The epidemiology, clinical characteristics, histopathology and management of juvenile- and adult-onset corneoscleral limbus xanthogranuloma.

PURPOSE: Adult-onset xanthogranuloma (AOX) of the corneoscleral limbus is a rare inflammatory condition of unknown aetiology. Similar to limbal juvenile xanthogranuloma (JXG), it presents as a growing mass at the corneoscleral junction. Limbal AOX and JXG can lead to sight-threatening complications if not managed in a timely manner. This systematic review summarises the main clinical and histopathological features of limbal AOX/JXG and discusses the management of this uncommon disease. METHODS: We performed a literature search in the MEDLINE database for all historical entries, using the search terms "limbus", "limbal" and "xanthogranuloma", and retrieved all articles reporting on limbal xanthogranuloma. After refining the search to articles relevant to limbal AOX, we were able to identify ten adult cases of limbal AOX and compare those with all reported cases of limbal JXG. RESULTS: Clinically, AOX usually presents as an isolated smooth, yellowish, dome-shaped nodule at the corneoscleral junction, similar to an ocular presentation of JXG, with which it also shares similar histopathological features. CONCLUSION: Limbal JXG and AOX may represent the same disease entity. Diagnosis relies on the clinical presentation, pathology and immunohistochemical profile. Spontaneous regression is unlikely, and thus prompt surgical intervention should be considered to prevent sight-threatening complications. Xanthogranuloma should be included in the differential diagnosis of corneoscleral limbal masses in patients of all age groups.

Republished review. [corrected] Late-onset retinal macular degeneration: clinical insights into an inherited retinal degeneration.

AIM: This study describes, in detail, the phenotype of late-onset retinal macular degeneration (L-ORMD) an inherited condition affecting both the retina and anterior segment. A staging based on clinical characteristics is proposed, and the relevance of this condition to current understanding of age-related macular degeneration is discussed. METHODS: A systematic review of the literature regarding this condition supports a detailed description of the natural history. Clinical experiences in identifying, monitoring and managing patients are also presented. RESULTS: L-ORMD is a rare fully penetrant autosomal dominant condition resulting from a mutation in the C1QTNF5 gene on chromosome 11. Affected individuals develop bilateral loss of vision, dark-adaptation abnormalities, fundus drusen-like yellow spots, midperipheral pigmentation, choroidal neovascularisation, chorioretinal atrophy and long anteriorly inserted lens zonules. Patients may benefit from treatment with high-dose vitamin A. CONCLUSIONS: Raised awareness of L-ORMD should lead to earlier diagnosis and improved care for patients. New antivascular endothelial growth factor treatment may provide a new possibility for management. A deeper insight into molecular and genetic mechanisms of L-ORMD may suggest avenues to explore new treatments of this disorder.

Exploring factors predicting changes in patients' expectations and psychosocial issues during the course of treatment with intravitreal injections for wet age-related macular degeneration.

PurposePatients with wet age-related macular degeneration (AMD) often require long courses of treatment. We investigate the psychosocial issues that could hinder compliance, including patient expectations of treatment. The aims of this study were to explore the factors related to changes in patient expectations, pain, and anxiety during treatment.Patients and methodsA structured interview was carried out among 50 patients selected from the list attending the AMD unit at the Princess Alexandra Eye Pavilion (PAEP). The interview was based on a questionnaire. Additionally, a visual analogue scale was created as a tool for measuring patient expectations, pain, and anxiety. Data were analysed using multinomial regression analysis.ResultsThere were significantly more patients who had a fall in expectations (P<0.05) during the course of treatment. A fall in expectations was found to be predicted by higher starting expectations (P=0.00001), greater decline in visual acuity (P=0.008), and perceived deterioration of vision after starting treatment (P=0.013). Of the patients, 32% planned to stop attending for further injections. Planning to stop attending was correlated with worse final visual acuity (P=0.026, 95% CI). Pain and anxiety with intravitreal therapy (IVT) was significantly reduced when patients were accompanied to the clinic by a friend or relative (P<0.01) using Pearson's correlation (r=0.597).ConclusionPatients require appropriate counselling at the start of a course of treatment to align expectations with perceived treatment outcomes in order to improve adherence. Additionally, a large minority of patients would consider stopping treatment. Patients' expectations should be assessed at relevant time points along a course of treatment.

Floppy iris behaviour during cataract surgery: associations and variations.

