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References
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Subretinal/Submacular
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Haemorrhage
7
7.1 Introduction
Haemorrhage under the retina, especially the
macula, portends an underlying serious ocular
disease and occasionally a life-threatening systemic disease. If not treated urgently, itmay lead
to irreversible loss of central vision. Submacular
haemorrhages may occur at all ages under the
retinal pigment epithelium (RPE) or the neurosensory retina, varying from a small thin blood
lm to extensive and massive mounds of blood
clots. When unilateral and small, these often go
unnoticed by the patient. When discovered, the
symptoms may vary from distortion of objects to
more signicant vision loss. This central dark
spot moves with the eye or causes a complete loss
of central vision, including the ability to read,
recognize people, or identify colours from the
affected eye. Ambulatory vision is often preserved if the haemorrhage remains limited to the
macula. It is important to distinguish the location
of the blood. It appears bright red when under the
neurosensory retina (transparent) and dark when
under the RPE (pigmented). Unlike supercial
retinal haemorrhages that obscure the retinal vessels, submacular haemorrhages do not obscure
the overlying retinal structures and the vessels
are seen running normally over the blood. It may
be challengingto clinically distinguish between
the intraretinal haemorrhages in the Henle’s layer
(often assumes a petaloid pattern) and the sub-
macular location, which can be easily solved
with a structural OCT scan.
Submacular haemorrhages are commonly
seen in old age and result from the rupture of
abnormal new vessels from the choroid (choroidal neovascular membrane, or CNVM) that
develop in nearly 10% of people with age- related
macular degeneration (AMD). It is commonly
designated as the wet form of AMD or neovascular age-related macular degeneration (nAMD).
Notably, nearly 190 million people across the
world suffer from AMD. In the Asia- Pacic
region, massive submacular haemorrhages may
occur from a specic variant ofnAMD known as
polypoidal choroidal vasculopathy (PCV). In
young people, blunt trauma may cause rupture of
the choroid resulting in submacular haemorrhage. Rupture of retinal macroaneurysms, seen
more often in older women with hypertension,
may cause intraocular haemorrhage that may
dissect below the retina. Several posterior uveitis
entities include toxoplasmic retinochoroiditis,
Vogt-Koyanagi-Harada’s (VKH) disease, tubercular choroiditis, punctate inner choroidopathy,
and multifocal choroiditis with panuveitis may
get complicated by the development of CNVM
and present with a submacular haemorrhage.
Less commonly, degenerative myopia, angioid
streaks, choroidal osteoma, choroidal melanoma,
metastatic lesions, and leukaemia also present
with subretinal haemorrhages.
© 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_7
139
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7 Subretinal/Submacular Haemorrhage
7.2 Age-Related Macular
Degeneration
Age-related macular degeneration (AMD) is the
most common cause of visual disability in old
age (>50 years) inWestern countries. It is fast
emerging as a challenge in the ageing population
of developing countries. AMD is mainly of two
types:the non-exudative or the dry type, characterized by the formation of soft drusen and pigmentary changes that progress to geographic
atrophy in the macula, and the exudative or the
wet type, the neovascular stage, a sightthreatening complication marked by the development of abnormal macular neovascularization
(MNV) in the macula that causes exudation,
haemorrhage, and sometimes deposition of hard
exudates. If untreated, the nAMD results in
b
extensive brosis in the macula. The late stage of
non-exudative AMD is remarkable for atrophy of
the choriocapillaris, RPE and the overlying photoreceptors in the macula, known as geographic
atrophy (GA) (Fig.7.1). There is no known treatment to prevent or reverse this late stage of dry
AMD.Even the exudative AMD, whether treated
or not, ultimately progresses to geographic
atrophy.
The most characteristic feature of the AMD
that distinguishes it from other causes of CNVM
is the deposition of extracellular debris between
the plasma membrane and the basement membrane of the RPE (basal laminar deposit) or
between the basement membrane of the RPE and
the inner collagenous layer of the Bruch’s membrane called a basal linear deposit that is responsible for drusen formation [1]. Drusen, the
Fig. 7.1 A sharply demarcated area of RPE atrophy (blue
arrows) with baring of the large choroidal vessels (a), seen
as a dark hypoautouorescent area on fundus autouores-
cence (b). OCT (c) shows loss of outer retinal layers with
atrophy of inner retina (yellow arrows) and the choroid
(red arrow)
7.4 Pathogenesis ofAMD
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141
hallmark of AMD, is extracellular deposits
between the basement membrane of the RPE and
Bruch’s membrane.
