Visual Improvement Despite Macular Pucker After Inverted Internal Limiting Membrane Flap Technique for Idiopathic Macular Hole.

Purpose: To report a case of a macular pucker forming after macular hole (MH) repair with the inverted internal limiting membrane (ILM) flap technique, with resolution after secondary inverted ILM flap peeling. Methods: A single case was evaluated. Results: A 76-year-old woman presented with reduced central vision (28 letters) in the right eye. Optical coherence tomography (OCT) identified an idiopathic full-thickness MH measuring 629 µm in diameter. The patient had pars plana vitrectomy with inverted ILM flap formation. One month postoperatively, the visual acuity (VA) in the right eye was 47 letters and OCT confirmed MH closure. However, the patient developed deterioration in the central vision 10 months postoperatively. A macular pucker in the inverted ILM flap region was found on OCT. Repeat vitrectomy with inverted ILM flap peeling was performed. Postoperatively, the VA in the right eye improved to 60 letters and OCT showed resolution of the macular pucker. Conclusions: A complication of the inverted ILM flap technique for MH is formation of a macular pucker in the region of the inverted ILM flap. Secondary inverted ILM flap peeling results in resolution of the macular pucker.

New method to measure interbreath intervals in infants for the assessment of apnoea and respiration.

BACKGROUND: Respiratory disorders, including apnoea, are common in preterm infants due to their immature respiratory control compared with term-born infants. However, our inability to accurately measure respiratory rate in hospitalised infants results in unreported episodes of apnoea and an incomplete picture of respiratory activity. METHODS: We develop, validate and use a novel algorithm to identify interbreath intervals (IBIs) and apnoeas in preterm infants. In 42 preterm infants (1600 hours of recordings), we assess IBIs from the chest electrical impedance pneumograph using an adaptive amplitude threshold for the detection of breaths. The algorithm is refined by comparing its accuracy with clinically observed breaths and pauses in breathing. We develop an automated classifier to differentiate periods of true apnoea from artefactually low amplitude signal. We assess the performance of this algorithm in the detection of morphine-induced respiratory depression. Finally, we use the algorithm to investigate whether retinopathy of prematurity (ROP) screening alters the IBI distribution. RESULTS: Individual breaths were detected with a false-positive rate of 13% and a false-negative rate of 12%. The classifier identified true apnoeas with an accuracy of 93%. As expected, morphine caused a significant shift in the IBI distribution towards longer IBIs. Following ROP screening, there was a significant increase in pauses in breathing that lasted more than 10 s (t-statistic=1.82, p=0.023). This was not reflected by changes in the monitor-derived respiratory rate and no episodes of apnoea were recorded in the medical records. CONCLUSIONS: We show that our algorithm offers an improved method for the identification of IBIs and apnoeas in preterm infants. Following ROP screening, increased respiratory instability can occur even in the absence of clinically significant apnoeas. Accurate assessment of infant respiratory activity is essential to inform clinical practice.

Quantifying noxious-evoked baseline sensitivity in neonates to optimise analgesic trials.

Despite the high burden of pain experienced by hospitalised neonates, there are few analgesics with proven efficacy. Testing analgesics in neonates is experimentally and ethically challenging and minimising the number of neonates required to demonstrate efficacy is essential. EEG (electroencephalography)-derived measures of noxious-evoked brain activity can be used to assess analgesic efficacy; however, as variability exists in neonate's responses to painful procedures, large sample sizes are often required. Here, we present an experimental paradigm to account for individual differences in noxious-evoked baseline sensitivity which can be used to improve the design of analgesic trials in neonates. The paradigm is developed and tested across four observational studies using clinical, experimental, and simulated data (92 neonates). We provide evidence of the efficacy of gentle brushing and paracetamol, substantiating the need for randomised controlled trials of these interventions. This work provides an important step towards safe, cost-effective clinical trials of analgesics in neonates.