AIM: To assess the association of floppy iris behaviour during cataract surgery with use of alpha-1-antagonists and diabetes mellitus. METHODS: 1842 eyes of 1786 patients undergoing phacohoemulsification surgery were prospectively enrolled. The use of commonly prescribed alpha-1-antagonists and the presence or absence of diabetes mellitus were noted. The occurrence of any of the features of the intraoperative floppy iris syndrome (IFIS) was noted by surgeons blinded to the patient's history. RESULTS: 57% of patients receiving tamsulosin showed features of IFIS compared with 1% of the non-tamsulosin group (p<0.001). Of these, more than half the patients manifested the syndrome in an incomplete form. Only 1 of the 51 patients receiving other alpha-1-antagonists had IFIS. Diabetes was also not associated with IFIS (p = 1). CONCLUSIONS: Tamsulosin is significantly associated with floppy iris behaviour during cataract surgery. But not all of these patients will necessarily show all or any features of IFIS. The floppy iris syndrome is likely to represent a continuum of severity. Various undefined factors, diabetes not being one of them, may have a contributory role. Non-selective alpha-1-antagonists are unlikely to be associated with IFIS.

Temporal artery biopsies in south-east Scotland: a five year review.

Temporal artery biopsy is the gold standard investigation for the diagnosis of giant cell arteritis. The aim of this retrospective study was to investigate the use of temporal artery biopsy in diagnosing giant cell arteritis in south-east Scotland over a five-year period. We aimed to quantify success rates, and predictive factors for a positive biopsy, as well as compare the different specialities performing the biopsies. The data should enable the development of better criteria for referral for investigation of giant cell arteritis. Methods Patients were identified using a database of temporal artery biopsies generated by the pathology department in NHS Lothian (south east Scotland), for all biopsies examined between January 2010 and December 2015. An electronic patient record was used to retrospectively examine the records of patients in the database. Results A total of 715 biopsies were included in the study, of which 250 (35.0%) showed features of giant cell arteritis. The main predictors for a positive biopsy were age at biopsy, specialty performing biopsy, erythrocyte sedimentation rate, jaw claudication/pain, and ophthalmic symptoms. The most important predictor of a positive biopsy was erythrocyte sedimentation rate. The length of biopsy was not found to be a predictor of positive biopsy; however, diameter of biopsy was predictive. Conclusions We have shown that many temporal artery biopsies are negative, and finding ways to reduce the number of patients unnecessarily undergoing biopsy will be essential in reducing workload and streamlining services. This study demonstrates some key predictive factors for patients with positive biopsies. The study also shows that a large proportion of biopsies taking place do not result in the recommended length of specimen, but this does not necessarily reduce the likelihood of a positive biopsy.

Long-term visual outcomes of intravitreal ranibizumab treatment for wet age-related macular degeneration and effect on blindness rates in south-east Scotland.

AIMS: To evaluate patient visual acuity outcomes and blindness rates attributable to wet AMD with a potential 5-year follow-up from intravitreal ranibizumab treatment (IVTR) in south-east Scotland. METHODS: Data was analysed from 104 eyes of 96 patients who initiated treatment prior to September 2008. The main outcome measures were LogMAR visual acuity, number of clinic visits and the number of injections. Annual blind registration data in south-east Scotland were analysed using blind certifications recorded by the Royal National Institute of Blind People. RESULTS: Patients had a mean clinical follow-up of 4 years and 1 month and a mean loss of 5.5 letters over the study period. Of the treated eyes 9.6% gained ≥ 15 letters whilst 24.0% lost ≥ 15 letters during this period. An average of 9.56 injections were administered per patient. The age-sex standardised incidence of legal blindness attributable to wet AMD in south-east Scotland peaked at 9.1 cases per 100,000 of the population in 2006 in either eye. Following the introduction of IVTR there were annual decreases in the incidence of blindness attributable to AMD falling to a trough of 4.8 cases per 100,000 of the population in 2011. CONCLUSIONS: This study demonstrates that the majority of patients in a south-east Scotland maintain their vision following IVTR in wet AMD in the real-world setting. Our study also suggests that the introduction of IVTR has had population wide benefits in reducing the blindness attributable to wet AMD in the south-east Scotland population.

Real-time quantitative monitoring of hiPSC-based model of macular degeneration on Electric Cell-substrate Impedance Sensing microelectrodes.

