The fractal properties of the retinal vascular architecture

Purpose: The human retinal vasculature has been demonstrated to exhibit fractal, or statistically self similar properties. Fractal analysis offers a simple quantitative method to characterise the complexity of the branching vessel network in the retina. Several methods have been proposed to quantify the fractal properties of the retina. Methods: Twenty five healthy volunteers underwent retinal photography, retinal oximetry and ocular biometry. A robust method to evaluate the fractal properties of the retinal vessels is proposed; it consists of manual vessel segmentation and box counting of 50 degree retinal photographs centred on the fovea. Results: Data is presented on the associations between the fractal properties of the retinal vessels and various functional properties of the retina. Conclusion Fractal properties of the retina could offer a promising tool to assess the risk and prognostic factors that define retinal disease. Outstanding efforts surround the need to adopt a standardised protocol for assessing the fractal properties of the retina, and further demonstrate its association with disease processes.

Reproducibility-repeatability of choroidal thickness calculation using optical coherence tomography

Purpose. To evaluate the repeatability and reproducibility of subfoveal choroidal thickness (CT) calculations performed manually using optical coherence tomography (OCT). Methods. The CT was imaged in vivo at each of two visits on 11 healthy volunteers (mean age, 35.72 ± 13.19 years) using the spectral domain OCT. CT was manually measured after applying ImageJ processing filters on 15 radial subfoveal scans. Each radial scan was spaced 12° from each other and contained 2500 A-scans. The coefficient of variability, coefficient of repeatability (CoR), coefficient of reproducibility, and intraclass correlation coefficient determined the reproducibility and repeatability of the calculation. Axial length (AL) and mean spherical equivalent refractive error were measured with the IOLMaster and an open view autorefractor to study their potential relationship with CT. Results. The within-visit and between-visit coefficient of variability, CoR, coefficient of reproducibility, and intraclass correlation coefficient were 0.80, 2.97% 2.44%, and 99%, respectively. The subfoveal CT correlated significantly with AL (R = -0.60, p = 0.05). Conclusions. The subfoveal CT could be measured manually in vivo using OCT and the readings obtained from the healthy subjects evaluated were repeatable and reproducible. It is proposed that OCT could be a useful instrument to perform in vivo assessment and monitoring of CT changes in retinal disease. The preliminary results suggest a negative correlation between subfoveal CT and AL in such a way that it decreases with increasing AL but not with refractive error.

Retinal and systemic vascular function in health and disease: the effect of smoking and coronary artery disease

The purpose of the following studies was to explore the effect of systemic vascular and endothelial dysfunction upon the ocular circulation and functionality of the retina. There are 6 principal sections to the present work. Retinal vessel activity in smokers and non-smokers: the principal findings of this work were: chronic smoking affects retinal vessel motion at baseline and during stimulation with flickering light; chronic smoking leads to a vaso-constrictory shift in retinal arteriolar reactivity to flicker; retinal arteriolar elasticity is decreased in chronic smokers. The effect of acute smoking on retinal vessel dynamics in smokers and non-smokers: the principal finding of this work was that retinal reactivity in chronic smokers is blunted when exposed to clicker light provocation immediately after smoking one cigarette. Ocular blood flow in coronary artery disease: The principal findings of this work were: retrobulbar and retinal blood flow is preserved in CAD patients, despite a change pulse wave transmission; arterial retinal response to flickering light provocation is significantly delayed in CAD patients; retinal venular diameters are significantly dilated in CAD patients. Autonomic nervous system function and peripheral circulation in CAD: The principal findings in this work were: CAD patients demonstrate a sympathetic overdrive during a 24 period; a delay in peripheral vascular reactivity (nail-fold capillaries) as observed in patients suffering from CAD could be caused by either arteriosclerotic changes of the vascular walls or due to systemic haemodynamic changes. Visual function in CAD: The principal findings in this work were: overall visual function in CAD patients is preserved, despite a decrease in contrast sensitivity; applying a filtering technique selecting those with greater coefficient of variance which in turn represents a decrease in reliability, some patients appear to have an impaired visual function as assessed using FDT visual field evaluation. Multiple functional, structural and biochemical vascular endothelial dysfunctions in patients suffering from CAD: relationships and possible implications: The principal findings of this work were: BMI significantly correlated with vWF (a marker of endothelial function) in CAD patients. Retinal vascular reactivity showed a significant correlation with peripheral reactivity parameters in controls which lacked in the CAD group and could reflect a loss in vascular endothelial integrity; visual field parameters as assessed by frequency doubling technology were strongly related with systemic vascular elasticity (ambulatory arterial stiffness index) in controls but not CAD patients.

