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3. LITERATURE REVIEW
3. A Influence of environmental factors, demographics and genes on retinal
vascular morphology
Residing in regions with higher air pollution concentrations and experiencing daily
increases in air pollution were each associated with narrower retinal arteriolar
diameters in older individuals; (Adar et.al.,2010) findings which support the
hypothesis that important vascular phenomena are associated with small increases in
short or long-term air pollution exposures, even at current exposure levels, and
further corroborate reported associations between air pollution and the development
and exacerbation of clinical cardiovascular disease. Smoking has been found related
to larger retinal arterial and venous diameters in three large population studies on
vascular abnormalities(Ikram et al.,2004;Kleinet al.,2003).Such a tendency was also
found in a recent Danish Twin Study(Taarnhoj et al.,2006). The underlying
mechanism may be that high carbon monoxide levels in smokers cause decreased
oxygen delivery to the retina, resulting in retinal hypoxia, which causes vessel
dilation. Even though sporadically reported in certain studies,there are yet no
conclusive or unequivocal data on the association between retinal vessel calibres and
alcohol consumption, or with estrogen replacement therapy in women, or with the use
of ocular betablockers, or the use of systemic antihypertensive medications. Because
of various systemic, environmental and genetic effects, it is challenging to define
uniform reference values that can be applied across populations even though it has
already been shown that separate reference values are needed for children, (Mitchell
et al.,2007) . The results of a 2008 study on Danish Twins (Taarnhoj et al.,2006)
suggests that genetic factors determine much of the variation in retinal vessel
calibres. Theresesrchers quoted that there is a large variation intortuosity of retinal
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arteries in healthy subjects and the predominant determinants are genetic, accounting
for 82% of the observed variations.A genome-wide linkage study of the Beaver Dam
population established that retinal artery and vein diameters were linked to multiple
gene loci in regions associated with hypertension, endothelial dysfunction, and
vasculogenesis. (Xing et al.,2006). Generalized retinal arterial narrowing was
associated with present or past blood pressure and increasing age; with the arterial
diameters decreasing by 2.3 to 4.8 micrometer per decade while the mean retinal
arterial diameters were higher in women than in men across all age groups (Wong &
Michelle,2004).
Unique biometric technology based retinal recognition is now being deployed in
commercial identification applications through retinal scanning devices. Two famous
studies have confirmed the uniqueness of the blood vessel pattern found in the human
retina. The first one was published by Dr Carleton Simon and Dr Isodore Goldstein
(Simon & Goldstein 1935), and describes how every retina contains a unique blood
vessel pattern. In another paper, they even suggested usage of photographs of these
patterns as a means of personal identification. The second study was conducted
during the 1950s by Dr Paul Towerwho discovered that - even among identical twins
- the blood vessel patterns of the retina are unique and different(Tower,1950).It is
likely that genetic, systemic and environmental factors proactively interact to
contribute to variations in retinal artery and veins and assessing these specific factors
in new studies may allow for a greater understanding, prevention and treatment of
complex vascular diseases in humans in the future.
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3B. Retinal vascular signs: Systemic associations and health implications
The retinal vasculature is the only microcirculation that can be visualized in vivo in
humans and analysis of the retinal vessels can provide potentially valuable disease
biomarkers.Retinal microvascular abnormalities, like generalized / focal arteriolar
narrowing, branching pattern, tortuoisity, arteriovenous nicking and retinopathy
reflect cumulative vascular damage from aging, hypertension, diabetes,
inflammations, infections and other systemic phenomenon. These abnormalities can
be observed in 2-15% of non symptomatic general population and are often the first
indicators of underlying pathology(Pose et al.,2005). Generalized arteriolar
narrowing and arteriovenous nicking appear to be irreversible long-term markers of
hypertension, related to current as well as past blood pressure levels. There is an
association between retinal microvascular abnormalities and stroke. Retinal
vasculature is a useful risk indicator for impending cerebrovascular diseases. The
retina and brain are highly metabolically active tissues with increased demands on
metabolic substrates via specialized vascular networks. Embryologically, the human
retina is an extension of diencephalon, and both these organs share a similar
vascularization pattern during development ( Lutty et al. 2002). There is a close
anatomical relationship between the macrovascular and microvascular blood supply
to the brain and retina, and both networks share similar vascular regulatory
processes (Delaey & Van de Voorde, 2000). Assessment of cerebral and retinal
vasculature is important in determining an individual’s risk of cerebrovascular
diseases, such as vascular dementia (Yoshikawa et al. 2003) and stroke.