Hospitalized newborns often undergo medical procedures, like blood tests, without pain relief. This can cause the baby to experience short-term distress that may have negative consequences later in life. However, testing the effects of pain relief in newborns is challenging because, unlike adults, they cannot report how much pain they are experiencing. One way to overcome this is to record the brain activity of newborns during a painful procedure and to see how these signals are modified following pain relief. Randomized controlled trials are the gold standard for these kinds of medical assessments, but require a high number of participants to account for individual differences in how babies respond to pain. Finding ways to reduce the size of pain control studies could lead to faster development of pain relief methods. Here, Cobo, Hartley et al. demonstrate a way to reduce the number of newborns needed to test potential pain-relieving interventions. In the experiments, the brain activity of nine babies was measured after a gentle poke and after a painful clinically required procedure. Cobo, Hartley et al. found that the babies' response to the gentle poke correlated with their response to pain. Further data analysis revealed that this information can be used to predict the variability in pain experienced by different newborns, reducing the number of participants needed for pain relief trials. Next, Cobo, Hartley et al. used this new approach in two pilot tests. One showed that gently stroking an infant's leg before blood is drawn from their heel reduced their brains' response to pain. The second showed that giving a baby the painkiller paracetamol lessened the brain's response to immunisation. The new approach identified by Cobo, Hartley et al. may enable smaller studies that can more quickly identify ways to reduce pain in babies. Furthermore, this work suggests that gentle brushing and paracetamol could provide pain relief for newborns undergoing hospital acute procedures. However, more formal clinical trials are needed to test the effectiveness of these two strategies.

Treatment outcomes for amblyopia using PEDIG amblyopia protocols: a retrospective study of 877 cases.

BACKGROUND: The landmark Pediatric Eye Disease Investigators Group (PEDIG) Amblyopia Treatment Studies (ATS) 2A and 2B concluded that 6 hours of occlusion were as efficacious as full-time occlusion in treating severe amblyopia and that 2 hours occlusion were as effective as 6 in treating moderate amblyopia. We present the first retrospective study of real-world outcomes of amblyopia treatment using PEDIG amblyopia protocols in 877 patients treated at a single center. METHODS: Electronic patient records were reviewed retrospectively to identify children meeting ATS2A (severe amblyopia) and ATS2B (moderate amblyopia) inclusion criteria who presented at the Gloucestershire Eye Unit from 2013 to 2017. Clinical data for each patient were entered during routine clinical care. Severely amblyopic children were prescribed 6 hours occlusion daily, and moderately amblyopic children 2 hours, after 12 weeks refractive adaptation. RESULTS: A total of 288 children were in the ATS2A group and 589 in the ATS2B group. Of the severely amblyopic eyes, 40% achieved best-corrected visual acuity better than 0.4 logMAR at 32 weeks, increasing to 55% at 48 weeks; of the moderately amblyopic eyes, 71% achieved best-corrected visual acuity better than 0.3 logMAR at 32 weeks. The mean number of lines of visual improvement was 4.2 for severely amblyopic eyes and 2.1 for moderately amblyopic eyes. CONCLUSIONS: This is the largest reported series of amblyopia treated according to PEDIG protocols. The study population achieved outcomes comparable to those demonstrated by the PEDIG studies. This audit represents a "real-world" benchmark for treatment outcomes in clinical practice.

Analgesic efficacy and safety of morphine in the Procedural Pain in Premature Infants (Poppi) study: randomised placebo-controlled trial.

BACKGROUND: Infant pain has immediate and long-term effects but is undertreated because of a paucity of evidence-based analgesics. Although morphine is often used to sedate ventilated infants, its analgesic efficacy is unclear. We aimed to establish whether oral morphine could provide effective and safe analgesia in non-ventilated premature infants for acute procedural pain. METHODS: In this single-centre masked trial, 31 infants at the John Radcliffe Hospital, Oxford, UK, were randomly allocated using a web-based facility with a minimisation algorithm to either 100 µg/kg oral morphine sulphate or placebo 1 h before a clinically required heel lance and retinopathy of prematurity screening examination, on the same occasion. Eligible infants were born prematurely at less than 32 weeks' gestation or with a birthweight lower than 1501 g and had a gestational age of 34-42 weeks at the time of the study. The co-primary outcome measures were the Premature Infant Pain Profile-Revised (PIPP-R) score after retinopathy of prematurity screening and the magnitude of noxious-evoked brain activity after heel lancing. Secondary outcome measures assessed physiological stability and safety. This trial is registered with the European Clinical Trials Database (number 2014-003237-25). FINDINGS: Between Oct 30, 2016, and Nov 17, 2017, 15 infants were randomly allocated to morphine and 16 to placebo; one infant assigned placebo was withdrawn from the study before monitoring began. The predefined stopping boundary was crossed, and trial recruitment stopped because of profound respiratory adverse effects of morphine without suggestion of analgesic efficacy. None of the co-primary outcome measures differed significantly between groups. PIPP-R score after retinopathy of prematurity screening was mean 11·1 (SD 3·2) with morphine and 10·5 (3·4) with placebo (mean difference 0·5, 95% CI -2·0 to 3·0; p=0·66). Noxious-evoked brain activity after heel lancing was median 0·99 (IQR 0·40-1·56) with morphine and 0·75 (0·33-1·22) with placebo (median difference 0·25, 95% CI -0·16 to 0·80; p=0·25). INTERPRETATION: Administration of oral morphine (100 µg/kg) to non-ventilated premature infants has the potential for harm without analgesic efficacy. We do not recommend oral morphine for retinopathy of prematurity screening and strongly advise caution if considering its use for other acute painful procedures in non-ventilated premature infants. FUNDING: Wellcome Trust and National Institute for Health Research.