Retinal vascular dysfunction relates to cognitive impairment in Alzheimer's disease

Cerebral vascular dysregulation has been increasingly implicated as a risk factor in the development of Alzheimer disease (AD)1; however, because of the difficulties associated with assessing and visualizing the cerebral vasculature directly, the ability to detect such dysregulation, noninvasively, is currently limited.2 Consequently, one concept that is being increasingly explored is the possibility of using the eye as a "window to the brain"; this approach has reasonable scientific validity as the retinal and brain vessels share a large number of embryological, anatomic, and functional similarities.2 Indeed, previous research has demonstrated a correlation between cognition and the geometry of the retinal vessels in elderly people.3 The aim of this pilot study, therefore, was to explore whether microvascular functional anomalies are evident at the retinal level in mild AD patients and to determine whether these anomalies relate to the degree of concurrent cognitive deficit..

Retinal arteriolar diameter response to flicker light provocation - A useful marker for risk stratification in cardiovascular disease?

Purpose: To to evaluate the benefit of bilinear and linear fitting to characterize the retinal vessel dilation to flicker light stimulation for the purpose of risk stratification in cardiovascular disease. Methods: Forty-five patients (15 with coronary artery disease (CAD), 15 with Diabetes Mellitus (DM) and 15 with CAD and DM) all underwent contact tonometry, digital blood pressure measurement, fundus photography, retinal vessel oximetry, static retinal vessel analysis and continous retinal diameter assessment using the retinal vessel analyser (and flicker light provocation). In addition we measured blood glucose (HbA1c) and keratinin levels in DM patients. Results: With increased severity of cardiovascular disease a more linear reaction profile of retinal arteriolar diameter to flicker light provocation can be observed. Conclusion: Absolute values of vessel dilation provide only limited information on the state of retinal arteriolar dilatory response to flicker light. The approach of bilinear fitting takes into account the immediate response to flicker light provocation as well as the maintained dilatory capacity during prolonged stimulation. Individuals with cardiovascular disease however show a largely linear reaction profile indicating an impairment of the initial rapid dilatory response as usually observed in healty individuals

Retinal microvascular dysfunction occurs similarly in Alzheimer's disease and primary open angle glaucoma patients

Purpose: The exact nature of the relationship between Alzheimer’s disease (AD) and primary open angle glaucoma (POAG) is still the subject of debate. One factor attributed to the aetiology of both conditions is vascular dysfunction. This study aimed to investigate the similarities and differences in retinal microvascular function between mild AD patients, early stage POAG patients and healthy controls Methods: Retinal vessel reactivity to flickering light was assessed in 10 AD, 19 POAG and 22 healthy age matched control patients by means of dynamic retinal vessel analysis (DVA, IMEDOS, GmbH, Jena, Germany) according to an established protocol. All patients additionally underwent BP measurements and blood analysis for glucose and lipid metabolism markers Results: AD and POAG patients demonstrated comparable alterations in retinal artery reactivity, in the form of an increased arterial reaction time (RT) to flicker light on the final flicker cycle (p=0.014), which was not replicated in the healthy age and cardiovascular risk matched controls (p>0.05). Furthermore, the sequential changes in RT on progressing from flicker one to flicker three were found to differ between healthy controls and the two disease groups (p=0.001) Conclusions: AD and POAG patients demonstrate comparable signs of vascular dysfunction in their retinal arteries at the early stages of their disease process. These comparable signs may reflect similarities in the pathophysiological processes that occur in the development of both conditions

Altered blood vessel responses in the eye and finger in coronary artery disease

Cardiac function, such as heart rate variability, is abnormal in coronary artery disease, but its relation with the function of ocular and nail-fold blood vessels is unknown. The hypothesis was that there is abnormal retinal and peripheral microvascular endothelial function compared with large blood vessel and cardiac function. Twenty-four patients with coronary artery disease (CAD) and 30 healthy, age- and sex-matched control subjects were enrolled in the study.