The
severity of retinal characteristics is proportional to atherosclerosis, ischemic heart
disease and cardiovascular mortality. Increasing age and arterial hypertension are
associated with reductions in retinal vascular caliber and the extent of narrowing
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has been recognized as a major sign of end-organ damage. Retinal vessel tortuosity
has been linked to unexplained retinal haemorrhages and endocrinopathies.
Pituitary hormone insufficiencies show specific ocular fundus characteristics with
isolated tortuosity of retinal veins that may facilitate early diagnosis and treatment.
The association between retinal vascular abnormalities, midline brain lesions and
hormone deficiencies has been well described in septo-optic dysplasia
syndrome(Hellstro¨m et al.,1999).Patientswith hydrocephalus have significantly
straighter retinal arteries and fewer vessel branching points (Kaufman &
Alm,2003).Preterm birth affects the retinal vascular system functionally as well as
structurally, resulting in lower threshold for the development of vascular disease
along with an increased casual blood pressure in these subjects; suggesting that
birth status has effects on retinal vasculature that persist up to adult life.Increased
retinal vein tortuosity is caused by increase in vascular transmural pressurewhile
diameters
are
more
sensitive
than
(Andersson&Hellstorm,2009).People
with
tortuosity
Growth
at
lower
Hormone
pressures
insufficiencies,
regardless of hormonal treatment, have a significantly lower number of vascular
branching points.Impaired retinal perfusion occurs in cases with cerebral malaria;
filling defects (ghost vessels) and mottling of blood (dark columns)being evidence
of hypoxia and ischemia(White&Lewallen,2009).It has been suggested that
hepatocyte growth factor and blood cell count, particularly platelets are associated
with retinal vessel diameter and may be important in the pathogenesis of micro
vascular disease(Chiea et al.,2010).During Sickle Cell retinopathy, a remodeling of
the retinal vascular bed occurs; the tortuosity can change or a part of the vascular
tree can disappear. Retinal vessels can become blocked with emboli, cholesterol or
calcium plaques, that travel with the blood flow and become lodged at sites of
narrowing. The risk of occlusion is proportional to the number of arterial-venous
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overcrossings and branching degree of vessel arcades. Retinal vascular occlusive
disorder collectively constitutes one of the major causes of blindness.Retinopathy
that includes unique vessel abnormalities, appearance of narrowed and blocked
blood vessels, neovascularization and patterns of retinal whitening suggests
impaired perfusion that has diagnostic value in patients and its presence and
severity can predict the length of coma and risk of death. Retinal blood vessel
appearance is an important indicator for physical activity level, fasting and
dehydration, diabetes, hypertension and arteriosclerosis and is useful to access the
severity and progression of these conditions (Heitmar et al.,2008; Wong et
al.,2005). Retinal vascular net and particularly the bifurcation points are specific
anatomical landmarks for diagnostic and invasive procedures. There is clear
evidence
regarding
involvement
of
aging,
hypertension,
arteriosclerosis,
inflammation, endothelial dysfunction, smoking, and blood lipids in retinal vascular
characteristics, even to the extent that retinal vessel abnormalities may precede
health
events
like
arterial
hypertension,
stroke
and
coronary
heart
disease(Yoshikawa et al.,2003). Wider retinal venous calibre has been reported to
be independently associated with progression of diabetic retinopathy, diabetic
macular edema, and incidence of proliferative diabetic retinopathy Generalized
arterial narrowing was significantly associated with 10-year cardiovascular death in
the famous Beaver Dam Study(Wong &McIntosh,2005), showing a relationship
between retinal arterial narrowing and various diseases and disease markers;
therefore,an association would be expected between increased mortality and retinal
arterial narrowing. Cerebral and retinal microcirculations share similaranatomical,
embryological, and physical characteristics. There is evidence that small-vessel
disease is related to both clinical and sub-clinical stroke but the underlying
mechanisms are not fully understood.Retinal imaging has revealed relatively
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narrow retinal venules in patients with early Alzheimer Disease.White matter
lesions, which are caused by small vessel abnormalities, were associated with
increased risk of clinical stroke. However, the clinical utility of using vascular
calibers in cardiovascular or cerebrovascular risk prediction and in disease
management requires further evaluation. In a conclusive note, we can say that
because of its unique architecture and dictated by its function; both, the diseases of
the eye, as well as diseases that affect the circulation and the brain can manifest
themselves in the human retina. These include ocular diseases like macular
degeneration and glaucoma, the first and third most important causes of blindness in
the developed world. Also, a number of systemic diseases can affect the retina.
