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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2589_Библиотеки_им_академика_М_И_Перельмана
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Part I
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Intraocular Signs
Retinal Capillary Microaneurysms
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1.1 Introduction
Microaneurysms (MAs) are one of the most signicant intraocular signs of an underlying systemic disease. Retinal MAs are the earliest lesion
seen in patients with diabetic retinopathy and the
sine qua non of diabetic retinopathy. The early
stages of diabetic retinopathy and the associated
comorbidities are completely asymptomatic and
require regular screening and prompt control.
The patients become aware only when the vision
is affected due to macular oedema, or they are at
the threshold of severe visual loss or have already
lost vision from complications of diabetic retinopathy. As the disease carries signicant morbidity and mortality, it must be detected by
purposeful screening to detect the early stages of
retinopathy (Box 1.1). See Box 1.2 for clinical
clues for diabetes and other diseases that may
cause MAs.
Box 1.1 Common Causes of Retinal Capillary
Microaneurysms
1. Diabetes mellitus is the most common
2. Hypertension
3. Carotid atherosclerosis
4. Takayasu’s arteritis
5. Ocular ischaemic syndrome (OIS)
6. Branch retinal vein occlusion
7. Central retinal vein occlusion
8. Coats’ disease
9. Type 1 macular telangiectasia
10. Radiation retinopathy
Box 1.2 Key Points in History and Clinical
Examination in Diabetes and MAs Related
Disorders
1. Duration and control of diabetes
2. Check blood pressure in both upper
arms
3. History of smoking
4. Nocturnal obstructive sleep apnea
5. Check for body mass index
6. Check for asymmetry/absence of
peripheral pulses and for the presence
of arterial bruits or tenderness over the
carotids (Takayasu’s arteritis)
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
A. Gupta et al., Ophthalmic Signs in Practice of Medicine,
https://doi.org/10.1007/978-981-99-7923-3_1
3
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7. Detailed neurological examination,
including vibration sense and joint position sense in patients with diabetes having MAs
8. Palpate for vessel wall thickness as a
clue to atherosclerosis
Abbreviation: MAs microaneurysms
1 Retinal Capillary Microaneurysms
DM affects practically all organs of the body.
DM co-morbidities compound each other, and it
is essential that all DM patients undergo regular
screening for early detection of these for prompt
management (see Box 1.4). For detailed information on the current screening, diagnostic, and
therapeutic guidelines of diabetes and comorbidities, the readers are advised to consult the
American Diabetic Association guidelines [1].
Often the detection of MAs in the retina may
be the rst clue toward diagnosing type 2 diabetes mellitus (DM). Patients with type 2 diabetes
mellitus have an insidious onset and remain
asymptomatic till they get detected by a routine
laboratory test carried out in the context of other
illnesses. Thus, the duration of type 2 DM is not
known. MAs in the retina indirectly show that
type 2 DM has been present for at least 5years.
Detection of retinal microaneurysms should
prompt a thorough clinical history, examination,
and laboratory workup to detect DM and other
causes of MAs. Depending upon the cause of the
MAs, minimum laboratory investigations that
should be done are listed in Box 1.3.
Box 1.3 Lab Investigations to Be Considered
Based upon the Underlying Condition
1. Check for fasting blood sugar, HbA1C,
lipidogram, Hb
2. APLA workup and procoagulant
workup for BRVO and CRVO
3. Urinalysis to look for microalbuminuria/proteinuria in patients with diabetes to look for nephropathy
4. Arterial Doppler examination of carotid
arteries
Abbreviations: HbA1C glycosylated
haemoglobin, Hb haemoglobin, APLA
anti-phospholipid antibodies, BRVO branch
retinal vein occlusion, CRVO central retinal vein occlusion
Box 1.4 Key Points in Screening for Diabetes
and Comorbidities
1 DM is diagnosed if FBSL is >126mg/dL or
HbA1c is >6.5%, or random BSL or OGTT
at 2h is >200mg/dL
2 Screening for diabetic retinopathy should
be done at diagnosis of DM type 2 and
5years after the onset of DM type 1. An
ophthalmologist should do screening in a
dilated eye or tele-screening using a
non-mydriatic camera
3 If no DR is detected, screening is done
every 2years. More frequently if MAs are
detected. If sight-threatening DR is
detected, refer immediately to an
ophthalmologist for treatment
4 Screen for co-morbidities at least
annually—anaemia, nephropathy,
peripheral neuropathy, and foot sensations.
