Retinal Changes in Uncomplicated and Severe Plasmodium knowlesi Malaria.

BACKGROUND: Plasmodium knowlesi causes severe malaria, but its pathogenesis is poorly understood. Retinal changes provide insights into falciparum malaria pathogenesis but have not been studied in knowlesi malaria. METHODS: An observational study was conducted in Malaysian adults hospitalized with severe (n = 20) and nonsevere (n = 24) knowlesi malaria using indirect ophthalmoscopy (n = 44) and fundus photography (n = 29). RESULTS: The patients' median age was 44 years (range, 18-74 years). No coma or deaths occurred. Photography detected retinal changes in 11 of 12 patients (92%) with severe and 14 of 17 (82%) with nonsevere knowlesi malaria. Nonspecific retinal whitening occurred in 3 (35%) and 5 (29%) patients with severe and nonsevere disease, respectively; hemorrhages in 2 (17%) and 3 (18%); loss of retinal pigment epithelium in 1 (8%) and 4 (24%); and drusen in 9 (71%) and 12 (75%). All changes were mild, with no significant differences between severe and nonsevere disease. Patients with retinal hemorrhages had lower platelet counts than those without (median, 22 vs 43 × 10(9)/L; P= .04). CONCLUSIONS: The paucity of specific retinal findings associated with disease severity in knowlesi malaria contrasts with the retinopathy of severe adult falciparum malaria with and without coma, suggesting that falciparum-like microvascular sequestration in the brain is not a major component in severe knowlesi malaria pathogenesis.

Stem cell therapies in the management of diabetic retinopathy.

Diabetic retinopathy is the leading cause of blindness in the working population. We now understand that the pathogenesis of the disease contains both a neurodegenerative and vasodegenerative component. Yet despite this, current treatment is still limited to combating the proliferative end stage component of the disease rather than addressing its underlying causes. In recent years, much basic research has focused on demonstrating the potential that several classes of stem cells have in conferring both neuro- and vasoprotection on the diabetic retina. Further, progress has been made in using stem cells to stimulate both neuro and vascular regeneration. This review will discuss the current understanding as to what mechanisms underlie diabetic retinopathy while highlighting the types of stem cells which offer hope as potential novel therapies for diabetic retinopathy, including those that are now in clinical trial.

Digital ophthalmology in Scotland: benefits to patient care and education.

Tackling visual impairment remains an important public health issue. Due to limited resources and the increasing demand on hospital eye services (HES), delivery of quality eye care within the community is essential. Training of clinical ophthalmic specialists and allied health-care professionals in the detection and management of common eye conditions can thus help to reduce the burden of eye disease and improve prognostic outcomes. Digital imaging has become a useful tool in facilitating eye-care delivery in both the community and hospital setting. In the last decade, the advent of electronic image exchange via a centralized referral unit in Scotland has revolutionized screening for ophthalmic disease, referrals, and shared care between community and HES clinicians. A government-led initiative known as the Scottish Eyecare Integration Project introduced electronic transfer of digital images within referrals from community optometrists to HES, which greatly reduced outpatient waiting times and improved patient satisfaction. The catalogue of live clinical information and digital images that resulted from the project led to the creation of a virtual learning platform through the University of Edinburgh. Participating professionals involved in eye care have interactive discussions about common eye conditions by sharing digital images of cases and investigations on a global online platform. This has received worldwide attention and inspired the creation of other university courses, e-learning platforms in eye-health education, and shared-care schemes in the screening of eye disease. We show that digital ophthalmology plays a vital role in the integration of community and HES partnership in delivery of patient care and in facilitating eye-health education to a global audience.

Tear production and corneal sensitivity in diabetes.

AIM: Diabetic patients are at significant risk of developing corneal lesions such as superficial punctate keratitis, recurrent corneal erosions, persistent epithelial defects, and microbial keratitis. The aim of this study was to investigate whether diabetes mellitus is correlated with both reduced corneal sensation and reduced tear production. METHODS: In 25 type II diabetic patients with a history of retinopathy only and in 25 nondiabetic control subjects (age and sex matched), we performed noncontact corneal aesthesiometry and assessed basal tear production using Schirmer's test with topical anesthesia. The noncontact corneal aesthesiometer (NCCA) is a new noninvasive device for quantifying threshold corneal sensitivity. RESULTS: The diabetic patients demonstrated a significantly reduced Schirmer's test result (P<.001) and significantly reduced corneal sensitivity (P<.01). CONCLUSION: Our study supports previous reports of reduced basal tear production, lending more support to the theory of a peripheral neuropathy affecting lacrimal gland function in diabetes. We also confirmed reduced threshold corneal sensitivity in diabetic patients using the NCCA.