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. Humanized disease models are required to develop new therapies for currently incurable forms of AMD. In this work, a tissue-on-a-chip approach was developed through combining human induced pluripotent stem cells, Electric Cell-substrate Impedance Sensing (ECIS) and reproducible electrical wounding assays to model and quantitatively study AMD. Retinal Pigment Epithelium (RPE) cells generated from a patient with an inherited macular degeneration and from an unaffected sibling were used to test the model platform on which a reproducible electrical wounding assay was conducted to model RPE damage. First, a robust and reproducible real-time quantitative monitoring over a 25-day period demonstrated the establishment and maturation of RPE layers on the microelectrode arrays. A spatially controlled RPE layer damage that mimicked cell loss in AMD disease was then initiated. Post recovery, significant differences (P < 0.01) in migration rates were found between case (8.6 ± 0.46 µm/h) and control cell lines (10.69 ± 0.21 µm/h). Quantitative data analysis suggested this was achieved due to lower cell-substrate adhesion in the control cell line. The ECIS cell-substrate adhesion parameter (α) was found to be 7.8 ± 0.28 Ω(1/2)cm for the case cell line and 6.5 ± 0.15 Ω(1/2)cm for the control. These findings were confirmed using cell adhesion biochemical assays. The developed disease model-on-a-chip is a powerful platform for translational studies with considerable potential to investigate novel therapies by enabling real-time, quantitative and reproducible patient-specific RPE cell repair studies.

Gaze and pupil changes during navigation in age-related macular degeneration.

BACKGROUND: The central visual field is particularly affected in age-related macular degeneration (AMD), and this can impinge on a variety of functional tasks, including navigation, which can affect activities of daily living. It has been difficult to assess navigational function under standardised conditions. The aim of this study is to examine gaze function and pupil diameter during navigation in patients with AMD. METHODS: This study was designed as an observational case-control investigation. 34 patients with AMD and 23 controls were recruited. We simulated a walking journey using video projection and monitored patients using automated eye tracking. Visual acuity, fixation count, fixation duration and pupil diameter were recorded while subjective measurements included recorded voice comments. RESULTS: The pupil diameters were significantly greater in the AMD group compared with the control group in both easy and difficult segments of navigation (p=0.002). Fixation counts were significantly higher in the AMD group during difficult segments of navigation (p=0.001). The differences in both pupil diameter and fixation count correlated with subject visual acuity. CONCLUSIONS: Fixation count is a marker of difficult navigational environments in patients with AMD. The combination of video projection and eye tracking to assess visual navigation function is a useful clinical tool and an adjunct to current investigation tools in AMD intervention studies providing objective clinical measures under standardised settings.

Getting serious with retinopathy: approaching an integrated hypothesis for central serous chorioretinopathy.

Development of the prefrontal cortex is believed to play an important role in the maturation of higher cognitive functions such as decision making, cognition and control of part of the neural element of the stress response. The prefrontal cortex undergoes considerable maturation during childhood, including a reduction of synaptic and neural density, a growth of dendrites, and an increase in white matter volume, thereby forming distributed neural networks appropriate for complex cognitive processing, but maturation is not complete until approximately 25 years of age. Serotonin and its receptors (HTRs) play critical roles in brain development and in the regulation of cognition, mood, and anxiety. HTRs are highly expressed in the human prefrontal cortex and exert control over prefrontal excitability. Studies of post-mortem prefrontal brain tissue found distinct developmental patterns of expression of these receptors occurring in early postnatal development and also into adulthood. The general pattern of improved cognitive control and emotion regulation with maturation of the prefrontal cortex, suggests a linear increase in development from childhood to adulthood. Animal studies have shown that dopamine is crucial for communication between the accumbens, amygdala, and prefrontal cortex. Dopamine projections to the prefrontal cortex continue to develop into early adulthood. Central Serous Chorioretinopathy (CSC) is an eye disease affecting people of working age, commonly resulting in repeated unpredictable visually disabling serous retinal detachments and occasionally leading to irreversible reduction in central vision. The disease has been closely linked to the stress response. Despite a concerted effort to understand aetiopathogenesis, disease mechanisms are still largely unclear. This paper, supported by evidence in the literature, proposes a systemic approach to CSC and explains how interactions of the eye with the cerebral cortex could lead to disease. We propose that the lack of development of the neural element of the stress response and in particular the prefrontal cortex is the reason for the absence of CSC in childhood and adolescence. Additionally, we attempt to explain why excess stress hormones do not always result in CSC and why acute attacks occur only once in over half of cases. Finally, we summarise the implications that an integrated systemic hypothesis has for future CSC research and the requirement of a holistic management practice for the identification and treatment of patients with CSC.

Using human induced pluripotent stem cells to treat retinal disease.