For epidemiological studies, many classications have been used. In one such classication
based oncolourdigital fundus images of the macula, AMD was classied as: Stage 0a, no evidence of AMD, 0b, hard drusen <63μ in size; 1a,
soft drusen with distinct borders ≥63 μ; 1b, no
drusen and only pigmentary changes; 2a, soft
drusen ≥125μ with indistinct borders or reticular
drusen; 2b, soft drusen ≥63μ and ≤ to 125μ with
pigmentary changes; 3, soft drusen ≥125μ with
indistinct borders or reticular drusen with pigmentary changes; 4, geographic atrophy; and 5,
neovascular AMD [2]. Stages 2 and 3 are classied as early AMD and stages 4 and 5 as late
AMD.Data based on this classication from ten
European countries showed the prevalence of
early AMD varying from 3.5% in the youngest
population (55–59years) to 17.5% in the oldest
population (≥85years). The late AMD (Stage 4)
was seen in nearly 10% of the oldest group
(≥85 years) [3]. Until the introduction of antiVEGF therapy in 2006 for nAMD, no effective
therapyeither improved or prevented further loss
of vision in such eyes. Following the availability
of this treatment,while there has been a signicant decrease in the prevalence of late AMD,
early AMD continues to show a rising prevalence
[3]. These numbers are expected to rise further in
the coming decades [4].
7.3 Risk Factors forAMD
has also been shown to reduce the incidence of
late AMD by almost 40% [6]. Additionally, prospective population-based cohorts have shown
benecial effects of high levels of physical
activity in preventing the occurrence of early
AMD [7].
Box 7.1 Systemic Associations of AgeRelated Macular Degeneration
1. 10-year progression of coronary artery
calcium (CAC) [8].
2. Persons with AMD shares risk factors
with atherosclerosis. These patients
have a high incidence of CVD
3. Persons with AMD have a higher risk of
stroke-intracerebral hemorrhage than
cerebral infarction [9].
Box 7.2 Systemic Risk Factors for AMD and
PCV
1. Aging
2. Smoking
3. High blood pressure
4. Obesity/High Body mass index
5. Sedentary lifestyle
6. Nutritional lack of vegetables/fruits
7. Genetic factors—single nucleotide
polymorphisms in inammation, lipid
metabolism, and oxidative stress
pathways
AMD is a complex multifactorial disease with
signicant genetic and environmental risk factors. Interestingly, besides ageing, several common and preventable risk factors are shared
between AMD and cardiovascular disease
(CVD). See Boxes 7.1 and 7.2. All these factors,
namely family history, hypertension, smoking,
obesity, and sedentary lifestyle, are well known
to cause chronic systemic inammation and
increase oxidative stress [5]. The Mediterranean
diet recommended for preventing CVD, consisting of leafy vegetables, fruits, sh, and legumes,
7.4 Pathogenesis ofAMD
As stated above, drusen are extracellular deposits
between the basement membrane of RPE and
Bruch’s membrane. Detection of some components of the alternate complement system in these
deposits indicates a low-grade inammation [10].
Complement factor H encodes for a protein that
is vital in controlling inammation. A singlepoint mutation in the genes coding for this pro-
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7 Subretinal/Submacular Haemorrhage
tein rst pointed out the role of genetics in the
causation of AMD [11–13].
Obesity and smoking in people who show
SNPs CFH Y402H and ARMS 2 (LOC387715
A69S) genes raise the risk of progressive AMD
by 19-fold [14].
Since the original studies in 2005, although
more than 30 more loci have been discovered in
genome-wide association studies,there is still a
dearth of information on the exact transcriptomewide associations or the gene expressions directly
responsible for the causation of AMD pathology
[15]. However, most of the loci discovered in
AMDare involved in either complementmediated inammation or lipid metabolism.
ARMS2 gene located on chromosome 10
plays an essential role in the complement pathway by opsonization of the necrotic cells. Single
nucleotide point mutation rs10490924 in this
gene interferes with the normal apoptotic mechanisms and the complement-mediated clearance
ofthe cellular debris. A deciency of the normal
ARMS2 protein may be responsible for drusen
formation [16]. It is proposed that environmental
factors with defective innate and adaptive
immune mechanisms in aged peopledue to their
genetic predisposition lead to low-gradesystemic
inammation,which in the eye leads to AMD.The
same factors also lead to systemic atherosclerosis, which explains the high risk of CVD in
patients with AMD.
