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4 Retinal Hard Exudates
Ultimately, homeostasis is reached in the retinal
microenvironment, which remains static or worsens over time until an intervention to stop uid
leakage from the MAs reverses the pathology.
Using a high-resolution real-time camera
employing adaptive optics, two patterns of hard
exudates can be observed. Those associated with
the resolution of macular oedema are associated
with the breaking down of aggregates into smaller
foci. In persistent macular oedema, smaller exudates get aggregated into larger ones. These
changes happen over a short time and are not
assessable clinically [5].
4.7 Hyperreective Foci
asForme Fruste ofRetinal
Hard Exudates
Using optical coherence tomography (OCT),
Bolz et al. [6] described the presence of highly
characteristic and well-demarcated hyperreective foci (HF) in the retina in eyes with diabetic
macular oedema. These HF could not be appreciated clinically either on fundoscopy or conventional fundus or infrared imaging and were seen
distributed throughout the thickness of the neurosensory retina. These were seen in the walls of the
microaneurysms and retinal vessels. These HF
had the same hyperreective character as the hard
exudates and correlated well when the hard exudates were present in aggregates. Most of these
were plaque lesions in the outer plexiform layer
and its junction with the outer nuclear layer. Bolz
etal. [6] believed that the HF represented extravasated lipids from microaneurysms. Previously,
Cusick et al. [7] using immunouorescent and
lipid histochemistry techniques, had demonstrated a heavy deposition of apolipoprotein B
and cholesteryl ester (components of LDL) in the
perivascular space in the retina, foam cells, and
heavy inltration by macrophages. It was also
proposed that the efux of lipids by endocytosis
by macrophages can overcome the inux of lipids
following treatment with lipid-lowering agents
and laser photocoagulation [7]. On adaptive optics
scanning laser ophthalmoscopy, irrespective of
the cause of macular oedema, two types of hard
exudates are seen—(1) round and (2) irregular.
The round hard exudates are about 27μm in size
(macrophage=20μm) and are likely to be swollen macrophages due to endocytosis of lipids. The
hyperreective foci (HF) seen on OCT are likely
the round lesions seen on adaptive optics-scanning laser ophthalmoscope (AO-SLO) ophthalmoscopy. Notably, histopathological studies have
shown the presence of foam cells in hard exudates, which are lipid-lled macrophages or retinal microglia. The round lesions evolve into the
irregular type, likely representing the bursting of
macrophages and deposition of extravascular lipids and hyaline material. These extravasated lipids
may be responsible for the persistent hard exudates in patients with diabetes, as the macrophages are believed to be dysfunctional in patients
with diabetes [8]. After the initial discovery of HF
[6], several other reports have conrmed the presence of these HF in the early stages of diabetic
retinopathy and diabetic macular oedema [9, 10].
In diabetic macular oedema, HF are nearly
always present in the inner retina, but as many
as 50% of eyes may have these in the outer retina. The HF in the outer retina are associated
with disruptions in the external limiting membrane, IS/OS junction and poorer visual acuity
[11]. The absence of HF, intact IS/OS (ellipsoid
zone), and the presence of subretinal uid are
OCT biomarkers for the improvement of vision
following the use of DEXA implants in patients
with naïve or chronic diabetic macular oedema
[12]. The HF seen in the diabetic macular
oedema get resolved by the DEXA implants and
the anti-vascular endothelial growth factor
(VEGF) agents (Fig. 4.7) [13]. However, the
anti-VEGF agents cause a dynamic shift of
these HF from the inner to the outer retinal layers suggesting an inammatory origin of these
HF.These HF may be precursors of hard exudates, microglia-macrophages, degenerated
photoreceptors, or migrated RPE cells (in agerelated macular degeneration). Some of these
HF are visible on fundoscopy as aggregates of
hard exudates in the outer retinal layers [14]. On
OCT, the HF are also seen in the subretinal
uid, which on resolution of the serous uid get
deposited as hard exudates [15, 16].