The eye is an ideal target for exploiting the potential of human induced pluripotent stem cell (hiPSC) technology in order to understand disease pathways and explore novel therapeutic strategies for inherited retinal disease. The aim of this article is to map the pathway from state-of-the art laboratory-based discoveries to realising the translational potential of this emerging technique. We describe the relevance and routes to establishing hiPSCs in selected models of human retinal disease. Additionally, we define pathways for applying hiPSC technology in treating currently incurable, progressive and blinding retinal disease.

Using electronic referral with digital imaging between primary and secondary ophthalmic services: a long term prospective analysis of regional service redesign.

PURPOSE: Demands on publicly funded ophthalmic services worldwide continue to increase with new treatments, waiting time targets, working time limits, and restricted budgets. These highlight the necessity to develop innovative ways of utilising existing capacity more effectively. METHOD: A new regional, fully electronic ophthalmic-referral service with digital imaging was trialled using existing information-technology (IT) infrastructure. Following successful pilot study, the service was rolled out regionally. Service delivery data was prospectively collated for all the attendances in the year prior to (2006) and the year following (2008) introduction. RESULTS: Comparing 2006 against 2008, median waiting times reduced (14 vs 4 weeks), and fewer new patients were observed (8714 vs 7462 P<0.0001), with 1359 referrals receiving electronic diagnosis (e-diagnosis). New patient did not arrive (635 vs 503 P<0.0001) and emergencies also reduced (2671 v 1984 P<0.0001). DISCUSSION: Novel use of existing IT infrastructure improves communication between primary and secondary care. This promotes more effective use of limited outpatient capacity by retaining patients with non-progressive, asymptomatic pathology in the community, whilst fast-tracking patients with sight-threatening disease. Resultant significant, sustained improvements in regional service delivery point to a simple model that could easily be adopted by other providers of universal healthcare globally.

Clinicopathological review of ocular surface squamous neoplasia in Malawi.

BACKGROUND: Ocular surface squamous neoplasia (OSSN) is the most common cause of malignancy of the conjunctiva. Variable clinical presentation means that invasive malignant OSSN is often difficult to discriminate from other similarly presenting differential diagnoses which can be managed more conservatively. AIMS: Identification of clinical factors associated with a histopathological diagnosis of conjunctival squamous cell carcinoma (SCC). METHODS: Prospective consecutive case series of suspected OSSN cases presenting at two hospitals in Central Malawi over a 1 year period. A pro forma was completed assessing preidentified clinical variables. Suspected lesions underwent excisional biopsy followed by histopathological investigation. RESULTS: Fifty-eight patients were recruited. Mean age was 35.8 (range 22-62). 51 cases of histopathologically confirmed OSSN were found. 30 (50%) patients were confirmed HIV seropositive which rose to 86.67% in invasive SCC. Larger size of tumour (p=0.008), male gender (p=0.025) and HIV seropositivity (p=0.010) were associated with invasive SCC pathology. CONCLUSIONS: A clinicopathological study of OSSN has not previously been performed in Malawi. The association of HIV with SCC corresponds to previous reports from sub-Saharan Africa. A new finding in our study is a relationship between larger tumour size and invasive lesions confirmed by histopathology. When integrated into a clinical decision-making model, tumour area provides a simple clinical measure for ophthalmic practitioners to use in order to differentiate higher risk OSSN from more benign pathology. The higher risk lesions can subsequently be treated with greater surgical care and undergo closer follow-up.

Improving the economic value of photographic screening for optical coherence tomography-detectable macular oedema: a prospective, multicentre, UK study.