These include complications of diabetic retinopathy from diabetes, the second most
common cause of blindness in the developed world, hypertensive retinopathy from
cardiovascular disease, and multiple sclerosis. Thus, while on the one hand, retina is
vulnerable to organ-specific and systemic diseases; on the other hand, retinal
imaging allows diseases of the eye proper, as well as complications of diabetes,
hypertension and other cardiovascular diseases to be timely detected, diagnosed and
managed.
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3C. Imaging based visualization of blood vessels in the retina: History and
current status
3C.1History of Retinal Imaging
Somewhat paradoxically, the same optical properties of the human eye that allow
image formationalso prevent the direct inspection of retina. The red reflex, a
blurred reflection of the retina makes the pupil appear red if light is shined into the
eye at the appropriate angle, was known for centuries and this red reflex prevents
the visibility of retina in imaging. Therefore, special techniques are needed to
obtain a focused image of the retina. The French physician Jean Mery made the
first attempt to image the retina in a cat by demonstrating that if a live cat is
immersed in water, its retinal vessels are visible from the outside. Quite logically,
the impracticality of such an approach for humans lead to the invention of the
principles of the ophthalmoscope in 1823 by a Czech scientist Jan Evangelista
Purkyně (Purkinje) and its reinvention in 1845 by Charles Babbage (Abramoff et
al. ,2010) . Here,it is imperative to note that Babbage alsooriginated the concept of
a programmable computer and thus the link between computationand retinal
imaging is not a new one. Finally, the ophthalmoscope was reinvented againby von
Helmholtz in 1851(Abramoff et al. ,2010) . Thus, inspection and evaluation of the
retinabecame routine for ophthalmologists, and in 1853,the first images of the
human retina werepublished by the Dutch ophthalmologist 'Van Trigt' while earlier
sketches by Purkyněprovided drawings of his own retinal vasculature . (Fig.7 a)
Considering the prevalence of infectious diseases at the time and because the
ophthalmoscoperequired the physician to come quite close to the face of the
patient, it was preferably attractive to image the eye photographically. Thus, the
first useful photographic images of the human retina, showing bloodvessels, were
obtained in 1891 by the German ophthalmologist Gerloff. In 1910, Gullstrand
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developed the fundus camera, a concept still used to image the retina today .He
received the Nobel Prize for this invention (Abramoff et al.,2010).Because of its
safety and cost effectiveness at documenting retinal abnormalities, fundus imaging
has till date remained the primary method of retinal imaging.The second most
important development in eye imaging was the invention of fluorescein
angiography where a fundus camera with additional narrow band filters is used to
image a fluorescent dyeinjected into the bloodstream. It still remains widely used
because it allows an understanding of the functional state of the retinal circulation.