Suitability of UK Biobank Retinal Images for Automatic Analysis of Morphometric Properties of the Vasculature.

PURPOSE: To assess the suitability of retinal images held in the UK Biobank--the largest retinal data repository in a prospective population-based cohort--for computer assisted vascular morphometry, generating measures that are commonly investigated as candidate biomarkers of systemic disease. METHODS: Non-mydriatic fundus images from both eyes of 2,690 participants--people with a self-reported history of myocardial infarction (n=1,345) and a matched control group (n=1,345)--were analysed using VAMPIRE software. These images were drawn from those of 68,554 UK Biobank participants who underwent retinal imaging at recruitment. Four operators were trained in the use of the software to measure retinal vascular tortuosity and bifurcation geometry. RESULTS: Total operator time was approximately 360 hours (4 minutes per image). 2,252 (84%) of participants had at least one image of sufficient quality for the software to process, i.e. there was sufficient detection of retinal vessels in the image by the software to attempt the measurement of the target parameters. 1,604 (60%) of participants had an image of at least one eye that was adequately analysed by the software, i.e. the measurement protocol was successfully completed. Increasing age was associated with a reduced proportion of images that could be processed (p=0.0004) and analysed (p<0.0001). Cases exhibited more acute arteriolar branching angles (p=0.02) as well as lower arteriolar and venular tortuosity (p<0.0001). CONCLUSIONS: A proportion of the retinal images in UK Biobank are of insufficient quality for automated analysis. However, the large size of the UK Biobank means that tens of thousands of images are available and suitable for computational analysis. Parametric information measured from the retinas of participants with suspected cardiovascular disease was significantly different to that measured from a matched control group.

New light for old eyes: comparing melanopsin-mediated non-visual benefits of blue-light and UV-blocking intraocular lenses.

BACKGROUND/AIMS: Melanopsin-expressing photosensitive retinal ganglion cells form a blue-light-sensitive non-visual system mediating diverse physiological effects including circadian entrainment and cognitive alertness. Reduced blue wavelength retinal illumination through cataract formation is thought to blunt these responses while cataract surgery and intraocular lens (IOL) implantation have been shown to have beneficial effects on sleep and cognition. We aimed to use the reaction time (RT) task and the Epworth Sleepiness Score (ESS) as a validated objective platform to compare non-visual benefits of UV- and blue-blocking IOLs. METHODS: Patients were prospectively randomised to receive either a UV- or blue-blocking IOL, performing an RT test and ESS questionnaire before and after surgery. Optical blurring at the second test controlled for visual improvement. Non-operative age-matched controls were recruited for comparison. RESULTS: 80 participants completed the study. Those undergoing first-eye phacoemulsification demonstrated significant improvements in RT over control (p=0.001) and second-eye surgery patients (p=0.03). Moreover, reduced daytime sleepiness was measured by ESS for the first-eye surgery group (p=0.008) but not for the second-eye group (p=0.09). Choice of UV- or blue-blocking IOL made no significant difference to magnitude of cognitive improvement (p=0.272). CONCLUSIONS: Phacoemulsification, particularly first-eye surgery, has a strong positive effect on cognition and daytime alertness, regardless of IOL type.

Transorbital sonographic evaluation of normal optic nerve sheath diameter in healthy volunteers in Bangladesh.

INTRODUCTION: Measurement of optic nerve sheath diameter (ONSD) by ultrasound is increasingly used as a marker to detect raised intracranial pressure (ICP). ONSD varies with age and there is no clear consensus between studies for an upper limit of normal. Knowledge of normal ONSD in a healthy population is essential to interpret this measurement. METHODS: In a prospective observational study, ONSD was measured using a 15 MHz ultrasound probe in healthy volunteers in Chittagong, Bangladesh. The aims were to determine the normal range of ONSD in healthy Bangladeshi adults and children, compare measurements in males and females, horizontal and vertical beam orientations and left and right eyes in the same individual and to determine whether ONSD varies with head circumference independent of age. RESULTS: 136 subjects were enrolled, 12.5% of whom were age 16 or under. Median ONSD was 4.41 mm with 95% of subjects in the range 4.25-4.75 mm. ONSD was bimodally distributed. There was no relationship between ONSD and age (≥4 years), gender, head circumference, and no difference in left vs right eye or horizontal vs vertical beam. CONCLUSIONS: Ultrasonographic ONSD in Bangladeshi healthy volunteers has a narrow bimodal distribution independent of age (≥4 years), gender and head circumference. ONSD >4.75 mm in this population should be considered abnormal.