Ultra-Widefield Imaging for Pediatric Retinal Disease.

This article explores the development of retinal imaging, with particular emphasis on ultra-widefield imaging and the key concept of field of view. Two ultra-widefield imaging platforms are examined in detail-Optomap and Spectralis-noncontact imaging systems that include protocols for performing angiography in infants. Applications of ultra-widefield imaging are illustrated using case studies, including diagnosis, monitoring, and screening.

The use of miltefosine in the management of refractory Acanthamoeba keratitis.

Acanthamoeba keratitis (AK) is a sight threatening infection most commonly affecting contact lens wearers. The authors report a case of intractable A.polyphaga and A.castellanii, with extensive intraocular spread, managed using oral miltefosine. A 59-year old male contact lens wearer was referred to the tertiary corneal service at Bristol Eye Hospital. Vision was hand movements on the left and 6/6 on the right. Clinical examination was consistent with left AK (confirmed by corneal scrape). Management included biguanide (polyhexamethylene biguanide (PHMB) 0.02%, later 0.06%) and diamidine (hexamidine 0.1%). Further treatment included imidazole (guttae voriconazole, oral posaconazole) and fortified biguanide (chlorhexidine 0.2%). Therapeutic PKP was performed. Microscopy revealed Acanthamoeba throughout host stroma. Corneal scrape and anterior chamber tap revealed persistent infection with Acanthamoeba. Intracameral voriconazole was administered twice. Clinically there was scleritis, with concerns regarding posterior segment involvement. There was a severe necrotic keratitis with almost complete corneal melt, requiring enucleation. Oral miltefosine was commenced to reduce the risk of transmission of Acanthamoeba beyond ocular structures at the time of the enucleation. Histopathological analysis detected A.polyphaga and A.castellanii in vitreous but not retina, choroid or optic nerve suggesting that infection had not progressed posteriorly through the ocular structures and the central nervous system was not involved. The use of miltefosine as a component of combination anti-parasitic therapy is associated with long-term survival in cases of Acanthamoeba infection of the central nervous system. This case reports its first systemic use in the United Kingdom in a case of severe intractable AK with intraocular spread.

Full-thickness macular hole: a rare complication of Borrelia burgdorferi neuroretinitis.

Borrelia burgdorferi is a known infective cause of neuroretinitis. We present a case of B burgdorferi neuroretinitis complicated by macular hole in a 22-year-old man. The neuroretinitis was managed with early high-dose intravenous corticosteroid and oral antibiotic. The macular hole was managed with macular hole surgery after intraocular inflammation had resolved.

UK Age-Related Macular Degeneration Electronic Medical Record System (AMD EMR) Users Group Report IV: Incidence of Blindness and Sight Impairment in Ranibizumab-Treated Patients.

PURPOSE: To study the incidence of blindness and sight impairment in treatment-naive patients receiving ranibizumab (Lucentis) for neovascular age-related macular degeneration (nAMD) in the United Kingdom (UK) National Health Service. DESIGN: Multicenter nAMD database study. PARTICIPANTS: A total of 11 135 patients who collectively received 92 976 treatment episodes to 12 951 eyes. METHODS: Data were extracted from 14 UK centers using the same electronic medical record system (EMR). The EMR-mandated collection of a data set (defined before first data entry) including: age, Early Treatment Diabetic Retinopathy Study visual acuity letter score (VA) for both eyes at all visits, and injection episodes. Participating centers used overwhelmingly a pro re nata re-treatment posology at intended monthly follow-up visits following a loading phase of 3 monthly injections. MAIN OUTCOME MEASURES: Incidence of blindness and sight impairment (VA in the better-seeing eye <38 letters [≤20/200 Snellen, approximately], and <68 letters [≤20/50 Snellen, approximately] at 2 consecutive visits, or 1 visit if no further follow-up data) in each year after initiating treatment. RESULTS: Information from >300 000 clinic visits (2.8 million data points) collected over 5 years was collated from 14 centers. Mean age at first treatment was 79.7 years (standard deviation = 9.19 years), with a female preponderance (63%). The mean (median) VA at baseline in the better-seeing eye was 67.2 (72.0) letters, 20/40- (20/40+) approximate Snellen conversion. The cumulative incidence of new blindness and sight impairment in patients with treated nAMD in at least 1 eye at years 1 to 4 after first injection were 5.1%, 8.6%, 12% and 15.6% for new blindness and 29.6%, 41.0%, 48.7%, and 53.7% for new sight impairment, but with significant reductions in the rates between year cohorts initiating treatment (blindness [P = 4.72 × 10-08], sight impaired [P = 3.27 × 10-06]). CONCLUSIONS: To the best of our knowledge, this is the first multicenter real-world study on the incidence of blindness and sight impairment based on VA data in patients treated with ranibizumab for nAMD, and its results show low incidences of both blindness and sight impairment, which both declined during the study period.

