin 12 allele in corneal limbal epithelial cells grown from patients with Meesmann's epithelial corneal dystrophy.

PURPOSE: The aim of this study is to further assess our previously reported keratin 12 (K12)-Leu132Pro specific siRNA in silencing the mutant allele in Meesmann's Epithelial Corneal Dystrophy (MECD) in experimental systems more akin to the in vivo situation through simultaneous expression of both wild-type and mutant alleles. METHODS: Using KRT12 exogenous expression constructs transfected into cells, mutant allele specific knockdown was quantified using pyrosequencing and infrared Western blot analysis, while the silencing mechanism was assessed by a modified rapid amplification of cDNA ends (5'RACE) method. Corneal limbal biopsies taken from patients suffering from MECD were used to establish cultures of MECD corneal limbal epithelial stem cells and the ability of the siRNA to silence the endogenous mutant KRT12 allele was assessed by a combination of pyrosequencing, qPCR, ELISA, and quantitative-fluorescent immunohistochemistry (Q-FIHC). RESULTS: The siRNA displayed a potent and specific knockdown of K12-Leu132Pro at both the mRNA and protein levels with exogenous expression constructs. Analysis by the 5'RACE method confirmed siRNA-mediated cleavage. In the MECD cells, an allele-specific knockdown of 63% of the endogenous mutant allele was observed without effect on wild-type allele expression. CONCLUSIONS: Combined with an effective delivery vehicle this siRNA approach represents a viable treatment option for prevention of the MECD pathology observed in K12-Leu132Pro heterozygous individuals.

Development of allele-specific gene-silencing siRNAs for TGFBI Arg124Cys in lattice corneal dystrophy type I.

PURPOSE: This study aimed to investigate the potency and specificity of short-interfering RNA (siRNA) treatment for TGFBI-Arg124Cys lattice corneal dystrophy type I (LCDI) using exogenous expression constructs in model systems and endogenous gene targeting in an ex vivo model using corneal epithelial cell cultures. METHODS: A panel of 19 TGFBI-Arg124Cys-specific siRNAs were assessed by a dual-luciferase reporter assay. Further assessment using pyrosequencing and qPCR was used to identify the lead siRNA; suppression of mutant TGFBIp expression was confirmed by Western blot and Congo red aggregation assays. An ex vivo model of LCDI was established using limbal biopsies from corneal dystrophy patients harboring the Arg124Cys mutation. Treatment efficiency of the siRNA was assessed for the inhibition of the mutant allele in the primary patient's corneal epithelial cells using pyrosequencing, quantitative PCR (qPCR), and an ELISA. RESULTS: A lead siRNA was identified, and demonstrated to be potent and specific in inhibiting the TGFBI-Arg124Cys mutant allele at the mRNA and protein levels. Besides high allele specificity, siRNA treatment achieved a 44% reduction of the endogenous Arg124Cys allele in an ex vivo model of LCDI. CONCLUSIONS: We have identified a lead siRNA specific to the TGFBI-Arg124Cys mutant allele associated with LCDI. Silencing of exogenous TGFBI was observed at mRNA and protein levels, and in an ex vivo model of LCDI with an efficient suppression of the endogenous mutant allele. This result indicates the potential of siRNA treatment as a personalized medicine approach for the management of heritable TGFBI-associated corneal dystrophies.

Acute-onset diplopia.

PURPOSE: To investigate the clinical features of all patients with acute-onset diplopia presenting to the ophthalmology department. METHODS: The notes of every patient who presented with acute onset (<4-week duration) diplopia to the ophthalmology clinic over a 2-year period were reviewed. Data regarding clinical features, underlying aetiology, past medical history, investigations and outcomes were extracted. RESULTS: One hundred and forty-nine patients presented with 53.7% having an isolated third, fourth or sixth nerve palsy, 10.7% a mechanical cause, 10.1% a dysfunction of higher control, 8.1% decompensation of a pre-existing heterophoria, 6.7% idiopathic, 5.4% causes of monocular diplopia and 5.3% another diagnosis. Neuroradiological investigation identified that <5% of patients had a serious underlying pathology, which required immediate management; 80.5% had a diagnosis and underlying aetiology, which were obvious at presentation based only on clinical information and evaluation. CONCLUSIONS: Acute onset diplopia is an uncommon and challenging presentation for the ophthalmologist to manage. These results demonstrate that the aetiology is commonly identifiable at the first presentation based on clinical evaluation, only a small percentage require urgent radiological investigation and a small minority of cases are likely to have serious emergent pathology.

Decrease in the rate of esotropia surgery in the United Kingdom from 2000 to 2010.

BACKGROUND/AIMS: A decrease in strabismus surgery in children has been previously documented in the UK. This study aims to examine whether the incidence of strabismus surgery in children is still decreasing and, if so, the possible reasons for this. METHODS: Data on strabismus surgery from 2000 to 2010 in children in Scotland, England and Wales were obtained. Population statistics for the age group 0-14 years were obtained for England, Scotland and Wales. Annual incidence of strabismus surgery per 100 000 age-specific population was calculated. Data on the number of sight tests in children conducted by the hospital eye service from 1995 to 2004 in these regions were also obtained. RESULTS: From 2000 to 2006, the annual incidence of paediatric strabismus operations decreased significantly in England (p=0.01) and Scotland (p=0.03), and showed a decreasing trend in Wales (p=0.06). Surgical rates, however, remained fairly constant from 2006 to 2010. The number of sight tests in children performed by the hospital eye service has remained fairly constant from 1995 to 2004 in England, Wales and Scotland. CONCLUSIONS: Rates of strabismus surgery in children, especially for esotropia, continued to decrease between 2000 and 2006, but may have stabilised from 2006 to 2010.