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4.7 Hyperreective Foci asForme Fruste ofRetinal Hard Exudates
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Fig. 4.7 Fundus photograph showing hard exudates
(black arrows) in moderate non-proliferative diabetic retinopathy at presentation (a). Following intravitreal injections of anti-VEGF therapy, hard exudates (black arrows)
Contiguous hyperreective dots lining the
cystic cavities in the outer plexiform layer have
been called ‘Pearl necklace sign’. These HF are
believed to be formed by lipid-laden macrophages [17]. Patients with diabetic macular
oedema have hyperreective cystic spaces, most
of which have associated HF. On the resolution
of hyperreective cystic spaces, nearly one-third
show the deposition of hard exudates in the same
area [18].
On OCT angiography, the HF may be seen in
intraretinal cysts as non-vascular decorrelation
signals representing suspended scattering particles in motion (SSPiM) which may determine the
response to treatment. Following treatment with
intravitreal corticosteroids, the intraretinal cysts
are seen to respond to the treatment. However,
the cysts with the SSPiM do not seem to respond,
and this sign may serve as a useful treatment
response biomarker in diabetic macular oedema
[19]. Earlier, it was shown that the SSPiM arise
from the intraretinal cysts containing hyperreective material/HF. Most of which are seen in
are signicantly resolved at 6months (b). Optical coherence tomography shows dense hyperreective foci (yellow arrows) in the outer plexiform layers before treatment
(c), which resolved almost completely after treatment (d)
Henle’s bre layer. These cysts consist of suspended lipid particles in the uid and produce
non-vascular decorrelation signals from the
movement of these particles in the cystic uid.
When some of these patients were followed, the
resolution of these cysts resulted in the formation
of hard exudates [20]. Decorrelation signals in
Henle’s bre layer were associated with the HF
but not with HF in the INL. On OCTA, HF were
seen attached to the capillaries in the INL [21].
Using quantitative data automatically extracted
from the colour fundus photographs and SD-OCT,
a high degree of correlation between HF and hard
exudates was shown for different stages of diabetic retinopathy [22]. Some of the HF in the
inner or outer retina are too small to be visible in
fundus pictures. Still, the HF are likely to be precursors of the hard exudates.
It has been our experience that following the
resolution of diabetic macular oedema, irrespective of the intervention, the hard exudates tend to
move posteriorly and centrally, get aggregated,
and deposited under the fovea. Concomitant use
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4 Retinal Hard Exudates
of statins to decrease the LDL and triglyceride
levels in patients with diabetic macular oedema is
strongly recommended to prevent this complication [23]. Dramatic resolution of massive retinal
hard exudates has been observed following
statins [24].
4.8 Histopathology ofHard
Exudates
There are hardly any histopathological studies in
patients with diabetic retinopathy after the early
studies in the 1950–1960s. One of the more recent
immunohistochemical studies has shown the presence of oxidized apolipoprotein B100 (ApoB100),
a marker for LDL, in the retina of diabetic eyes
even without retinopathy but not in eyes from nondiabetic individuals. Moreover, there were increasing amounts of ApoB100 staining with increasing
severity of retinopathy. Macrophages were colocalized with ApoB100 only in eyes with proliferative retinopathy. It was proposed that
extravasated heavily oxidized- glycated LDL may
lead to the apoptotic loss of pericytes even before
the onset of clinical retinopathy [25].
4.9 Hard Exudates: ASurrogate
forAtherosclerosis
Dyslipidaemia is an independent risk factor for
cardiovascular complications of diabetes. It is
well known that Apo-B LDL moves across the
arterial wall extracellularly and more so in atherosclerotic arteries and sets up inammation.
Macrophage is the major immune cell in all
stages of atherosclerosis and is derived from the
progenitor cells of bone marrow origin [26].
