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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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7 Subretinal/Submacular Haemorrhage
a
c d
b
Fig. 7.6 Drusen appear as yellow, discrete lesions in the
macula (a), and are seen as focal RPE elevations on OCT
(b). OCT angiography reveals an underlying CNV com-
drusen even when clinically, these eyes were seen
as non-exudative AMD [25]. On the structural
OCT, the type 1 MNV is seen as a heterogeneous
hyperreective lesion under an elevated RPE,
while the OCTA additionally shows ow within
this heterogeneous material. The enface OCTA
images of the RPE-choriocapillaris slab clearly
show the presence of these so-called occult new
vessels. Interestingly, SS-OCT angiography can
also detect the non-exudative type of MNV previouslyreported only with ICG angiography
plex in the outer retina (c) and choriocapillaris (d) (nonexudative AMD)
(Fig.7.6). A high number of such eyes go on to
develop the exudative AMD [26]. The type 2
MNV, earlier labelled ‘classical CNVM’ on the
other hand, being under the transparent neurosensory retina, is seen as well-dened hyperuorescent lesionsin the early frames of FFA and shows
profuse leakage in the late frames. In many
patients,variable components of both type 1 and
type 2 MNV may be seen, one being more predominant than the other. On OCT angiography,
the type 2 MNV appears as a well-dened
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cartwheel- like lesion above the RPE.However, a
mixed type 1 and 2 MNV mayalso show a similar
lesion below the RPE slab [1]. B-scan OCT can
show the type 2 MNV breaching the RPE layer
and proliferating in the subretinal space, accumulating uid, blood, and lipids. Fluid may extend
into the outer retina as well. The presence of submacular haemorrhage, in either case, blocks uorescence. Fundus autouorescence studies can
help to distinguish fresh submacular haemorrhage from the old. The red blood is hypoautouorescent, but the old grey submacular
haemorrhage is hyperautouorescent. MNV type
1 is most commonly seen in nAMD, while MNV
type 2 is more common in pathologies other than
nAMD, such as myopia, multifocal choroiditis,
and Angioid streaks. Type 3 MNV, earlier called
RAP (retinal angiomatous proliferation), arises
from the deep capillary plexus and extends into
the outer retinal layer. It is often associated with
SDD.It is characterized by small haemorrhages
in the inner retinal layers, likely due to higher
pressure in the retinal circulation causing bleeds
from the fragile new vessels. Early lesions show
tiny dot-like hyperuorescence on the FFA and
the ICG angiography. In addition, feeding and
draining vessels may be seen on ICG angiography. Type 3 MNV is a hyperreective lesion
extending from the inner nuclear layer to the
outer retina on the B-scan OCT.It ismore often
associated with intraretinal cystic spaces than the
other two types. OCT angiography detects these
new vessels in the outer retina [1].
Type 3 MNV progress through 3 stages. In the
earliest stage A, it does not breach the external
limiting membrane/ellipsoid zone; in stage B, the
new vessels breach the ELM/ellipsoid zone, and
in stage C, they breach the RPE layer. The stage
of the type 3 MNV determines the location of the
uid collection. In stage A, uid is seen in the
intraretinal space on B-scan OCT as hyporeective cavities. Stage A of type 3 MNV carries the
best visual outcome following treatment with
anti-VEGF agents. In stages B and C, the uid
collects in the subretinal and the sub-RPE space,
respectively. However,if intraretinal uid is collected in type 1or 2 MNV, the visual outcome following treatment seems poor [27].
7.8 Polypoidal Choroidal
Vasculopathy
Polypoidal choroidal vasculopathy (PCV), a variant of type 1 MNV, is characterized by the presence of a network of branching vessels (BVN)
under the RPE withsingle or multiple aneurysmal
dilatations called polyps at the ends of the branching vascular network. Both the BVN and the polyps are variable in size and location. The polyps
may be clinically visible as orange nodular
lesions under the retina. While PCV lesions are
rare in Caucasians, nearly half of the AMD
patients in the Asian population may show
PCV. The PCV remains asymptomatic till the
polyps show exudation or rupture to cause, often,
a massive haemorrhagic pigment epithelial
detachment which may break through into the
subretinal space and even cause a vitreous haemorrhage (Figs.7.7, 7.8, and 7.9). The serosanguinous collection under the retina and the RPE was
initially labelled a posterior uveal bleeding syndrome [28]. However, these lesions were characterized as idiopathic PCV, a distinct clinical
entity different from AMD [29]. Patients with
PCV lack tell-tale signs of AMD, such as soft
drusen, pigmentary changes, and RPE atrophy.