Development of allele-specific therapeutic siRNA in Meesmann epithelial corneal dystrophy.

BACKGROUND: Meesmann epithelial corneal dystrophy (MECD) is an inherited eye disorder caused by dominant-negative mutations in either keratins K3 or K12, leading to mechanical fragility of the anterior corneal epithelium, the outermost covering of the eye. Typically, patients suffer from lifelong irritation of the eye and/or photophobia but rarely lose visual acuity; however, some individuals are severely affected, with corneal scarring requiring transplant surgery. At present no treatment exists which addresses the underlying pathology of corneal dystrophy. The aim of this study was to design and assess the efficacy and potency of an allele-specific siRNA approach as a future treatment for MECD. METHODS AND FINDINGS: We studied a family with a consistently severe phenotype where all affected persons were shown to carry heterozygous missense mutation Leu132Pro in the KRT12 gene. Using a cell-culture assay of keratin filament formation, mutation Leu132Pro was shown to be significantly more disruptive than the most common mutation, Arg135Thr, which is associated with typical, mild MECD. A siRNA sequence walk identified a number of potent inhibitors for the mutant allele, which had no appreciable effect on wild-type K12. The most specific and potent inhibitors were shown to completely block mutant K12 protein expression with negligible effect on wild-type K12 or other closely related keratins. Cells transfected with wild-type K12-EGFP construct show a predominantly normal keratin filament formation with only 5% aggregate formation, while transfection with mutant K12-EGFP construct resulted in a significantly higher percentage of keratin aggregates (41.75%; p<0.001 with 95% confidence limits). The lead siRNA inhibitor significantly rescued the ability to form keratin filaments (74.75% of the cells contained normal keratin filaments; p<0.001 with 95% confidence limits). CONCLUSIONS: This study demonstrates that it is feasible to design highly potent siRNA against mutant alleles with single-nucleotide specificity for future treatment of MECD.

Endonasal versus external dacryocystorhinostomy for nasolacrimal duct obstruction.

BACKGROUND: Dacryocystorhinostomy (DCR) procedures can be performed using external or endonasal approaches. The comparative success rates of these procedures are unknown. OBJECTIVES: To compare the success rates of external and endonasal approaches to DCR. SEARCH STRATEGY: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2010, Issue 11), MEDLINE (January 1950 to December 2010), EMBASE (January 1980 to December 2010), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to December 2010), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (December 2010), ClinicalTrials.gov (www.clinicaltrials.gov) (December 2010) and Web of Science Conference Proceedings Citation Index- Science (CPCI-S) (January 1990 to December 2010). There were no language or date restrictions in the search for trials. The electronic databases were last searched on 7 December 2010. We requested or examined relevant conference proceedings for appropriate trials. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing external and endonasal dacryocystorhinostomies. DATA COLLECTION AND ANALYSIS: Two review authors independently performed data extraction and assessment of quality with a predefined form. We contacted investigators to clarify the methodological quality of the studies. MAIN RESULTS: We identified one trial that fulfilled the inclusion criteria. This trial compared 64 DCR procedures (32 external and 32 endonasal procedures). Endonasal DCR was four times more likely to fail compared to external DCR. This was statistically significant (95% confidence interval (CI) 1.25 to 12.84). AUTHORS' CONCLUSIONS: The only trial included in the review provides evidence that endonasal DCR has statistically higher risk of failure compared to external DCR. However, this conclusion is limited by paucity of RCTs, small number of participants and lack of clarity of the methodological process. Well conducted RCTs with sufficient power are required to answer the research question.

Clues to duration of undiagnosed disease from retinopathy and maculopathy at diagnosis in type 2 diabetes: a cross-sectional study.

AIMS: To extrapolate, from the proportion of subjects with observable retinopathy at diagnosis of type 2 diabetes mellitus in routine clinical practice, the mean duration of undiagnosed diabetes. METHODS: On 1 October 1999, there were 4313 patients with type 2 diabetes in the 41 participating practices in the Tayside region (registered with one of 166 GPs). 501 (12%; 95% CI 11 to 13%) patients were selected using a pseudo-random number allocation algorithm, and practice lists checked for recently deceased, non-residents (45 exclusions). Retinopathy was graded by validated slit lamp biomicroscopy and four-field stereo photography. Date of first diagnosis of diabetes was ascertained from the regional diabetes register created using multiple source data capture. RESULTS: Of living Tayside resident patients, 295 from 456 invited type 2 patients (65%) were examined. 14.68% (95% CI 12.48 to 16.88%) were found to have retinopathy at diagnosis. Assuming a linear model, these data suggest that the onset of detectable retinopathy occurs 5.77 years (95% CI 4.6 to 7 years) before diagnosis. Comparison using the log rank test with survival to onset of sight threatening retinopathy/maculopathy in 291 patients with type 1 diabetes mellitus also examined from the same population cohort showed the 95% CIs of length of preclinical diabetes to be between 3.0 and 9.4 years. CONCLUSION: There is accumulating evidence to question the assumption of linearity as a model of choice. The authors' understanding of a distinct glycaemic threshold for retinal change is also overly simplistic and consequently the bounds of uncertainty concerning the preclinical duration of disease are considerable.