Macrophages are functionally highly plastic cells
capable of producing pro and anti-inammatory
microenvironments in the atheromatous plaque
[27]. Lipids get deposited in the subendothelial
space and later move into the media and even the
adventitia of the arteries. In the early atherpomatous lesions the foam cells (lipid laden cells) are
of monocytic origin but in late atheromatous
lesions these are of myocytic origin. Macrophages
play a role in the deposition of lipids by acting as
opsonizers for myocytes and scavenging these
deposits [28]. Macrophages carry scavenger
receptors on their surface to phagocytose lipoprotein aggregates and modify LDL [26]. The
pathology of the hard exudates is similar to atherosclerosis, perhaps the only difference being
that atherosclerosis occurs in the artery walls,
and hard exudates are deposited in the retina.
4.10 Serum Lipids andDiabetic
Retinopathy
Notably, cholesterol and triacylglycerol (commonly called triglyceride) are hydrophobic and
carried in the blood plasma in the core of hydrophilic complex proteins called apolipoproteins,
making these soluble. Low-density lipoproteins
(LDL) carry 70% of the total cholesterol and the
remaining 30% is carried by high-density lipoproteins (HDL) [29]. Apolipoproteins act as a ligand
to facilitate the entry of lipoproteins into the intracellular compartment of various cells. Apo-A is
the structural protein associated with HDL and
responsible for the accumulation of lipids in the
peripheral tissues. In contrast, Apo-B is the protein of LDL and a predictor of cardiovascular disease. In recent years, the study of apolipoproteins
as markers of lipid metabolic metabolism has
drawn increasing attention. Serum levels of Apo
B and the Apo B/Apo A1 ratio are positively associated with DR [30]. These are also the most signicant metabolic risk factors for proliferative
diabetic retinopathy (PDR) and clinically signicant macular edema (CSME) [31].
4.10.1 Hyperlipidaemia andDiabetic
Retinopathy
Hyperlipidaemia is a known risk factor for
peripheral neuropathy, a microangiopathic complication of diabetes [32]. In the past, several
attempts to explore the role of dyslipidaemia/
hyperlipidaemia in the onset and progression of
4.10 Serum Lipids andDiabetic Retinopathy
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diabetic retinopathy had met with inconsistent
results. More recently, however, a large prospective cohort study from Taiwan found a signicant
increase in the cumulative incidence of diabetic
retinopathy and diabetic macular oedema but not
the PDR in patients with diabetes and dyslipidaemia. Moreover, statins, the lipid-lowering agents,
were protective in preventing the development of
non- proliferative diabetic retinopathy [33].
Previously, lowering the cholesterol levels in
younger-onset diabetics did not protect either the
incidence or progression of diabetic retinopathy
and diabetic macular oedema [34]. However,
dyslipidaemia has always been associated with
the severity of retinal hard exudates in diabetic
retinopathy. In a large population-based study,
the Wisconsin epidemiologic study diabetic retinopathy (WESDR), increasing cholesterol levels
were associated with the severity of hard exudates in diabetic retinopathy in type 1 diabetic
patients [35]. In a multicentric landmark trial, the
early treatment diabetic retinopathy study
(ETDRS), raised cholesterol and LDL levels at
the baseline were twice as likely as the normal
levels for the presence of hard exudates [36].
Moreover, reducing the lipid levels was associated with a 50% risk reduction in doubling the
visual angle [36, 37].
Higher total and LDL cholesterol levels were
associated with the severity of hard exudates in
African-American patients with type 2 diabetes
[38]. A similar association of elevated serum
lipid levels with the severity of hard exudates in
diabetic retinopathy was seen in the
‘Atherosclerosis risk in communities’ study
wherein the carotid artery intima-medial wall
thickness was associated with diabetic retinopathy [39].
Multicolour imaging may be superior to conventional colour fundus pictures for detecting
hard exudates in the macula. Using multicolour
retinal imaging, serum lipid levels were signicantly associated with hard exudates in the macula [40].
4.10.2 Role ofStatins inHard
Exudates
Notably, increasing severity of hard exudates is
associated with increasing vision impairment.
Although limited by small numbers, early trials
showed the effectiveness of using either simvastatin [41] or atorvastatin [23] for successfully
lowering the LDL levels and improving diabetic
macular oedema and/or disappearance of hard
exudates (Fig.4.8). These early studies laid the
ground for establishing the role of using statins in
lowering cholesterol and LDL in diabetic retinopathy patients. A more recent large-scale study
from Taiwan has shown the protective effect of
statin in decreasing the incidence of diabetic retinopathy and the need for treatment for visionthreatening retinopathy complications [42].