Anaemia is often overlooked in patients
with DM/DR
5 Control of BSL, lipid, and blood pressure.
Blood pressure should be checked every
visit with a target BP <130/80 if ASCVD
risk is >15%. DM patients most often
require statins. Control of these factors
delays the onset of diabetic retinopathy and
if present, reduces the severity of DR and
the need for interventions
6 Encourage physical activity, weight control,
a Mediterranean diet, and no smoking
a
Abbreviations: Dm diabetes mellitus,
FBSL fasting blood sugar level, HbA1c glyco-
sylated haemoglobin, OGTT oral glucose tolerance test, DR diabetic retinopathy, ASCVD
atherosclerotic cardiovascular disease
a
https://www.acc.org/Tools- and- Practice-
Support/Mobile- Resources/Features/
2013- Prevention- Guidelines- ASCVD-
Risk- Estimator
1.2 Anatomical Considerations oftheRetina
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If the patients are detected to be suffering
from DM, the guidelines for follow-up and referral for diabetic retinopathy should be meticulously adhered to.
1.2 Anatomical Considerations
oftheRetina
The retina is a highly organized, multi-layered
innermost lining of the eyeball. It converts photons into electrical signals to transmit to the
visual cortex located in the occipital lobes of the
brain for ultimately transforming reected light
from the objects around into their 3-D visual perception. Maintaining the light path transparency
is critical to achieving sharp and high-resolution
images. Several anatomical and physiological
factors must work in perfect harmony to project a
sharp image of the object on the photoreceptors.
The retina consists of two layers, the transparent
neurosensory retina anteriorly and a dark retinal
pigment epithelial (RPE) layer posteriorly, separated by a potential space. The neurosensory retina is a multi-layered structure consisting of
several highly organized cells of neural and glial
origin and their processes. The light has to pass
through from front to back, the internal limiting
membrane (footplates of the macroglia, the
Muller cells), the retinal nerve bre layer (RNFL,
the axons of the retinal ganglion cells), retinal
ganglion cells (RGC), the inner plexiform layer
(the synaptic junction of the dendrites of the
RGC, amacrine cells, and the axons of the bipolar
cells), the bipolar cell layer (it also has the cell
bodies of the Muller cells, amacrine, and horizontal cells), the outer plexiform layer (the synaptic junctions of the dendrites of the bipolar
cells and the axons of the photoreceptor rods and
cones; with horizontal cell processes controlling
transmission), the external limiting membrane
(Muller cell apical processes joining each other
and the inner segments of the photoreceptors),
the outer nuclear layer (ONL), and the cell bodies
of the rods and cones. The neurosensory retina is
further divided into an inner retina up to the outer
border of the inner nuclear layer and the outer
retina, from the outer plexiform layer (OPL) to
the photoreceptor layer. The neural cells and
bres are tightly packed in all the layers and are
oriented vertically in the outer retina but become
near parallel in the anterior retina. The blood supply of the retina is also layered. The anterior neurosensory retina gets its blood supply from the
central retinal vessels that run their course in the
RNFL and supply the inner retina through four
capillary plexuses. The supercial plexus (SCP)
in the ganglion cells layer, the intermediate
plexus (ICP) at the inner border of the inner
nuclear layer (INL), and the deep plexus (DCP)
at the outer border of the INL (Fig. 1.1). The
radial capillaries from the optic disc supply the
RNFL peripapillary retina. If the cilioretinal
artery is present, it supplies nutrients and oxygen
to all the layers of the macula.
The retinal capillaries do not cross beyond the
inner one-third of the OPL, also known as the
middle limiting membrane. The OPL in the
fovea is known as the Henle bre layer. The
cones and the Muller cell bres have a radial orientation in this zone. The retinal vessels have
tight endothelial junctions (inner blood-retinal
barrier) and do not allow macromolecules, cellular elements, and uid movement into the
extravascular space. The central 400–500μm of
the anterior neurosensory retina is called the
foveal avascular zone and is a vessel-free zone.
The outer retina is avascular and receives nutrition and oxygen requirements from the choroid.