Concerns about its patient safety and long term cost-effectiveness are leading it to
be slowly but surely replaced by tomographic imagingmethods for its primary
applications, namely image-guided treatment of macular edema andthe “wet form”
of macular degeneration. One of the major limitations of fundus photography is
that it obtains a 2-D representation of the 3-D semi-transparent retinal tissues
projected onto the imaging plane.The initial approach, as first described by Allen
in 1964 was to depict the 3-D shape of the retina in stereo fundus photography,
where multi-angle images of the retina are combined by the human observer into a
3-D shape. Subsequently, using the confocal aperture to obtain multiple images of
the retina at different confocal depths, "Confocal scanning laser ophthalmoscopy"
was developed, yielding estimates of 3-D shape. Tomographic imaging of the
human retina became commonplace with the development of femtosecond lasers
,super-luminescent diodes and the application of optical coherence tomography to
retinal imaging , which allows truly 3-D optical sectioning of the retina.
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3C.2. Current Status of Retinal Imaging
During the past 160 years, retinal imaging has developed remarkably and is a now
a mainstay of the clinical care and management of patients with retinal as well as
systemic diseases.
Fundus photography is now widely used for population-based, large scale detection
of diabeticretinopathy, glaucoma, and age-related macular degeneration. Optical
coherencetomography (OCT) and fluorescein angiography are widely used in the
clinical diagnosis andmanagement of patients with diabetic retinopathy, macular
degeneration, and inflammatory retinal diseases. Also, OCT is widely used in
preparation for and follow-up in vitreo-retinalsurgery.
The following modalities/techniques all belong to the broad category of fundus
imaging:
.Fundus photography including the red-free photography
. Color fundus
. Stereo fundus photography
. Hyperspectral imaging
. Scanning laser ophthalmoscopy (SLO)
. Adaptive optics SLO
. Fluorescein angiography and indocyanine angiography—image intensities
represent the amounts of emitted photons from the fluorescein or indocyanine
green fluorophore that was injected into the subject’s circulation.(Fig.7 b)
Retinal angiography allows the physician to analyze intraretinal circulation and to
define the interrelationships between various layers of the retina, Retinal Pigment
Epithelial complex(RPE), and choroid. Angiography is not only documentary and
supportive of clinical differential diagnosis but also enables opthalmologists to
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make reasoned therapeutic decisions, particularly in the treatment of Age Related
Macular Degeneration and diabetic maculopathy. Angiography allows to confirm
the diagnosis and retain a "hard copy" for analysis throughout the course of the
disease. Accurate analysis and meaningful diagnostic conclusions result from the
recognition of several important phenomena that occur during the course of an
angiographic study and a standard protocol should be followed when interpreting a
fluorescein angiogram. Sodium fluorescein is a fluorescent dye compound which
can be administered intravenously or orally. It adheres to leucocytes of blood and
when stimulated by the "exciting" light of the fundus camera, it emits yellow-green
light, which is captured either with film or with digital imaging. In traditional
fluorescein angiography, 5 ml of 10% sodium fluorescein is injected into the
antecubital vein of forearm in a 3- to 7-second bolus. Mild, moderate, and severe
reactions to the injection of sodium fluorescein have sporadically been described
and should be watched out for. The dye flows to the heart and lungs and back
through the heart before entering the postequatorial choroidal circulation via the
short posterior ciliary arteries. This initiates the transit phase of the angiogram. The
transit phase (10-30 seconds post injection) records the first passage of dye as it
flows through the ocular blood vessels and into the ocular tissue. The earliest stage
of dye filling is called the prearterial phase when the dyediffuses throughout the
choroid and into the choriocapillaris, where it appears as "choroidal flush" or
"irregular background fluorescence." Cilioretinal arteries fill with dye concurrently
with choroid. A second later, the arterial phase begins as the retinal arteries fill.
During the venous stage, veins completely fill with dye and the arteries begin to
empty. The arteriovenous phase shows laminar flow in the venous system which
refers to the pattern of filling in the outer region of the blood column, within the
major retinal veins. This causes the vessel to appear more fluorescent at its margin
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than at the center. Most notable in the arteriovenous phase are fine vascular details
of the macular arterioles, the foveal avascular zone, and the diffuse background
choroid.The recirculation phase photographs provide a less distinct picture of
retinal vascular pattern due to staining of retinal and choroidal vasculature and the
diffusion of dye through retinal tissues. In general, the first complete circulation of
fluorescein through the eye reveals the most distinct picture of retinal pathology
from which the terms hypofluorescence and hyperfluorescence are evaluated.