Similar conclusions were reached in a systematic
review and meta-analysis of the use of statins
[43]. Combining fenobrate with simvastatin and
tight glycemic control reduced the severity of
diabetic retinopathy by 40% compared to the
statins alone [44] or the need for laser photocoagulation by 31% [45, 46]. Among the patients
with type I diabetes who participated in the diabetes control and complications trial (DCCT)
trial, higher serum lipid levels, especially the
total cholesterol to HDL ratio, were signicantly
associated with hard exudates and macular
oedema. In the DCCT cohort (type 1 DM),
inammatory markers high sensitivity CRP and
circulating levels of inter-cellular adhesion molecules- 1 (ICAM-1) were signicantly associated
with clinically signicant macular oedema and
the severity of hard exudates [47]. These are
well-established markers for coronary artery disease. It is well known that statins lower hs-CRP
and ICAM-1, reduce the inammatory activity of
coronary artery atherosclerotic plaques, and
improve endothelial dysfunction. [48]. It is recommended that among type 1 diabetics, statins
not only decrease the risk of cardiovascular risk
but reduce the risk of diabetic macular oedema
and improve quality of life as well [49].
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4 Retinal Hard Exudates
a
b
c
Fig. 4.8 Dense hard exudates (a) in a patient with dia-
betic macular oedema with hyperlipidaemia. Following
the initiation of atorvastatin, there was a decrease in the
4.11 Complications ofRetinal
Hard Exudates
Currently, the standard of care for managing diabetic macular oedema involves using either antiVEGF or intravitreal steroids. Both have been
found effective in reducing the extent of hard exudates in the macula, although steroids led to a
quicker clearance of hard exudates [50]. If subfoveal hard exudates persist, they may develop subretinal brosis even following the standard of care
intravitreal ranibizumab injections [51]. If under
the fovea, these brous scars cause irreversible
hard exudates at one year (b), which resolved almost completely at 27months (c)
damage to the vision (Fig.4.9). It should be noted
that subretinal brosis is extremely uncommon in
eyes with clinically signicant macular oedema
who do not have hard exudates. However, uncommonly, focal laser photocoagulation may also lead
to subfoveal brosis. The risk factors for subretinal brosis noted in the ETDRS study were the
extent and severity of hard exudates and elevated
levels of serum lipids (total cholesterol and triglyceride). Subretinal brosis is a mound-like
plaque under the retina [52]. A clinicopathological study of subretinal brous plaque in a patient
with diabetic retinopathy did not nd any break in
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4.12 Treatment ofRetinal Hard Exudates Associated withMacular Oedema
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Fig. 4.9 Persistence of hard exudates leads to the development of subfoveal brosis (black arrows), which affects
vision adversely (a and b). Optical coherence tomography
Bruch’s membrane or the choroidal neovascular
membrane, the common causes of subretinal scarring. The presence of the hard exudates itself was
responsible for the brous plaque [53, 54]. To prevent this complication, attempts have been made
to surgically wash out these hard exudates from
under the neurosensory retina with a balanced salt
solution, using a 38-size cannula through a hole
created in the retina in the macular area [55].
These plaque-like hard exudates have also been
surgically excised [56].
(c and d) shows dense mound-like plaque (yellow arrows)
under the fovea (c and d)
monthly injections of an anti-VEGF injection.