The OPL is avascular and falls in the watershed
zone of the two vascular supply systems. The
dark RPE at the back of the neurosensory retina
has tight junctions and maintains the outer
blood–retina barrier. The vertebrate outer limiting membrane (OLM) also has adherent and
tight junction proteins. It provides a partial semipermeable barrier function that allows diffusion
of only small protein molecules (<35 radius
Angstrom units) that are present in the extracellular space around the photoreceptors [2].
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1 Retinal Capillary Microaneurysms
Fig. 1.1 A highly schematic representation of the retina’s
microstructure shows the retinal capillary plexuses limited to the anterior retina. (Modied from Fig.5.4 Gupta
A. Bench-to-Bedside research in Ophthalmology. in
1.3 Pathogenesis ofRetinal
Capillary Microaneurysm
Formation inDiabetic
Retinopathy
The earliest change in diabetic retinopathy is the
thickening of the capillary basement membrane
(BM) across all body organs, most pronounced in
the retina. The thickening of the BM is due to the
deposition of the extracellular matrix proteins by
the non-enzymatic glycation of proteins in longterm hyperglycaemia. The thickened BM leads to
the loss of cell-to-cell talk between the pericytes
and the endothelial cells and the resultant loss of
Biomedical translational research-From disease diagnosis
to treatment. Sobti RC and Ganju AK (Eds). With permission of the publisher. Springer Nature, Singapore Pte Ltd.
2022)
the pericyte–endothelial cell ratio. This leads to
loss of contact and control by the pericyte over
the endothelial cell. In normal retinal capillaries,
the ratio of pericyte to endothelial cells is maintained at 1:1. Along with the Muller cells, these
form a neurovascular unit that plays a major role
in maintaining metabolic homeostasis in the retina [3]. Once there is a loss of contact between
the Muller cells, pericytes, and endothelial cells,
normal homeostasis is lost, activating the retinal
microglia, which release proinammatory cytokines. There is an overexpression of hypoxiainducible factor 1-α (HIF-1α) in the endothelial
and Muller cells. HIF-1α is a regulator of vascu-
1.5 Retina Examination toDetect Retinal Capillary Microaneurysms
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lar endothelial growth factor (VEGF). Hypoxic
Muller cells also produce VEGF, which promotes
endothelial cell proliferation and break down of
the tight endothelial junctions [4]. Unlike endothelial cells, pericytes do not have the potential to
regenerate. Microaneurysms (MAs) are usually
formed around the area of acellular capillaries by
a fusiform or saccular dilation of the capillaries,
which may be cellular or acellular. The endothelial cells lining the MAs lack junctional proteins
and leak uid and macromolecules like
lipoproteins.
1.4 Historical Perspective
ontheDetection ofRetinal
Capillary Microaneurysms
Photographic documentation of the retinal vasculature by injecting a bolus of uorescein dye
into the antecubital vein called the fundus uorescein angiography (FFA) was a disruptive
technological breakthrough since the discovery
of a direct ophthalmoscope more than 100years
ago. The technique gave a major llip to the
study of retinal involvement in several systemic
and ophthalmological disorders. [5, 6]. Although
initially the dye was injected into the antecubital
vein, attempts were made for a short while to
perform FFA by intraarterial cannulation of the
innominate artery [7]. It was believed that injecting uorescein dye directly into the innominate
artery allowed the dye bolus to reach the retinal
arterioles, followed by the retinal capillaries, and
nally move on to the retinal veins. The brachial
artery was punctured in the antecubital fossa of
the right arm and cannulated with a 60-cm polyethylene tube. A small bolus of heparinized
sucrose was injected to determine that the cannula had reached the innominate artery. When
the patient felt the sweet taste on the right side of
the tongue, they knew that it had reached the
innominate artery and then the uorescein
sodium dye was injected. Using this technique,
Eva Kohner erroneously believed that MAs in
diabetes were located on the venous end of the
capillaries [8]. It was undoubtedly a highly cum-
bersome technique and soon reverted to the original technique of Novotny and Alvis of dye
injection through the antecubital vein, a technique so simplied that it is followed till now.
The availability of FFA made it possible to visualize, invivo, MAs and the areas of retinal perfusion, which till then had been seen and
documented only on trypsin digestion studies of
the retina obtained from the harvested eyes of
patients with DM.