OBJECTIVES: To determine the best photographic surrogate markers for detecting sight-threatening macular oedema (MO) in people with diabetes attending UK national screening programmes. DESIGN: A multicentre, prospective, observational cohort study of 3170 patients with photographic signs of diabetic retinopathy visible within the macular region [exudates within two disc diameters, microaneurysms/dot haemorrhages (M/DHs) and blot haemorrhages (BHs)] who were recruited from seven study centres. SETTING: All patients were recruited and imaged at one of seven study centres in Aberdeen, Birmingham, Dundee, Dunfermline, Edinburgh, Liverpool and Oxford. PARTICIPANTS: Subjects with features of diabetic retinopathy visible within the macular region attending one of seven diabetic retinal screening programmes. INTERVENTIONS: Alternative referral criteria for suspected MO based on photographic surrogate markers; an optical coherence tomographic examination in addition to the standard digital retinal photograph. MAIN OUTCOME MEASURES: (1) To determine the best method to detect sight-threatening MO in people with diabetes using photographic surrogate markers. (2) Sensitivity and specificity estimates to assess the costs and consequences of using alternative strategies. (3) Modelled long-term costs and quality-adjusted life-years (QALYs). RESULTS: Prevalence of MO was strongly related to the presence of lesions and was roughly five times higher in subjects with exudates or BHs or more than two M/DHs within one disc diameter. Having worse visual acuity was associated with about a fivefold higher prevalence of MO. Current manual screening grading schemes that ignore visual acuity or the presence of M/DHs could be improved by taking these into account. Health service costs increase substantially with more sensitive/less specific strategies. A fully automated strategy, using the automated detection of patterns of photographic surrogate markers, is superior to all current manual grading schemes for detecting MO in people with diabetes. The addition of optical coherence tomography (OCT) to each strategy, prior to referral, results in a reduction in costs to the health service with no decrement in the number of MO cases detected. CONCLUSIONS: Compared with all current manual grading schemes, for the same sensitivity, a fully automated strategy, using the automated detection of patterns of photographic surrogate markers, achieves a higher specificity for detecting MO in people with diabetes, especially if visual acuity is included in the automated strategy. Overall, costs to the health service are likely to increase if more sensitive referral strategies are adopted over more specific screening strategies for MO, for only very small gains in QALYs. The addition of OCT to each screening strategy, prior to referral, results in a reduction in costs to the health service with no decrement in the number of MO cases detected. STUDY REGISTRATION: This study has been registered as REC/IRAS 07/S0801/107, UKCRN ID 9063 and NIHR HTA 06/402/49. SOURCE OF FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 51. See the HTA programme website for further project information.

Surgical outcome and risk stratification for primary retinal detachment repair: results from the Scottish Retinal Detachment study.

OBJECTIVES: To report the early surgical outcome, risk of failure and predictive value of rhegmatogenous retinal detachment (RRD) classification based on all participants in the Scottish Retinal Detachment study. METHODS: Over 2 years, all incident cases of RRD in Scotland were approached for recruitment. Early postoperative success was defined as an attached retina following one procedure with a minimum follow-up of 6-8 weeks. Using a regression model, the influence of clinical factors on the failure risk was estimated and the sensitivity and specificity of the Royal College of Ophthalmologists (RCOphth) grading for RRD and the vitrectomy in retinal detachment stratification risk formula (VR-SRF) in predicting operative failure were assessed. RESULTS: Primary outcome data were available for 86.2% (975/1130) of patients. The overall primary success rate was 80.8% (95% CI 78.1 to 83.3%). The presence of preoperative proliferative vitreoretinopathy of any degree and each additional clock hour of detachment increased the risk of failure by an OR of 2.4 and 1.13 respectively (p<0.05). A specificity of >95% in predicting early surgical failure was noted for highly complex RRDs according to the VR-SRF formula and the RCOphth classification. CONCLUSIONS: Consistent with previous series, the overall early success rate of RRD repair was 80% after one operation. The type of surgical repair did not influence overall success rates. Significant predictors of failure are the presence of preoperative proliferative vitreoretinopathy of any grade and the extent of detachment. The analytical value of current classification systems in predicting failure is most useful in complex RRDs.

Late-onset retinal macular degeneration: clinical insights into an inherited retinal degeneration.

AIM: This study describes, in detail, the phenotype of late-onset retinal macular degeneration (L-ORMD) an inherited condition affecting both the retina and anterior segment. A staging based on clinical characteristics is proposed, and the relevance of this condition to current understanding of age-related macular degeneration is discussed. METHODS: A systematic review of the literature regarding this condition supports a detailed description of the natural history. Clinical experiences in identifying, monitoring and managing patients are also presented. RESULTS: L-ORMD is a rare fully penetrant autosomal dominant condition resulting from a mutation in the C1QTNF5 gene on chromosome 11. Affected individuals develop bilateral loss of vision, dark-adaptation abnormalities, fundus drusen-like yellow spots, midperipheral pigmentation, choroidal neovascularisation, chorioretinal atrophy and long anteriorly inserted lens zonules. Patients may benefit from treatment with high-dose vitamin A. CONCLUSIONS: Raised awareness of L-ORMD should lead to earlier diagnosis and improved care for patients. New antivascular endothelial growth factor treatment may provide a new possibility for management. A deeper insight into molecular and genetic mechanisms of L-ORMD may suggest avenues to explore new treatments of this disorder.