Further, ageing decreases the choroidal blood
ow and thinning of the choroid, interfering with
the normal debris-clearing mechanisms from the
outer retina. This subject has been extensively
reviewed by Rozing etal. [17]. The cellular debris
is deposited under the retina in the Bruch’s membrane as well-dened hard drusen, ill- dened soft
drusen, or densely packed small reticular drusen.
On the other hand, subretinal drusenoid deposits
(SDD), earlier known as pseudo reticular drusen,
are deposited under the neurosensory retina. The
latter differs from the classic drusen in their location and lipid composition. The SDD may breach
the ellipsoid zone and extend into the retina. The
SDD is associated with type 3 new vessels and
geographic atrophy [18]. The site where the drusen will appear does not appear to be a random
phenomenon but relates to the areas of choroidal
ischemia. Although histopathological studies in
the past had shown thinning of choriocapillaris in
the AMD eyes, more recently, imaging studies
using OCT angiography have shown signicant
ow decits in choriocapillaris underlying the
existing drusen, expanding drusen or even those
that will appear in future suggesting that choroidal ischemia is a critical event in the development
of AMD [19]. Age-related thickening of Bruch’s
membrane, deposition of advanced glycosylated
end products (AGE) and extracellular debris as
basal laminar deposits, and increased expression
of VEGF from the RPE and microglia in an ischemic microenvironment lead to the formation of
pathological new vessels that grow most commonly under the RPE (type1), less commonly
under the neurosensory retina (type 2) or even
into the retina (type 3). These vessels do not have
tight endothelial junctions and leak uid or rupture to cause blood under the macula (submacular
haemorrhage).
7.5 Clinical Signs ofAge-Related
Macular Degeneration
The non-exudative AMD in early and intermediate stages is asymptomatic and gets diagnosed in
patients who may visit an ophthalmology/optometry clinic for a routine examination/screening for
cataracts and glaucoma. By and large nonexudative AMD is symmetric bilateral disease,
and 90% of patients do not progress to an exudative stage. Drusen are the hallmark of AMD and
vary in size from <63μ to nearly 1000μ (Fig.7.2).
Small drusen, <63 μ, are seen in the macula as
yellow-white discrete dot lesions and are commonly seen in older people. These are called hard
drusen and usually are not seen on fundus uorescein angiography (FFA). These stay unaltered for
several years and may show mineralization. They
appear as tiny nodular elevations over Bruch’s
membrane on structural OCT and do not progress
further to the GA or predispose to CNV formation
(Fig.7.2). Soft drusen are made ofsimilar lipoproteins debris but are larger than 63μ, are pale yellow, and have indistinct borders. The presence of
soft drusen <125μ is labelled as early AMD.These
may become conuent over time and increase in
ab
cd
ab
cd
7.5 Clinical Signs ofAge-Related Macular Degeneration
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Fig. 7.2 Drusen, the hallmark of AMD, are seen in the macula as yellow-white discrete dot lesions on clinical examination (a, b). They appear as tiny nodular elevations over Bruch’s membrane on structural OCT (c, d)
143
Fig. 7.3 Soft drusen indicate intermediate AMD, are
larger than 63μ, and appear as pale-yellow lesions (blue
arrows) with indistinct borders (a). OCT shows RPE ele-
numbers. More than 20 soft drusen >63–124μ or
multiple small with a single large soft druse
>125 μ is classied as an intermediate stage of
AMD. Pigmentary changes may accompany the
soft drusen, and both hyper and hypopigmentation may be seen. The soft drusen are mound-like
deposits on structural OCT between the RPE and
Bruch’s membrane. On autouorescence, some of
vations (red arrows) (b). Fluorescein angiography (c)
shows hyperuorescent lesions (blue arrows), and ICGA
(d) shows subtle hypocyanescent lesions (blue arrows)
these may show a central hypoautouorescence
with a ring of hyperautouorescence (Fig.7.3). A
thin layer of basal linear deposits may connect the
soft drusen. The most signicant type of drusen
isthe subretinal drusenoid deposits (previously
termed reticular pseudo drusen) under the neurosensory retina and overlie the RPE.These were
correctly localized only after the availability of
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7 Subretinal/Submacular Haemorrhage
Fig. 7.4 Right eye (a) shows hard drusen (blue arrows),
and the left eye shows hard drusen (blue arrows) along
with a subretinal haemorrhage (red arrow) suggestive of a
CNVM (b). OCT (c) shows sub-RPE drusenoid deposits
structural OCT.These may be best seen in blue
light rather than colour fundus or IR reectance
images [18]. Gass [20] rst showed the development of nAMD in 18% of eyes with drusen at an
average age of 75years and an average follow-up
of nearly 5years. These eyes were characterized
by the development of sub-RPE and subretinal
exudation through either an intact Bruch’s membrane or the growth of new vessels through breaks
in the Bruch’s membrane causing exudative and
haemorrhagic detachment of the RPE and the
neurosensory retina (Fig.7.4) [20].