1.5 Retina Examination
toDetect Retinal Capillary
Microaneurysms
MAs are seen as red dot-like focal dilatations of
the retinal capillaries. These are 10–100 μm in
size. Normal retinal capillaries and microaneurysms less than 30 μm in diameter cannot be
visualized on clinical examination. However,
MAs larger than 30 μm can be easily seen by
physicians with a monocular direct ophthalmoscope (15× magnication). Using a +60D, +78,
or +90D lens remains the most prevalent clinical
technique for the stereoscopic fundus examination on a slit lamp. It is convenient but provides a
lower resolution than a contact lens. The high
plus objective lens provides a real, inverted, and
laterally reversed image of the macula in front of
this lens and needs experience to master the technique. A +90 D lens provides a eld of view of
~90°, a working distance of 7mm from the cornea, and a magnication factor of 0.76×.
Choosing a 10× magnication on the slit lamp, a
nal retinal image magnication of 7.6× (cf. 15×
from direct ophthalmoscope) can be obtained.
Because of the lens’s small diameter and metallic
ring, it is convenient to hold it for a long time and
can be used even in an undilated pupil. A wider
area of the retina can be screened by asking the
patient to move his eye in different directions.
The +78D lens is bigger and can have a eld of
view of 81/97° and a magnication factor of
0.93× at 8 mm from the cornea. However, it
requires a dilated pupil and may be tiring if
required to hold for a long time.
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1 Retinal Capillary Microaneurysms
However, MAs and retinal capillaries can be
easily visualized on fundus uorescein angiography (FFA). This invasive technique involves
injecting a 3mL bolus of a water-soluble uorescent dye (uorescein sodium 20%) intravenously
and taking fundus photographs through a special
camera equipped with matched narrow-band
excitation and barrier lters. As the dye ows in
the retinal vessels, it is excited by the blue light
and emits light in the green spectrum, which has
a higher wavelength. This phenomenon was earlier captured on a photographic B&W lm that
required processing in a dark room. Digital cameras have completely replaced lm-based systems. The uorescein angiogram is instantly
available for review by the ophthalmologist as
soon as the images are saved.
1.6 Dierentiating Retinal
Capillary Microaneurysms
andDot Haemorrhages
Clinically, it is difcult to differentiate MAs from
dot haemorrhages, a common accompaniment in
diabetic retinopathy. MAs are globular with a
regular contour and show a shiny reex from
their surface. On the other hand, dot haemorrhages result from the extravasation of red blood
cells (RBCs) from the MAs in the various capillary plexuses. A careful examination would
reveal dot haemorrhages to be dull red in colour
that neither have a globular shape nor show a
light reex from their surface (Fig.1.2). These
leaked RBCs assume a dot-like shape because
they are in a tightly packed inner nuclear layer or
c
Fig. 1.2 Colour fundus photograph of the right eye (a)
showing microaneurysms (black arrows) and of the left
eye (b) showing dot haemorrhages (blue arrows). Fundus
uorescein angiography of the right eye (c) shows hyper-
d
uorescent lesions (red arrows) corresponding to microaneurysms, while in the left eye (d), the dot haemorrhages
appear hypouorescent (yellow arrows) due to blocked
uorescence
1.7 Location ofRetinal Microaneurysms
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the ganglion cell layer (GCL). The normal retina
is tightly packed with cellular elements with only
a potential extracellular space in the inner and
outer plexiform layers.
1.7 Location ofRetinal
Microaneurysms
It is now believed that the MAs in DM are located
on the arterial end of the capillaries. In the diabetic retina, the MAs are not distributed uni-
a b
formly. These are located preferentially in the
posterior pole, with a majority seen in the upper
and temporal sectors of the macula (Fig. 1.3).
The left eye shows more MAs than the right [9].
There are areas of the retina with an entirely normal capillary bed and areas with a loss of the retinal capillary bed. MAs are clustered around
capillary non-perfusion, as seen on fundus uorescein angiography (FFA). In at-mount trypsin
digestion studies, these are seen as hollow acellular tubes. Many more MAs are seen on FFA
than are visible on clinical examination (Fig.1.4).