Intravitreal corticosteroids such as long-acting
triamcinolone acetonide or slow-release depot
steroids like DEXA implants, such as Ozurdex
(Allergan, Inc., Irvine, CA, USA) or uocinolone
implants, Iluvien 0.19 mg (Alimera Sciences
Ltd., Alpharetta, Georgia, USA) or the
Fluocinolone 0.18 mg Yutiq (EyePoint
Pharmaceuticals Pvt. Ltd., Watertown,
Massachusetts), are used as a second-line treatment for patients who are either non-responders
to the anti-VEGF therapy or have a chronic persistent macular oedema. Monthly ranibizumab
4.12 Treatment ofRetinal Hard
Exudates Associated
withMacular Oedema
Currently, the standard of care for treating macular oedema associated with either diabetic retinopathy or retinal vascular occlusions involves
injections in diabetic macular oedema resulted in
the resolution of intraretinal hard exudates in parallel with macular thickness and volume resolution [57]. Likewise, the rapid resolution of hard
exudates is seen with intravitreal triamcinolone
acetonide [58]. In the RISE and RIDE trials,
intravitreal ranibizumab was associated with a
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4 Retinal Hard Exudates
signicant decrease in hard exudates, albeit more
gradual than the retinal oedema. Contrary to
expectations, there was no increase in the hard
exudates following this treatment [59]. The bevacizumab and DEXA implant effectively reduced
the area of hard exudates, although the response
was quicker with steroids [50].
4.13 Other Causes ofRetinal Hard
Exudates
4.13.1 Retinal Hard Exudates
inBranch Retinal Vein
Occlusion
Next to diabetic retinopathy, branch retinal vein
occlusion (BRVO) is the second most common
retinal vascular disease. The major risk factors
for the development of BRVO include increasing
age, hypertension, history of cardiovascular disease, smoking, low HDL levels, high BMI at the
age of 20, and focal arteriolar narrowing [60, 61].
The commonest site of BRVO is at the rst or the
second A-V crossing in the upper temporal quadrant or a little less common in the lower temporal
quadrant. The next common is a macular vein
occlusion that occurs when a small venous tributary draining the macula gets blocked. BRVO is
accompanied by retinal haemorrhages and
plasma uid leakage due to the blood-retinal barrier’s breakdown. By 3months, most of the hemorrhages were absorbed, leaving behind macular
oedema. At this time, a fundus uorescein angiography (FFA) is performed to determine the status of perfusion in the territory of the occluded
retinal vein. It may be a perfused or non-perused
BRVO.Within 6 weeks to 6 months of BRVO,
the retinal capillaries develop collateral channels
across the horizontal raphe and start draining the
blood/uid via the venous channels in the opposite quadrant [62]. Nearly 80% of these eyes
develop collateral channels to drain away the
leaked uid in the extravascular space [63], most
of which are located in the deep capillary plexus
of the retina [64]. Many of these collateral channels are leaky and may develop microaneurysms
that continue to leak uid [65] The leaked lipo-
proteins get deposited in the retina, most often in
the macula as circinate rings (Fig.4.10).
These circinate rings may mimic similar ring
like exudates seen in diabetic retinopathy.
However, unlike diabetic retinopathy, leaky vessels and microaneurysms in BRVO have a strict
quadrantic distribution, although the hard exudates often cross the horizontal raphe. Thus, FFA
plays an important role in distinguishing the two
pathologies in these patients. In the last 15years,
intravitreal injections of anti-VEGF agents have
supplanted gird laser photocoagulation for treating macular oedema due to BRVO.Many such
agents have been tested in several controlled trials and have found almost equivalent results with
the use of ranibizumab, bevacizumab, or aibercept that need to be given initially every month
for three injections and followed by a PRN (pro
re nata) basis.
4.13.2 Retinal Hard Exudates
inAdult Coats’ Disease
Coats’ disease is an uncommon unilateral sporadic disease of young children, mostly boys in
the rst two decades, characterized by telangiectatic retinal vessels in the periphery or midperiphery of the retina involving one or more
quadrants [66]. While the disease is of uncertain
origin, fundus uorescein angiography shows
highly characteristic large leaky microaneurysms
and macroaneurysms visible as lighted bulbs.
Leakage from the microaneurysms and the telangiectatic retinal vessels results in the deposition
of the hard exudates in variable amounts on the
retina and the subretinal space. Massive exudation may lead to a limited or total exudative retinal detachment. On histopathology, cholesterol
crystals, ghost cells (histiocytes), and glial cells
are seen in the inner retina. In contrast, the subretinal brinous exudates show lipid and pigmentladen macrophages and brous scars [67].