Ocular and systemic markers for vascular function in those at risk of type 2 diabetes mellitus and cardiovascular disease

The devastating impact of Type 2 Diabetes Mellitus (T2DM) -related morbidity and mortality on global healthcare is escalating with higher prevalences of obesity, poor diet, and sedentary lifestyles. Therefore, the clinical need for early diagnosis and prevention in groups of high-risk individuals is necessary. The purpose of this thesis was to investigate the use of surrogate markers, namely retinal vascular function, to determine future vascular endothelial dysfunction, atherosclerosis, large vessel disease and cardiovascular risk in certain groups. This namely covered normoglycaemic and normotensive South Asians (SAs), those with Impaired-Glucose Tolerance (IGT) and individuals with a familial history (FH) of T2DM. Additionally the effect of overweight and obesity was studied. The techniques and modified protocols adopted for this thesis involved the investigation of endothelial function by means of vascular reactivity at the ocular and systemic level. Furthermore, the relationships between retinal and systemic function with circulating markers for endothelial cell function and cardiovascular risk markers were explored. The principal studies and findings of the research were: Vascular Function in Normoglycaemic Individuals with and without a FH of T2DM WE FH individuals exhibited higher levels of total cholesterol levels that correlated well with the retinal arterial dilation amplitude to flicker light stimulus. However this did not extend to noticeable differences in markers for endothelial cell damage and impaired retinal and systemic function. Vascular Function in Normoglycaemic South-Asians vs. White-Europeans without a FH and Vascular Disturbances Compared to healthy WEs (normo -glycaemic and -tensive), SA participants exhibited levels of dyslipidaemia and a state of oxidative stress that extended to impaired vascular function as detected by reduced brachial artery flow-mediated dilation, slower retinal arterial vessel dilation reaction times (Appendix 3) and steeper constriction profiles. Furthermore, gender sub-group analysis presented in a sub-chapter shows that SA males demonstrated 24-hour systemic blood pressure (BP) and heart rate variability (HRV) abnormalities and heightened cardiovascular disease (CVD) risk. Vascular Function in Individuals Newly Diagnosed with IGT as compared to Normoglycaemic Healthy Controls Newly-diagnosed WE and SA IGT patients showed a greater risk for CVD and T2DM progression by means of 24-hour BP abnormalities, dyslipidaemia, increased carotid artery intimal-media thickness (c-IMT), Framingham scores and cholesterol ratios. Additionally, pre-clinical markers for oxidative stress and endothelial dysfunction, as evident by significantly lower levels of plasma glutathione and increased levels of von-Willebrand factor in IGT individuals, extended to impaired vascular systemic and retinal function compared to normal controls. This originally shows retinal, systemic and biochemical disturbances in newly-diagnosed IGT not previously reported before. Vascular Function in Normal, Overweight and Obese Individuals of SA and WE Ethnicity In addition to the intended study chapters, the thesis also investigated the influence of obesity and overweight on vascular function. Most importantly, it was found for the first time that compared to lean individuals it was overweight and not obese individuals that exhibited signs of vascular systemic and ocular dysfunction that was evident alongside markers of atherosclerosis, CVD risk and endothelial damage.

The electroretinogram:a useful tool for evaluating age-related macular disease?

With an ageing population, the number of age-related macular disease (ARMD) cases will inevitably rise. This gives greater impetus for the need to identify the disease earlier and assess treatments to slow disease progression. Differing electroretinogram (ERG) modalities have been reviewed in relation to the objective assessment of retinal function in ARMD and for monitoring the effectiveness of clinical interventions. Conflicting results have been found with regard to the efficacy of ERG findings in the investigation of ARMD in previous years. The newer multifocal ERG paradigm provides spatial topographical information about retinal function in ARMD. It has shown promising results in monitoring effectiveness of clinical interventions and studies are continuing in this area. Better knowledge of retinal function in ARMD may lead to enhanced treatments at each phase of the disease.