Diabetic retinopathy: intravitreal vascular endothelial growth factor inhibitors for diabetic macular oedema.

INTRODUCTION: Diabetic retinopathy is the most common microvascular complication of diabetes. It is also the most common cause of blindness in working-age adults in industrialised nations. Older people and those with worse diabetes control, hypertension, and hyperlipidaemia are most at risk. Diabetic macular oedema, which can occur at any stage of diabetic retinopathy, is related to increased vascular permeability and breakdown of the blood retinal barrier, in part related to increased vascular endothelial growth factor (VEGF) levels. About 1% to 3% of people with diabetes suffer vision loss because of diabetic macular oedema. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical questions: What are the effects of intravitreal VEGF inhibitors versus each other for diabetic macular oedema? What are the effects of intravitreal VEGF inhibitors plus laser therapy versus intravitreal VEGF inhibitors alone for diabetic macular oedema? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 240 studies. After deduplication and removal of conference abstracts, 149 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 90 studies and the further review of 59 full publications. Of the 59 full articles evaluated, eight systematic reviews and four RCTs were added at this update. We performed a GRADE evaluation for four PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for six comparisons based on information about the effectiveness and safety of intravitreal VEGF inhibitors aflibercept, bevacizumab, and ranibizumab, and each of these intravitreal VEGF inhibitors plus laser therapy.

Long-term outcomes of intravitreal ranibizumab for neovascular age-related macular degeneration in a well defined region of the UK.

AIMS: To study long-term, whole population 'real-world' clinical outcomes of ranibizumab therapy in treatment-naïve eyes for neovascular age-related macular degeneration. METHODS: Data collected prospectively from a single centre serving a defined population using an electronic medical record included: demographics, Early Treatment Diabetic Retinopathy Study visual acuity (ETDRS VA) at all visits, injection dates, central 1 mm retinal thickness, and operative and postoperative complications. RESULTS: 1483 eyes from 1278 patients were included in this study. The median age at the time of the patient's first injection was 82.5 years, 64.9% of patients were female, and another ocular pathology was present in 7.3% eyes. The baseline VA was 23-39, 40-54, 55-70 and >70 ETDRS letters for 17.3%, 23.1%, 42.7% and 16.9% of eyes, respectively. The median VA in all baseline VA groups improved after the loading phase but declined back to the baseline level by 2-5 years. The rate of endophthalmitis following intravitreal injection was 1 in 2124 injections. CONCLUSIONS: These long-term real-world data demonstrate that in general VA increases during the loading phase but returns to near baseline levels after 2-5 years of treatment for each baseline VA category. Patients should be identified and treated as early as possible, since presenting VA predicts the VA maintained after 5 years of treatment. National Institute of Health and Care Excellence guidance advising treatment only for eyes with vision below 70 letters does not promote best long-term VA outcomes for patients.

Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation.

Chondroitinase ABC treatment promotes spinal cord plasticity. We investigated whether chondroitinase-induced plasticity combined with physical rehabilitation promotes recovery of manual dexterity in rats with cervical spinal cord injuries. Rats received a C4 dorsal funiculus cut followed by chondroitinase ABC or penicillinase as a control. They were assigned to two alternative rehabilitation procedures, the first reinforcing skilled reaching and the second reinforcing general locomotion. Chondroitinase treatment enhanced sprouting of corticospinal axons independently of the rehabilitation regime. Only the rats receiving the combination of chondroitinase and specific rehabilitation showed improved manual dexterity. Rats that received general locomotor rehabilitation were better at ladder walking, but had worse skilled-reaching abilities than rats that received no treatment. Our results indicate that chondroitinase treatment opens a window during which rehabilitation can promote recovery. However, only the trained skills are improved and other functions may be negatively affected.