Niall Patton

Retinal vascular image analysis as a potential screening tool for cerebrovascular disease : a rationale based on homology between cerebral and retinal microvasculatures

The retinal and cerebral microvasculatures share many morphological and physiological properties. Assessment of the cerebral microvasculature requires highly specialized and expensive techniques. The potential for using non‐invasive clinical assessment of the retinal microvasculature as a marker of the state of the cerebrovasculature offers clear advantages, owing to the ease with which the retinal vasculature can be directly visualized in vivo and photographed due to its essential two‐dimensional nature. The use of retinal digital image analysis is becoming increasingly common, and offers new techniques to analyse different aspects of retinal vascular topography, including retinal vascular widths, geometrical attributes at vessel bifurcations and vessel tracking. Being predominantly automated and objective, these techniques offer an exciting opportunity to study the potential to identify retinal microvascular abnormalities as markers of cerebrovascular pathology. In this review, we describe the anatomical and physiological homology between the retinal and cerebral microvasculatures. We review the evidence that retinal microvascular changes occur in cerebrovascular disease and review current retinal image analysis tools that may allow us to use different aspects of the retinal microvasculature as potential markers for the state of the cerebral microvasculature.

Fractal analysis of retinal vessels suggests that a distinct vasculopathy causes lacunar stroke

Objectives: Lacunar strokes account for 25% of all ischemic strokes and may represent the cerebral manifestation of a systemic small vessel vasculopathy of unknown etiology. Altered retinal vessel fractal dimensions may act as a surrogate marker for diseased cerebral vessels. We used a cross-sectional study to investigate fractal properties of retinal vessels in lacunar stroke. Methods: We recruited patients presenting with lacunar stroke and patients with minor cortical stroke as controls. All patients were examined by a stroke expert and had MRI at presentation. Digital retinal photographs were taken of both eyes. Monofractal and multifractal analyses were performed with custom-written semiautomated software. Results: We recruited 183 patients. Seventeen were excluded owing to poor photographic quality, leaving 166 patients (86 with lacunar and 80 with cortical stroke). The mean age was 67.3 years (SD 11.5 years). The patients with lacunar stroke were younger but the prevalence of diabetes, hypertension, and white matter hyperintensities did not differ between the groups. The mean Dbox (monofractal dimension) was 1.42 (SD 0.02), the mean D0 (multifractal dimension) 1.67 (SD 0.03). With multivariate analysis, decreased Dbox and D0 (both representing decreased branching complexity) were associated with increasing age and lacunar stroke subtype after correcting for hypertension, diabetes, stroke severity, and white matter hyperintensity scores. Conclusions: Lacunar stroke subtype and increasing age are associated with decreased fractal dimensions, suggesting a loss of branching complexity. Further studies should concentrate on longitudinal associations with other manifestations of cerebral small vessel disease.

Fractal analysis of the retinal vascular network in fundus images

Complexity of the retinal vascular network is quantified through the measurement of fractal dimension. A computerized approach enhances and segments the retinal vasculature in digital fundus images with an accuracy of 94% in comparison to the gold standard of manual tracing. Fractal analysis was performed on skeletonized versions of the network in 40 images from a study of stroke. Mean fractal dimension was found to be 1.398 (with standard deviation 0.024) from 20 images of the hypertensives sub-group and 1.408 (with standard deviation 0.025) from 18 images of the non-hypertensives subgroup. No evidence of a significant difference in the results was found for this sample size. However, statistical analysis showed that to detect a significant difference at the level seen in the data would require a larger sample size of 88 per group.

Retinal microvascular abnormalities and cognitive dysfunction: a systematic review

Objective: To examine the evidence for an association between cognitive impairment or dementia and the presence of retinal microvascular abnormalities. Methods: A systematic review of observational studies identified through searching five electronic databases and reference lists. Studies were required to have both a recognised cognitive function assessment (either a structured neuropsychological test or a clinical evaluation of dementia), and assessment of the retinal microvasculature (either characteristics associated with generalised retinopathy or changes specific to arterioles or venules). Results: 6 studies were included. Studies were clinically and methodologically heterogeneous and of variable quality. Some degree of cognitive impairment was found to be associated with the presence of retinal microvascular abnormalities in all studies, although the extent of the association varied. The presence of retinal vascular signs was mostly associated with poorer verbal memory, mental speed and executive function in the general population, but not consistently associated with other cognitive modalities. Conclusions: There is some evidence suggesting a positive association between retinal microvascular abnormalities and cognitive impairment or dementia in elderly people and in patients with diabetes. Findings are inconclusive, and further better designed studies are required, with standardised and objective retinal vascular assessment and a range of sensitive cognitive tests.