Pathologic lesions can be defined as hypofluorescent if they appear less brilliant on
angiography than normal background fluorescence of the fundus, and
hyperfluorescent
if
they
appear
brighter
than
background
structures.
Hypofluorescent lesions are associated with decreased fluorescence due to
blocking or obscuration of the fluorescent pattern, as with sub retinal blood or scar
tissue. Alternatively, hypofluorescence is the result of poor filling of an area of
retinal vasculature. For example, in capillary nonperfusion associated with diabetic
retinopathy or retinal vein occlusion. Breakdown of the blood—inner retina barrier
and blood—outer retina barrier may be diagnostic in a variety of disease states.
Leakage from a breach in tight junctions of retinal vessel endothelium is reflective
of damage to the vessel wall and a corresponding loss of physiologic balance in the
osmotic gradient between the intra- and extravascular tissue compartments.
Defects in the RPE barrier are seen as leakage points or focal areas of
hyperfluorescence and imply that fluid from the choriocapillaris and choroid have
entered the subretinal space. Choroidal vessels in an abnormal location like in the
subretinal space anterior to the RPE cause dye to leak from choroidal intravascular
space, causing relative hyperfluorescence. Abnormal vessels having non-tight
junction endothelial cells , such as the neovascular blood vessels associated with
diabetes or venous occlusion leak dye or hyperfluorescence into the vitreous cavity.
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3C.3. Digital imaging of the ocular fundus
In the past years, retinal image analysis became a popular research field, with three
main factors explaining this trend: Firstly,the retina is the only location where
blood vessels can be visualizednon-invasively in vivo; Secondly, retinal images
can be produced and distributed with low timeand financial costs; Thirdly, retinal
vessels are strong indicators for the presence of diseases such as diabetic
retinopathy,retinal vessel occlusion ,glaucoma and arterial hypertension.The use of
retinal image analysis offers new techniques to analyze 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 the opportunity to study and to identify retinal
microvascular
abnormalities
as
markers
of
metabolic
and
systemic
disorders.Digital technology has revolutionized the way in which we can acquire,
store, and share retinal images, and it gives us considerably very many possibilities
for quantitative assessment of fundus and retinal vascular pathological changes.
The major advantage of digital imaging in clinical ophthalmology is its ability to
conveniently enhance and adjust photographs in order to visualize the smallest of
pathologic changes in the ocular fundus. A fundus camera is a specialized lowpower microscope with an attached camera which illuminates the fundus of the
eye(Fig.7c) .Light is projected through a set of filters and lenses on to an annular
mirror, creating a ring of illumination through the dilated pupil to form an image at
the film plane or the array sensor. The first step in digital imaging is digital image
capture, which is the electronic recording of light information and its conversion to
a set of numbers which are stored in a related image file. The advantage of digital
photography is immediate feedback control of image focus and luminosity,
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enabling immediate adjustment of exposure settings. Magnification of the eye
under fundus photography is very complex, and increases from the centre out
towards because the eyes are ball shaped. Sharpness in a photograph is a visual
phenomenon that is difficult to quantify and an image is described as sharp when
the borders defining the blood vessels are distinct and clear. Magnification differs
between eyes because of existing differences in the refraction, axial length,distance
and angle of the camera and refers to the number of specific points (pixels) of
picture information that are contained in an image file. High-resolution images
contain a high number of pixels and can exhibit greater image detail. The clarity of
fundus photography is related to the focus of the camera, the clarity of the patient’s
tear film,anterior chamber, lens and vitreous, since illuminating and imaging rays
pass twice through these structures. Dry or swollen corneas, cataracts, and vitreous
haemorrhages are conditions that can blur the image. The sharpness of a final
fundus photograph is also compromised by limitations in the specific camera’s
optical system(Tyler et al.,2003).Vessel measurements are reported in absolute
numbers or points and by setting a mean vertical disc diameter to 1.8 mm, the
measured distance in pixels in a digital image can be converted to mm. However,
this method is potentially prone to bias, since individuals have different sized optic
discs, refraction and axial length. But to get around this magnification issue would
be far too comprehensive for large population studies and researchers within the
field have accepted that which there is no good solution at the moment for the
magnification problem.