in the right eye (red arrows) and a CNV complex (red
arrow) with subretinal uid (yellow arrow) in the left eye
(d). (Images courtesy of Dr. Anita Agarwal, West Coast
Medical Retina Group, San Francisco, USA)
term CNVM (choroidal neovascular membrane)
in favour of macular neovascularization (MNV).
Further, the nomenclature for the nAMD has
been standardized. Type 1 MNV is the growth of
new vessels from choriocapillaris that stay
under the RPE and cause pigment epithelium
detachments (PED). In contrast, the type 2
MNV arise from the choriocapillaris and traverses through breaks in the Bruch’s membrane
and the RPE to grow under the neurosensory
retina (Fig.7.5). Type 3 new vessels arise from
the retina’s deep capillary plexus, grow towards
the outer retina, and communicate with vessels
arising from the choriocapillaris. In the past,
7.6 Current Nomenclature
forAMD Lesions [1]
based on fundus uorescein angiography studies, type 1 MNV were called occult CNVM,
while type 2 MNV were called classic
Development of advanced retinal imaging tools
in recent years has led to the recognitionthat
new vessels may also arise from the neurosensory retina prompting the abandonment of the
CNVM.Type 3 MNV was called occult chorio-
retinal anastomosis [21, 22] or retinal angioma-
tous proliferation [23] and was characterized by
intraretinal hyperuorescence.
7.7 Imaging Studies inMacular New Vessels (MNV)
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Fig. 7.5 A subretinal haemorrhage (red arrow) along
with drusen and area of geographic atrophy seen at baseline (a). OCT shows Type 2 CNVM with a breach in RPE
and Bruch’s membrane (b). Following intravitreal injec-
Leakage of uid from the new vessels more
than what can be absorbed by the normal mecha-
tion of anti-VEGF therapy, the subretinal haemorrhage
resolved (c), and OCT shows the resolution of subretinal
uid (d)
7.7 Imaging Studies inMacular
New Vessels (MNV)
nisms in the retina leads to the accumulation of
intraretinal uid. In contrast, the collection of
such uid under the retina results in subretinal
uid. The collection of serum, brin, and inammatory cells under the neurosensory retina, based
on characteristic reectivity seen on structural
OCT, is called subretinal hyperreective material
(SHRM). PED may occur due to the collection of
serous uid, drusenoid material, or haemorrhage
under the pigment epithelium. Serous PEDs in
AMD are usually associated with new vessels at
their margins. Haemorrhage may collect in the
sub-RPE, subretinal, or intraretinal space. The
RPE layer may rip due to contractile forces of the
brovascular tissue under the RPE that scrolls on
itself, leading to the baring of the choroid.
Persistent subretinal uid, large drusen, or regression of subretinal drusenoid deposits may lead to
outer retinal atrophy and is seen on OCT as loss
of ellipsoid, interdigitating zones and thinning of
the outer nuclear layerand loss of RPE [1].
Decades before the advent of OCT technology,
fundus uorescein angiography (FFA) and indocyanine green (ICG) angiography werethe standard imaging tools to study the presence of
CNVM, now rechristened as macular new vessels
(MNV). Type 1 MNV, earlier labelled as ‘occult
CNVM’, could not bevisualized on FFA because
of the masking effect of the RPE.However, these
were visible in the late frames of FFA as illdened diffuse/punctate hyperuorescence. As
theexact site of this hyperuorescence could not
be ascertained, thiswaslabelled as hyperuorescence of uncertain origin. In the late frames of
ICG angiography, however, these occult CNVM
were often seen as well-dened plaque-like
hyperuorescence and nearly 40% of these got
reclassied as classic CNVM [24].
The ICG angiography also predicted the
development of exudative AMD by demonstrating hyperuorescent plaques associated with soft
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