Unlike the nAMD, the submacular haemorrhages
show spontaneous resolution with minimal scarring. Nearly 50% of the PCV eyes may have a
favourable outcome. At the same time, there may
be recurrent episodes of exudation and haemorrhages that nally lead to visual loss from the
degenerative changes in the macula and subretinal brosis (Fig.7.10) [30]. In the Asian population, more than 90% of the patients with PCV
have unilateral disease,which is seen predominately in men [31].
On the other hand, PCV in the US was seen as
bilateral, more often in the peripapillary and predominantly in women of black and Asian origin
[32]. More recent data have shown signicant
ethnic differences in the clinical presentations of
PCV in the Caucasian versus the Asian population. While Asian patients present with more frequent and signicantly larger subretinal
haemorrhages, more eyes have thick (pachy)
choroidal vessels, choroidal hyperpermeability,
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7 Subretinal/Submacular Haemorrhage
c d
Fig. 7.7 (a–d): A 74-year-old man presented with drusen in the right eye (a) and PED in the left eye (b). OCT showed
mound-like RPE elevations in the right eye (c) and a hyperreective PED in the left eye (d)
Fig. 7.8 (a–d): 7 months later, while the patient was
asymptomatic in the right eye with almost similar drusen
(a), he complained of a sudden loss of vision in the left
eye due to a large submacular haemorrhage (b). OCT
showed an increase in the size of drusen (c) in the right
eye, while left eye OCT (d) massive subretinal and subRPE hyperreectivity due to haemorrhage (d)
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Fig. 7.9 (a–d): 2months after undergoing vitreous sur-
gery in the left eye, the right eye (a) drusen were the same.
The left eye showed a small residual subretinal haemor-
a
rhage (red arrow) (b). Right eye OCT remained stable (c),
and the left eye showed signicant resolution of subretinal
haemorrhage with a few residual cystoid spaces (d)
and polyps; Caucasian eyes havemore often drusen [33]. The PCV lesions are located at the
PED’s margin, creating a notch visible clinically
and angiographically as a ‘notched PED’. As the
PCV exudes serosanguinous uid, these lesions
detach from Bruch’s membrane and lie under the
pigment epithelium [34]. ICG better denes new
vessels located under the subretinal haemorrhage than FFA [35]. While the FFA is of little
help except for showing leakage of dye in the
exudative phase of PCV, suggesting at best the
presence of an occult CNVM, the ICG angiogra-
b
phy is highly diagnostic. ICG angiography, however, may only be available in some places.
Specic FFA characteristics, including hyperuorescence of the nodule, blocked uorescence
from subretinal haemorrhage, a notched PED,
and a pattern suggestive of occult CNVM, highly
Fig. 7.10 Subretinal brosis (a) resulting from a CNVM
leading to visual loss. OCT (b) shows foveal atrophy with
a dense underlying scar
suggests PCV rather than nAMD (Fig. 7.11)
[36]. The ICG angiography shows well-dened
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Fig. 7.11 A 40-year-old woman presented with a sudden
decrease in vision in the right eye with a foveal haemorrhage and a haemorrhagic PED in the superotemporalquadrant (a). Ten months later, there was a signicant
increase in the size of the foveal haemorrhage (b). At
BVN and the polyps in the early frames that
empty in the late frames. The polyps do not show
any hyperuorescence unless there is a rupture
of the polyp, sharply contrasting these from the
nAMD. The ICG angiography may also reveal
the pulsatile nature of the polyps. On the B-scan
OCT, the PCV lesions show characteristic multiple PEDs with a sharp notch, nger-like peaks,
and hyporeective lumen. Further, a double
layer sign can be appreciated on the SS-OCT
because the type1 MNV in PCV develops in
Bruch’s membrane. On the enface OCT, polyps
11months, while the subfoveal haemorrhage was resolving, the haemorrhage beneath the PED in the superotemporal quadrant increased (c). At 16 months, more
subretinal haemorrhage was seen in the macula (d)
appear as hyperreective RPE rings and closely
correlate with the polyps seen on the ICGA [37].