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Primitivefunduscopy with candle.First image of human retina drawn by Van Trigt ,1853
Early drawing of retinal vasculature including outlines of ONH and fovea published byPurkyne in 1823
Modern Fundus camera
Automated vessel analysis
Figure. 7 a. Retinal imaging: "Then and now"
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The characteristic phases in a normal fluorescein angiogram.A and B represent preinjection photographs; C–
E are the transit (early) phase of the angiogram; and F–I are the recirculation ("mid" and "late") phase.
Figure.7b.Fluorescein Angiography Entry of fluorescein into the choroidal and retinal
circulations. (Source:Kanski;200Ed.)
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Figure.7.c. Working of the modern Fundus camera: A fundus camera is a
specialized low-power microscope with an attached camera. (Source: Google images:fundus
camera)
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3C.4 Computer assisted methods for analysis of retinal blood vessels
In the context of clinical research, methods for automatically analyzing retinal
images hold high relevance as they offer the potential to examine a large number
of images with time and cost savings and provide more objective measurements
than current observer-driven techniques. Historically, researches on retinal
vescular morphology can be divided into three eras: the visual impression era, the
quantitative era, and the digital imaging era. The first era of visual impression was
basic
and
yielded
limited
data
based
on
subjective
and
qualitative
observations.Terminologies of the time wereretinal arterial 'narrowing' in
hypertensive retinopathy described by Gowers (Gowers ,1876) and arteriovenous
''nicking as a sign of hypertensive retinopathy described by Marcus Gunn (Gunn
,1898).The 1970s witnessed a movement into the quantitative era, thanks to the
introduction of the wide-angle fundus camera.A new era of modern digital imaging
began in the 1990s and like the rest of the imaging world today, fundus
photography also participated in the digital revolution. Recent advances in digital
image analysis have allowed objective, fast, and accurate semi-automated
quantitative measurements of retinal vessels, particularly vessel calibers (Hubbard
et al.,1999).The advantages of these methods include the ability to quickly and
easily measure retinal vessel diameters of large study populations and the ability to
follow them over prolonged periods of time. Another advantage is the ability to use
statistics in order to adjust for important systemic and environmentalfactors when
analyzing
associations
and
correlations
with
ocular
and
systemic
conditions.Completely automatic fundus photographic vessel measurement
programs that are quicker and highly accurate have recently been presented, but
have not yet been unequivocally tested in large population studies and of the many
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detection methods that are available, the results arenot always satisfactory.
Methods giving a sensitivity of 92% with a specificity of 91% are regarded
acceptable. In some applications, vessels are the main interest of the image
(Perdersenet al.,2000), while in other cases, they merely act to obstructthe
observed area(Waldock et al.,1998) . Blood vessels are also used as landmarks in
registration methods (Lloret et al.,2000 ;Zana &Klein,1999).
Methods for
detecting retinal blood vessels generally fall into one of three categories (Hoover et
al.,2000).
.
-Kernel-based
-Classifier-based
-Tracking-based
Kernel-based methods convolute the image with a kernel based on a predefined
model; Tracking methods use a model to track the vessels, starting at given points;
Classifier-based methods use a two-step approach starting with a segmentation step
(often by employing one of the mentioned kernel-based methods) and next the
regions are classified according to many features which allows the incorporation
oflarge-scale
properties,
but
only
after
an
initial
segmentation
step.