The Effect of nutritional supplementation on subjective and objective measures of visual and retinal function:a random controlled trial

In industrialised countries age-related macular disease (ARMD) is the leading cause of visual loss in older people. Because oxidative stress is purported to be associated with an increased risk of disease development the role of antioxidant supplementation is of interest. Lutein is a carotenoid antioxidant that accumulates within the retina and is thought to filter blue light. Increased levels of lutein have been associated with reduced risk of developing ARMD and improvements in visual and retinal function in eyes with ARMD. The aim of this randomised controlled trial (RCT) was to investigate the effect of a lutein-based nutritional supplement on subjective and objective measures of visual function in healthy eyes and in eyes with age-related maculopathy (ARM) – an early form of ARMD. Supplement withdrawal effects were also investigated. A sample size of 66 healthy older (HO), healthy younger (HY), and ARM eyes were randomly allocated to receive a lutein-based supplement or no treatment for 40 weeks. The supplemented group then stopped supplementation to look at the effects of withdrawal over a further 20 weeks. The primary outcome measure was multifocal electroretinogram (mfERG) N1P1 amplitude. Secondary outcome measures were mfERG N1, P1 and N2 latency, contrast sensitivity (CS), Visual acuity (VA) and macular pigment optical density (MPOD). Sample sizes were sufficient for the RCT to have an 80% power to detect a significant clinical effect at the 5% significance level for all outcome measures when the healthy eye groups were combined, and CS, VA and mfERG in the ARM group. This RCT demonstrates significant improvements in MPOD in HY and HO supplemented eyes. When HY and HO supplemented groups were combined, MPOD improvements were maintained, and mfERG ring 2 P1 latency became shorter. On withdrawal of the supplement mfERG ring 1 N1P1 amplitude reduced in HO eyes. When HO and HY groups were combined, mfERG ring 1 and ring 2 N1P1 amplitudes were reduced. In ARM eyes, ring 3 N2 latency and ring 4 P1 latency became longer. These statistically significant changes may not be clinically significant. The finding that a lutein-based supplement increases MPOD in healthy eyes, but does not increase mfERG amplitudes contrasts with the CARMIS study and contributes to the debate on the use of nutritional supplementation in ARM.

Community-Based Study of the Association of High Myopia in Children with Ocular and Systemic Disease

Purpose. High myopia in childhood is associated with important ocular and systemic conditions. However in the UK, high myopia in early childhood is not specifically identified in current ophthalmology, optometry, or orthoptic protocols for screening, referral, or investigation. An ongoing study in the West Midlands, UK, is investigating high myopia presenting to community health care clinics with the aim of compiling guidelines for assessment and subsequent referral. Methods. Children with high myopia were identified from community optometric and orthoptic sources and invited for an ophthalmology and optometry examination to ascertain possible ocular or systemic disease. Results. High myopia with no associated ocular or systemic condition was present in 15 (56%) of the children. In seven children (25%), associated ocular problems were found including unrecognized retinal dystrophies and amblyopia. Systemic disorders associated with high myopia were found in five children (19%) and included Sticklers syndrome, Weill-Marchesani syndrome, and homocystinuria. In one child, the diagnosis made before this study was found to be incorrect, and in another child, the results were inconclusive. In two cases, the diagnosis of a systemic condition in the child led to the identification of the disease in at least one relative. Conclusions. There is a high prevalence of ocular and systemic abnormality in young children seen in the community. Optometric and ophthalmologic assessment of children less than 10 years with myopia ≥5 D is likely to identify significant ocular or systemic disease, a proportion of which will respond to medical intervention. Detection and prompt referral of these cases by community health care services may be expected to prolong vision and possibly life expectancy.

Abnormal retinal vascular function and lipid levels in a sample of healthy UK South Asians

Background/aims To investigate ethnic differences in retinal vascular function and their relationship to traditional risk indicators for cardiovascular disease (CVD). Methods A total of 90 normoglycaemic subjects (45 South Asian (SA) and 45 age- and gender-matched white Europeans (WEs)) were recruited for the present study. Retinal vessel reactivity to flickering light was assessed by means of the dynamic retinal vessel analyser according to a modified protocol. Fasting plasma glucose, triglycerides (TG), total, LDL and HDL cholesterol were also measured in all individuals. Results SA individuals showed higher fasting triglyceride (p=0.001) and lower HDL levels (p=0.007), leading to a higher TG:HDL-C ratio (p=0.001) than age-matched WE subjects. Additionally, in SAs, the retinal arterial reaction time in response to flicker stimulation was significantly longer in the last flicker cycle than in the WEs (p=0.039), and this change correlated positively with measured plasma TG levels (r=0.60; p=0.01). No such relationship was observed in the WEs (p>0.05). Conclusion Even in the absence of overt vascular disease, in otherwise healthy SAs there are potential signs of retinal vascular function impairment that correlates with established plasma markers for CVD risk.