Massive mounds of lipids under the macula very
often lead to extensive brous scar formation.
When seen in adults over 35years, Coats’ disease is more benign and less extensive. Notably,
a proportion of these patients may have associ-
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4.13 Other Causes ofRetinal Hard Exudates
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Fig. 4.10 A case with lower temporal branch retinal vein
occlusion (a), showed resolution of retinal haemorrhages
at 18 months (b) following intravitreal anti-VEGF therapy. At 30 months, hard exudates (black arrows) devel-
ated hypertension [68]. In the past patients of
Coats’ disease have been treated with laser photocoagulation of the retinal periphery and the
microaneurysms or cryopexy of the retinal
periphery. Signicantly high levels of VEGF levels are found in Coats’ disease [69]. More
recently, anti-VEGF agents have been used in
addition to laser photocoagulation to treat these
patients [70]. There is evidence that proinammatory cytokines and VEGF are also at elevated
oped during the course (c), which migrated under the
fovea and caused subfoveal brosis (blue arrow) at
42months (d)
levels in Coats’ disease [71], hence an increasing
trend to combine laser photocoagulation, antiVEGF agents, and periocular corticosteroids or
even intravitreal DEXA implants. The recent
advances in the management of Coats’ disease
were recently reviewed [72]. Nearly 90% of the
patients show adequate response to treatment.
The visual outcome is often limited due to submacular brosis caused by delays in seeking
treatment.
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4 Retinal Hard Exudates
4.13.3 Retinal Hard Exudates
inIdiopathic Retinal
Vasculitis, Aneurysms
andNeuroretinitis (IRVAN)
form retinal arteriolar aneurysms at the branching of arterioles and on the optic disc are highly
characteristic and best demonstrated in fundus
uorescein angiography (Figs. 4.11 and 4.12)
[73]. Late complications involve retinal neovas-
IRVAN, an idiopathic retinal vasculitis, is a rare
retinal disease of young people characterized by
bilateral retinal vasculitis, arteriolar macroaneurysms, and neuroretinitis. In addition, usually,
there are areas of peripheral capillary nonperfusion and retinal telangiectasia. Macular
oedema with dense deposits of hard exudates
often compromises vision (Fig.4.11). The fusi-
cularization and vitreous haemorrhage or traction
retinal detachment. Rarely IRVAN may be complicated by branch retinal artery occlusion [74,
75]. The treatment has included laser photoco-
agulation of the ischemic peripheral retina and
anti-VEGF agents, DEXA implants, and systemic immunosuppressive therapy. The subject
was recently reviewed [73].
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Fig. 4.11 A case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) shows massive hard
exudates in the macula and peripapillary retina L>R (a,
c). The fundus uorescein angiography during the venous
phase shows aneurysmal dilatations along the temporal
retinal arterioles in both eyes (b, d). Note aneurysmal
dilatations on the optic disc in the left eye (red arrows)
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Fig. 4.12 A case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) having hard exudates
(black arrows) and subfoveal brosis (blue arrows) in
both eyes (a and b). Fundus uorescein angiography (c
and d) showed retinal arterial aneurysms along the arteri-
4.13.4 Retinal Hard Exudates inVon
Hippel–Lindau Disease
oles and optic disc (yellow arrows). Optical coherence
tomography (e and f) showed hard exudates (red arrows)
lining the cavities containing subretinal uid, and dense
mound-like plaque under the fovea (blue arrowheads) corresponding to subfoveal brosis
cal bilateral retinal capillary hemangiomas/
hemangioblastoma. More than half of the retinal
capillary hemangiomas/hemangioblastomas are
Retinal capillary hemangiomas are a rare retinal
disorder of young people presenting either sporadically as a unilateral, monofocal disorder or as
von Hippel –Lindau’s (VHL) disease, an autosomal dominant disorder characterized by multifo-
sporadic and present at a median age of 36. If the
patients with sporadic disease do not have systemic associations at the diagnosis, they are
unlikely to progress to VHL.VHL appears at a
median age of 18 years, and this distribution
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