Numerous algorithms have been presented in the last two decades for the
segmentation of retinal blood vessels. Many of them are based on the assumption
that the intensity profile of retinal vessels is Gaussian-like. Directional Gaussian
filters,as well as their first or second order derivatives,have been widely applied in
order to enhance the retinal blood vessels. Many other filters for highlighting the
vessels have been proposed like morphological filters with linear structuring
elements,modified
top-hat,
tramline
algorithms,
line
detectors
and
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wavelets(Rossant et al.,2011). In all cases, proper detection is crucial and till date,
due to the unique properties of each acquisition technique; a single generally
acknowledged vessel detection algorithm does not exist. Current methods of retinal
vessel measurements are subject to a considerable amount of subjective human
input and a fair amount of inter and intra-grader variability exists in retinal vessel
measurements. Accurate quantification of changes in vessels like calibre and
tortuosity or branching patterns is difficult to automate fully because of large
variations in image type, size and quality and in practice, measurements are
frequently obtained using semi-automated computer-assisted methods, which can
be both laborious and open to user bias.
.
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3C.5 Fundus photography and some prominent retinal vascular population
based researches
The field of quantitative fundus photographic vessel studies is extensive and
photographic assessment of retina, specially its arteries and veins has demonstrated
statistically significant effects of systemic variables, environmental conditions, and
genetic factors. Some major studies, covering fundus image based retinal analysis
of populations, including a total of 34480 subjects are enumerated here.
a. The Atherosclerosis Risk in Communities Study (ARIC): a prospective cohort
study of 15792 persons, from US communities, initiated in 1987 through 1989
which investigated cardiovascular disease and associated risk factors among
middle-aged people.(Wong &McIntosh,2005;Wong&Michelle,2004)
b. The Blue Mountains Eye Study (BMES):an Australian population based cohort
research of common eye diseases that included 3355 participants in 1992-94,
where mydriatic 30 degree fundus photos were used to examine microvascular
characteristics and their association with ocular and systemic diseases.(Wong
&McIntosh,2005;Wong&Michelle,2004)
c. The Beaver Dam Eye Study: a study of 4926 persons aged 43-84 years living in
Beaver Dam, Wisconsin. Baseline examinations were performed in 1988-1990 in
order to investigate relationships between microvascular characters and ocular and
systemic diseases.(Wong &McIntosh,2005;Wong&Michelle,2004)
d. The Cardiovascular Health Study (CHS): a prospective cohort study initiated
in 1989-1990 in 4 communities living in USA during 1997-98 . Fundus photos of
2405 people, aged 69-97 years were taken to study etiology and risk prediction of
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coronary
heart
disease
and
stroke
among
older
people
(Wong
&McIntosh,2005;Wong&Michelle,2004).
e. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (XVIII and XIX)
:this population based research included 996 persons diagnosed with diabetes at
age younger than 30 years who were taking insulin, and 225 controls without
diabetes, all from South Central Wisconsin during 1980-82.This study examined
epidemiologic and clinical features of diabetic retinopathy, retinal vein and artery
diameters and other ocular characteristics(Wong &McIntosh,2005).
f. The Rotterdam Study: a population-based cohort study on presence of chronic
diseases in the elderly; including 7983 persons, from a district near the city of
Rotterdam aged over 55 years in 1990-1993(Wong &McIntosh,2005).
Summary of the aforementioned research findings: These above mentioned large
scale population based studies (a-f) elucidate the following: There is evidence
suggesting that retinal arterial narrowing is associated with increasingage, elevated
blood pressure (past, current, and future), increasing degrees of macular diabetic
oedema, increasing severity of diabetic retinopathy, increased risk of Coronary
Heart Disease and increased mortality from Coronary Heart Disease and stroke.
Generalized arterial narrowing seems to be related to chronically elevated blood
pressure levels although which event precedes the other still remains to be
shown.Also, evidence suggests that arterial narrowing may precede the
development of hypertension. Lower mean Arterio Venous Ratio(AVR) indirectly
shares certain risk factors with atherosclerosis.Lower mean AVR is associated with
increased risk of diabetes mellitus and stroke, although this association is mostly
driven by venous dilation rather than arterial narrowing; reflecting the importance
of analyzingarterial and venous diameters separately.