Pain responses of Pascal 20 ms multi-spot and 100 ms single-spot panretinal photocoagulation: Manchester Pascal Study, MAPASS report 2.

Aims To evaluate pain responses following Pascal 20 ms multi-spot and 100 ms single-spot panretinal photocoagulation (PRP). Methods Single-centre randomised clinical trial. 40 eyes of 24 patients with treatment-naive proliferative diabetic retinopathy randomised to 20 and 100 ms PRP under topical 0.4% oxybuprocaine. A masked grader used a pain questionnaire within 1 h (numerical pain score (NPS)) and 1 month after treatment (numerical headache score (NHS)). Primary outcome measure was NPS immediately post-PRP. Secondary outcome measures were mean NHS scores and levels of photophobia reported within 4 weeks of primary PRP. Results Mean laser fluence was significantly lower using 20 ms PRP (4.8 J/cm2) compared to 100 ms PRP (11.8 J/cm2; p<0.001). Mean NPS scores for treatment were 2.4 (2.3) (mild) for 20 ms PRP group compared to 4.9 (3.3) (moderate) in 100 ms PRP group—a significant difference (95% CI 4.3 to 0.68; p=0.006). Mean NHS score within 1 month was 1.5 (2.7) in 20 ms PRP group compared to 3.2 (3.5) in the 100 ms PRP group (p<0.05). The median duration of photophobia after 20 ms PRP was 3 h, and significantly less compared to 100 ms PRP after which 72 h of photophobia was reported (p<0.001). Conclusions Multi-spot 20 ms PRP was associated with significantly lower levels of anxiety, headache, pain and photophobia compared to 100 ms single-spot PRP treatment. Possible reasons include lower fluence, shorter-pulse duration, and spatial summation of laser nociception with multi-spot Pascal technique.

Optos-guided pattern scan laser (Pascal)-targeted retinal photocoagulation in proliferative diabetic retinopathy

Purpose:  To investigate the clinical effects and safety of targeted pattern scan laser (Pascal) retinal photocoagulation (TRP) in proliferative diabetic retinopathy (PDR).

Intravitreal therapy for neovascular age-related macular degeneration and inter-individual variations in vitreous pharmacokinetics

This article aims to provide an interpretation and perspective on current concepts and recent literature regarding the evidence for individualizing intravitreal therapy (IVT), particularly considering iatrogenic and patient factors in the management of neovascular age-related macular degeneration (AMD). As ocular parameters that govern IVT pharmacokinetics do vary between individuals with AMD, developing a personalized strategy could improve safety and efficacy. This has to be derived from clinical measurements and data from laboratory animals; however, it is recognized that the animal models used in the development of intraocular formulations differ in their vitreous geometry from humans. These factors may be of relevance to the design of ophthalmic formulations and optimizing treatment outcomes in AMD. Further studies are needed to drive improvements in clinical practice which are aimed at maximizing the efficacy profile in IVT for AMD by a more rigorous evaluation of patient and surgeon-related variables.

In Vivo Laser-Tissue Interactions and Healing Responses From 20- vs 100-Millisecond Pulse Pascal Photocoagulation Burns