Validating retinal fundus image analysis algorithms: issues and a proposal.

This paper concerns the validation of automatic retinal image analysis (ARIA) algorithms. For reasons of space and consistency, we concentrate on the validation of algorithms processing color fundus camera images, currently the largest section of the ARIA literature. We sketch the context (imaging instruments and target tasks) of ARIA validation, summarizing the main image analysis and validation techniques. We then present a list of recommendations focusing on the creation of large repositories of test data created by international consortia, easily accessible via moderated Web sites, including multicenter annotations by multiple experts, specific to clinical tasks, and capable of running submitted software automatically on the data stored, with clear and widely agreed-on performance criteria, to provide a fair comparison.

Molecular profile of organ culture-stored corneal epithelium: LGR5 is a potential new phenotypic marker of residual human corneal limbal epithelial stem cells.

Long-term preservation of corneal limbal epithelium may decrease its quality and change the molecular signature of the limbal epithelial stem cells. In this study we have investigated the molecular profile of isolated corneal epithelial cells that have been in storage for an extended time. Isolated cells were characterised by the expression profile of different cytokeratins and markers of squamous metaplasia (vimentin and α­actin). Furthermore, we examined global markers of adult stem cells including p63α and ABCG2 but also LGR5 as a novel stem cell marker. Immunocytochemical staining and PCR analysis of p63α, ABCG2 and LGR5 revealed the existence of side-population cells with a stem-cell phenotype and maintenance of corneal limbal stem cell properties. LGR5 expression can be related to cellular stemness and can be considered as a new phenotypic marker of residual human corneal limbal stem cells. However, the existence of CK10 together with co-expressed α-actin and vimentin suggests that the corneas investigated were under oxidative stress and showed evidence of squamous metaplasia.

Retinal vessel tortuosity in response to hypobaric hypoxia.

PURPOSE: Retinal vascular tortuosity is associated with retinopathy of differing etiologies, including hypertension, diabetes, and hypoxia. However, detailed understanding of the underlying pathophysiology is lacking. The aim of this study was to map changes in tortuosity associated with hypoxia at high altitude, and to determine the influence of sildenafil and an antioxidant preparation on altitude-induced tortuosity. METHODS: We measured the tortuosity of retinal vessels using a semi-automated method in 35 young, healthy subjects exposed to hypobaric hypoxia for 7 days at 5200 m, and compared the measurements to those from the same vessels at sea level. These subjects simultaneously took part in a randomized double-blind placebo-controlled trial of sildenafil and antioxidant. Comparison of tortuosity between these subgroups was performed. RESULTS: High altitude was associated with the development of retinal tortuosity in individual vessels. A nonsignificant trend suggests this is limited by prophylaxis with sildenafil or antioxidant. CONCLUSIONS: Retinal vessel tortuosity increases rapidly at high altitude. We suggest that retinal vessel tortuosity at altitude may result from increased sheer stress causing elongation of vessel segments and that this might be limited by agents that act to preserve nitric oxide dependent vasodilation. TRIAL REGISTRATION NUMBERS: NCT00664001, NCT00627965.

Reaction time as a measure of enhanced blue-light mediated cognitive function following cataract surgery.

BACKGROUND/AIMS: Since 2002 the discovery of a novel population of intrinsically photosensitive retinal ganglion cells, expressing the photopigment melanopsin, has attracted broad interest in human blue-light mediated non-visual effects including circadian regulation and cognitive function. Ageing is associated with insomnia and cognitive decline. It has been postulated that reduced blue-light transmission through the formation of cataract impairs melanopsin dependant non-visual brain responses mediated by intrinsically photosensitive retinal ganglion cells. We aimed to establish if any objective improvement in cognition could be demonstrated using a reaction time task (RTT) following cataract surgery and intraocular lens implantation. METHODS: Following strict inclusion and exclusion criteria, 15 patients (age range 59-87, mean 75.4 years) with bilateral cataract performed the RTT before and after surgery on one eye. The mean and the SD of two modalities of reaction time, namely complex reaction time and simple reaction time, were measured and analysed. RESULTS: Responses became both quicker and more consistent following surgery, with statistically significant improvements in the complex reaction time (p=0.016) and the complex reaction time SD (p=0.055), which were not due to a learning effect or improved vision. CONCLUSION: The results suggest that improved blue-light transmission following cataract surgery has a beneficial effect on cognitive function. We advocate the RTT as an objective platform for exploring these benefits in large sample randomised controlled trials.