Visual symptoms in Parkinson's disease

Parkinson’s disease (PD) is a common disorder of middle-aged and elderly people in which degeneration of the extrapyramidal motor system causes significant movement problems. In some patients, however, there are additional disturbances in sensory systems including loss of the sense of smell and auditory and/or visual problems. This article is a general overview of the visual problems likely to be encountered in PD. Changes in vision in PD may result from alterations in visual acuity, contrast sensitivity, colour discrimination, pupil reactivity, eye movements, motion perception, visual field sensitivity and visual processing speeds. Slower visual processing speeds can also lead to a decline in visual perception especially for rapidly changing visual stimuli. In addition, there may be disturbances of visuo-spatial orientation, facial recognition problems, and chronic visual hallucinations. Some of the treatments used in PD may also have adverse ocular reactions. The pattern electroretinogram (PERG) is useful in evaluating retinal dopamine mechanisms and in monitoring dopamine therapies in PD. If visual problems are present, they can have an important effect on the quality of life of the patient, which can be improved by accurate diagnosis and where possible, correction of such defects.

Ocular and systemic vascular dysfunction in neurodegenerative disease

The important role played by vascular factors in the pathogenesis of neurodegenerative disease has been increasingly realised over recent years. The nature and impact of ocular and systemic vascular dysfunction in the pathogenesis of comparable neurodegenerative diseases such as glaucoma and Alzheimer’s disease (AD) has however never been fully explored. The aim of this thesis was therefore to investigate the presence of macro- and micro-vascular alterations in both glaucoma and AD and to explore the relationships between these two chronic, slowly progressive neurodegenerative diseases. The principle sections and findings of this work were: 1. Is the eye a window to the brain? Retinal vascular dysfunction in Alzheimer’s disease · Mild newly diagnosed AD patients demonstrated ocular vascular dysfunction, in the form of an altered retinal vascular response to flicker light, which correlated with their degree of cognitive impairment. 2. Ocular and systemic vascular abnormalities in newly diagnosed normal tension glaucoma (NTG) patients · NTG patients demonstrated an altered retinal arterial constriction response to flicker light along with an increased systemic arterial stiffness and carotid artery intima-media thickness (IMT). These findings were not replicated by healthy age matched controls. 3. Ocular vascular dysregulation in AD compares to both POAG and NTG · AD patients demonstrated altered retinal arterial reactivity to flicker light which was comparable to that of POAG patients and altered baseline venous reactivity which was comparable to that of NTG patients. Neither alteration was replicated by healthy controls. 4. POAG and NTG: two separate diseases or one continuous entity? The vascular perspective · POAG and NTG patients demonstrated comparable alterations in nocturnal systolic blood pressure (SBP) variability, ocular perfusion pressure, retinal vascular reactivity, systemic arterial stiffness and carotid IMT. · Nocturnal SBP variability was found to correlate with both retinal artery baseline diameter fluctuation and carotid IMT across the glaucoma groups.

Retinal drusen detection using the Nidek F-10 SLO in retro-mode

Presentaton Purpose:We conducted a small study to assess the novel, retro - mode imaging technique of the NIDEK F-10 scanning laser ophthalmoscope, for detecting and quantifying retinal drusen. Methods:Fundus photographs of 4 eyes of 2 patients taken in retro-mode on the Nidek F-10 SLO were graded independently by 6,experienced, masked fundus graders for the presence of retinal drusen , and compared to stereo colour fundus photographs taken with a Topcon TRC-50DX camera. Results:The mean number of retinal drusen detected in retro mode was 142.96+/- 60.8, range 63-265, and on colour fundus photography mean of 66.6+/-32.6, range 26-177. All observers independently detected approximately twice as many drusen on retro-mode than colour fundus photography (p<0.0001, Student’s paired t-test) . The statistical significance of interobserver variation in drusen detection was p=0.07 on colour fundus photography , and p=0.02 on retro mode ( ANOVA) . Conclusions:The retro-mode of the F-10 camera uses infrared laser and an aperture with a modified central stop, with the aperture deviated laterally from the confocal light path. This forms a pseudo -3D image which is a new means of detecting abnomalites in the deeper retinal layers. Retro-mode imaging of retinal drusen using the F-10 Nidek SLO is a highly sensitive technique for detecting and quantifying retinal drusen , and detected twice as many drusen than colour fundus photography. This small pilot study suggests that this novel type of imaging may have a role in the future detection and analysis of retinal drusen, a field that is likely to become increasingly important in future AMD prevention studies.