OBJECTIVES To compare in vivo burn morphologic features and healing responses of Pascal 20- and 100-millisecond panretinal photocoagulation (PRP) burns in proliferative diabetic retinopathy. DESIGN Prospective randomized controlled trial with 24 eyes assigned to either 20- or 100-millisecond Pascal PRP. Fundus autofluorescence and Fourier domain optical coherence tomography (FD-OCT) were performed 1 hour and 2 and 4 weeks after treatment. Main outcome measures included burn morphologic features on FD-OCT and greatest linear diameter (GLD) of laser burns as evaluated in 6 standard Early Treatment of Diabetic Retinopathy Study photographic fields using autofluorescence. RESULTS The contemporaneous increase in autofluorescence is observed with increasing pulse duration. Differences in mean GLD between 100- and 20-millisecond burns were 63 mum at 1 hour and 198 mum at 4 weeks (P < .001 for both). At 4 weeks, all burns corresponded to defects at the junction of inner and outer segments of photoreceptors (JI/OSP) and apical retinal pigment epithelium. After 4 weeks, the GLD of 20-millisecond burns reduced significantly by 35% (P < .001), with no change in 100-millisecond burns. CONCLUSIONS All burns initially appear as equivalent square-edged, columnar foci of hyperreflectivity in the outer retina. Pascal 20-millisecond burns progressively reduce in size, and this suggests a novel healing response localized to the JI/OSP and apical retinal pigment epithelium. The higher-fluence 100-millisecond burns develop larger defects due to thermal blooming and collateral damage.

Single-session vs multiple-session pattern scanning laser panretinal photocoagulation in proliferative diabetic retinopathy: The Manchester Pascal Study.

OBJECTIVE To investigate the effects of pattern scanning laser (Pascal; OptiMedica, Santa Clara, California) multispot panretinal photocoagulation given in a single-session (SS-PRP) vs single-spot multiple-session PRP (MS-PRP) on proliferative diabetic retinopathy (PDR). METHODS Single-center, randomized clinical trial of 40 eyes. Proliferative diabetic retinopathy was treated with a 400-mum spot size in 1500 burns given either as Pascal in 20-millisecond SS-PRP or in 3 sessions (100-millisecond MS-PRP) during a 4-week period. Visual acuity, central subfield retinal thickness (CRT), and 24-2 Swedish interactive thresholding algorithm visual fields were recorded at baseline and 4 and 12 weeks. MAIN OUTCOME MEASURES Central subfield retinal thickness, mean deviation, and PDR grade at 12 weeks. RESULTS There was a significant increase in mean CRT with MS-PRP (22 mum at 4 weeks, 95% CI, -32.25 to -10.75; 20 mum at 12 weeks, 95% CI, -28.75 to -10.82; P < .001) and no significant increase in the SS-PRP group. The mean deviation increased significantly in the SS-PRP group after 4 weeks (0.73 dB, P = .048), with no significant changes in either group at other points. A positive effect on PDR was observed in 74% of eyes in the SS-PRP group vs 53% in the MS-PRP group (P = .31). Mean treatment time for SS-PRP was 5.04 minutes (SD, 1.5 minutes) compared with 59.3 (SD, 12.7 minutes) in the MS-PRP group (P < .001). CONCLUSIONS There were no adverse outcomes (CRT, visual acuity, or visual field) from using multispot SS-PRP vs single-spot MS-PRP at 12 weeks postlaser, and treatment times were significantly shorter for multispot SS-PRP. Pascal SS-PRP was as effective as MS-PRP in the treatment of PDR. APPLICATION TO CLINICAL PRACTICE Twenty-millisecond Pascal SS-PRP may be safely and rapidly performed in 1500 burns with a similar efficacy to conventional MS-PRP. TRIAL IDENTIFIER: Research and Development Office PIN R00037, Central Manchester University Hospitals Foundation Trust.

Digital image analysis of plus disease in retinopathy of prematurity

An accurate assessment of retinopathy of prematurity (ROP) is essential in ensuring correct and timely treatment of this potentially blinding condition. Current modes of assessment are based upon clinical grading by expert examination of retinal changes. However, this may be subjective, unreliable and difficult and there has been significant interest in alternative means of measurement. These have been made possible through technological advancements in image capture and analysis as well as progress in clinical research, highlighting the specific importance of plus disease in ROP. Progress in these two fields has highlighted the potential for digital image analysis of plus disease to be used as an objective, reliable and valid measurement of ROP. The potential for clinical and scientific advancement through this method is argued and demonstrated in this article. Along with the potential benefits, there are significant challenges such as in image capture, segmentation, measurement of vessel width and tortuosity; these are also addressed. After discussing and explaining the challenges involved, the research articles addressing digital image analysis of ROP are critically reviewed. Benefits and limitations of the currently published techniques for digital ROP assessment are discussed with particular reference to the validity and reliability of outcome measures. Finally, the general limitations of current methods of analysis are discussed and more diverse potential areas of development are discussed.