The role of retinal regulation of sleep in health and disease.

The process of photoentrainment, through the activation of photoreceptor transduction cascades, influences the circadian physiology of many life forms from primitive invertebrates to primates. In humans, a population of intrinsically photosensitive retinal ganglion cells (ipRGC's) is responsible for mediating the circadian rhythm and is susceptible to primary dysfunction affecting this cell population specifically, or disorders influencing light activation of retinal ganglion photoreceptors. The former may arise through cell depletion in conditions such as inherited or acquired optic neuropathies or conditions like Parkinson's disease which may alter retinal dopamine-mediated neurotransmission, and the latter, secondary to common causes of light transmission reduction associated with ageing and cataract. This review examines the current evidence linking ocular pathology and the resultant reduction in retinal phototransduction with circadian disturbances and sleep disorders, with downstream effects on our overall physiological integrity. As our understanding of the effects of light pathways on circadian biology develops, therapeutic modalities based upon the underlying pathophysiological processes are emerging, although the direct measurement, consequences and treatment of relative or absolute ipRGC dysfunction remain to be fully and clearly elucidated in man.

Exploring the possibility of early cataract diagnostics based on tryptophan fluorescence.

A novel route for early cataract diagnostics is investigated based on the excitation of tryptophan fluorescence (TF) at the red edge of its absorption band at 317 nm. This allows penetration through the cornea and aqueous humour to provide excitation of the ocular lens. The steepness of the red edge gives the potential of depth control of the lens excitation. Such wavelength selection targets the population of tryptophan residues, side chains of which are exposed to the polar aqueous environment. The TF emissions around 350 nm of a series of UV-irradiated as well as control lenses were observed. TF spectra of the UV cases were red-shifted and the intensity decreased with the radiation dose. In contrast, intensity of non-tryptophan emission with maximum at 435 nm exhibited an increase suggesting photochemical conversion of the tryptophan population to 435 nm emitting molecules. We demonstrate that the ratio of intensities at 435 nm to that around 350 nm can be used as a measure of early structural changes caused by UV irradiation in the lens by comparison with images from a conventional slit-lamp, which can only detect defects of optical wavelength size. Such diagnostics at a molecular level could aid research on cataract risk investigation and possible pharmacological research as well as assisting surgical lens replacement decisions.

Retinal arteriolar geometry is associated with cerebral white matter hyperintensities on magnetic resonance imaging.

BACKGROUND: Cerebral small vessel disease (lacunar stroke and cerebral white matter hyperintensities) is caused by vessel abnormalities of unknown aetiology. Retinal vessels show developmental and pathophysiological similarities to cerebral small vessels and microvessel geometry may influence vascular efficiency. HYPOTHESIS: Retinal arteriolar branching angles or coefficients (the ratio of the sum of the cross-sectional areas of the two daughter vessels to the cross-sectional area of the parent vessel at an arteriolar bifurcation) may be associated with cerebral small vessel disease. METHODS: We performed a cross-sectional observational study in a UK tertiary referral hospital. An experienced stroke physician recruited consecutive patients presenting with lacunar ischaemic stroke with a control group consisting of patients with minor cortical ischaemic stroke. We performed brain magnetic resonance imaging to assess the recent infarct and periventricular and deep white matter hyperintensities. We subtyped stroke with clinical and radiological findings. We took digital retinal photographs to assess retinal arteriolar branching coefficients and branching angles using a semi-automated technique. RESULTS: Two hundred and five patients were recruited (104 lacunar stroke, 101 cortical stroke), mean age 68-years (standard deviation 12). With multivariate analysis, increased branching coefficient was associated with periventricular white matter hyperintensities (P=0.006) and ischaemic heart disease (P<0.001), and decreased branching coefficient with deep white matter hyperintensities (P=0.003), but not with lacunar stroke subtype (P=0.96). We found no associations with retinal branching angles. CONCLUSIONS: Retinal arteriolar geometry differs between cerebral small vessel phenotypes. Further research is needed to ascertain the clinical significance of these findings.