Fig. 1.3 Left eye colour fundus photograph (a) showing
microaneurysms in the posterior pole, more along temporal and superior macula (black arrows), which are more
a b
Fig. 1.4 Left eye colour fundus photograph (a) of a
patient with type 2 diabetes mellitus and early nonproliferative diabetic retinopathy showing a few clinically
visible microaneurysms (black arrows), which are seen
prominently seen as hyperuorescent lesions (blue
arrows) on fundus uorescein angiography (b)
much more in number on fundus uorescein angiography
(b), the black arrows corresponding to clinically visible
microaneurysms, and yellow arrows corresponding to
those seen only on FFA
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Fig. 1.5 Hard exudates appear as shiny deposits (black arrows) on fundus examination (a) and the causative microan-
eurysms (blue arrows) can be seen more clearly on FFA (b)
1 Retinal Capillary Microaneurysms
Some clinically seen MAs but not seen on FFA
are either dot haemorrhages or thrombosed MAs
[5].
MAs are present in the supercial and the
inner (located in the ganglion cell layer) and the
deep capillary plexus of the retina (located on
either side of the inner nuclear layer). It is impossible to discern whether a specic microaneurysm is in the supercial or deep capillary plexus
on fundoscopy or even on FFA. However, their
location can be determined using advanced imaging techniques such as optical coherence tomography angiography (Fig.1.9).
1.8 Leakage fromtheRetinal
Capillary Microaneurysms
Fig. 1.6 A complete ring of hard exudates, the circinate
ring (arrows), marks the outer boundary of the leaking
microaneurysms
Leakage from the MAs leads to the formation of
hard exudates. In the normal retina, endothelial
cells lining the retinal vessels have tight junctions
that do not allow the movement of uid and macromolecules into the extravascular space. Once
the MAs are formed in the retinal capillary bed,
the endothelial tight junctions are lost, with consequent leakage of uid and lipoproteins into the
extravascular space that results in the thickening
of the retina and accumulation of lipoproteins
seen as bright shiny hard exudates (Fig.1.5). The
leaked uid gets absorbed by the adjacent normal
capillary bed. However, the large lipoprotein exudates cannot move back into the intravascular
space. These stay in the extravascular space and
mark the boundary of the normal and abnormal
capillary beds. These hard exudates are carted
away by the phagocytes, but as the new exudates
keep forming and an equilibrium is reached, any
change in the number and size of these hard exudates may not be readily appreciated. Complete
or incomplete rings of hard exudates (circinate
rings) mark the outer boundary of the leaking
microaneurysms (Fig. 1.6). It was the basis of
focal laser photocoagulation to destroy the
leaking microaneurysms.
1.9 Life Cycle ofRetinal Capillary Microaneurysms
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c d
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Fig. 1.7 A 20-year-old type 1 woman with nonproliferative diabetic retinopathy (a) with many microaneurysms on FFA in the macula (b), 3months following
intravitreal injection of Ozurdex, most microaneurysms
1.9 Life Cycle ofRetinal Capillary
Microaneurysms
Once formed, the MAs in diabetes show a gradual increase in their numbers and over the years,
some of them become involute while the new
ones continue to form. The course of the MAs is
stable; once formed, they disappear at ~3% per
month when seen over a long follow-up. The formation of new MAs is a sign of the progression
of diabetic disease and the number of MAs indicates the severity of diabetic retinopathy [10]. An
increase in MAs by a factor of 16× from baseline
to the 4-year follow- up increased the 10-year risk
of proliferative diabetic retinopathy by 4.6 times
and clinically signicant macular oedema by 9.1
times [11]. Compared to the standard 7-eld 30°
stereoscopic colour fundus images (early treat-
have regressed (c). However, as the effect of Ozurdex
injection wanes off by 4months, many microaneurysms
have reappeared (d)
ment diabetic retinopathy study), a single eld
200° ultrawide fundus image detects ~50% more
MAs/dot haemorrhages [12]. In experimental
models, an intravitreal injection of VEGF led to
the formation of MAs mimicking diabetic retinopathy [13]. The use of anti-VEGF injections,
including ranibizumab and aibercept for treating diabetic macular oedema, reduces retinal
thickening and causes the regression of pre-existing MAs and fewer new MAs to form [14–16].
We have seen a similar regression of MAs with
intravitreal corticosteroids (Fig.1.7). This effect
is responsible for the apparent reversal of diabetic retinopathy. However, it is important to
realize that the non- perfused areas persist despite
the disappearance of the MAs following intravitreal injections of anti-VEGF agents [14].
Anaemia was recently recognized as a risk factor
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