The presence of intraretinal and subretinal uid
on the OCT indicates an active exudative phase
of the PCV.Compared to ICG angiography, the
role of OCT angiography in making a rm diagnosis of PCV is limited. Although the OCT angiography can demonstrate more BVN under the
RPE, it may not show all the polyps, possibly
due to the low blood ow. Compared to larger
polyps, smaller polypoidal lesions may be seen
on OCT angiography [38]. OCT angiography of
7.10 Treatment ofPolypoidal Choroidal Vasculopathy
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the PCV in eyes, which show subretinal hyperreective material on B-scan OCT and a classic
CNVM on the FFA, reveals the presence of type
1 MNV [39].
On ICG angiography, three distinct types of
BVN can be identied; type 1 shows a trunk with
branching vessels, type 2 shows an anastomosing branching network without an identiable
feeder trunk, and type 3 has a small stick-like
tangled vessel. Compared to types 2 and 3, type
1 BVN are large and associated with poorer initial vision and a poor visual outcome following
therapy [40]. The fundus autouorescence
images show conuent hypoautouorescence
surrounded by a ring of hyperautouorescence at
the site of polyps, whereas the site of the BVN
shows granular hypoautouorescent spots [41].
Histopathology of naïve early stage PCV, in
autopsy eyes, has shown thinning of the choriocapillaris, a thickened choroid, and arteriosclerotic arterioles in the Sattler layer intertwined
with dilated choroidal veins in the post pole. The
dilated veins showed sloughing of the endothelial cells and were lled with a brinous material. Dilated nodular new vessels were seen
under the RPE [42]. However, histopathological
studies of the excised polyps obtained during
retinal surgery have shown these polyps to be
located within the schitic Bruch’s membrane and
lled with a serosanguinous uid. Sometimes, a
neovascular complex may be associated with
polyps [43, 44]. Immunohistochemistry study of
the surgically removed PCV lesions shows
strong immunoreactivity for both pigment epithelium-derived factor (inhibitor of angiogenesis) and the VEGF (promotor of angiogenesis) in
the vascular endothelial cells and the RPE [45].
Interestingly, once they rupture and cause a subretinal haemorrhage, some polyps may not be
seen on ICG angiography again [46].
7.9 Pathogenesis andRisk
Factors forPolypoidal
Choroidal Vasculopathy
While AMD is associated with a thinner choroid,
PCV is often associated with a thick choroid suggesting a different pathogenic mechanism for
PCV [47]. The choroidal thickness is due to
expansion from hyperpermeability of the outermost large choroidal veins (pachyvessels) in the
Haller layer, which compress the middle Sattler
layer and the choriocapillaris. The PCV appears
to be a part of the spectrum of thick choroid disorders (pachychoroid), pachychoroid pigment
epitheliopathy, chronic central serous chorioretinopathy, and the pachychoroid neovasculopathy
[48–50]. Detection of type 1 MNV on OCT angiography under the shallow irregular PEDs in the
pachychoroid spectrum disorders appears more
sensitive than the ICG angiography for diagnosing PCV [51]. The anti-VEGF therapy (aibercept) leads to a signicant reduction in the
volume andor the resolution of the PEDs, a
decrease in the mean choroidal thickness and an
increased choroidal vascularity index leading to
speculation that PCV may represent high ow
arteriovenous shunts in the large choroidal vessels that cause transudation into the choroidal
stroma [52]. Although the pathogenic mechanisms of PCV may differ from AMD, the two
share several risk factors-most notably the history of smoking, higher body mass index, coronary artery disease, and inammatory risk factors
such as C-reactive proteins [37]. Genetic studies
have shown a signicant association of at least 31
SNPs in 10 ARMS2, HTRA1, CFH, and CETP
gene loci. Twelve polymorphisms in the ARMS2
and HTRA1 genes were found to be different in
patients with AMD and PCV and likely play a
role in the clinical manifestation of the two different phenotypes [53].
7.10 Treatment ofPolypoidal
Choroidal Vasculopathy
The endpoint for any treatment strategy for PCV
includes improvement of visual acuity, reduction/
regression of the polyps and stoppage of leakage
with the restoration of choroidal thickness and
prevention of recurrences. In the past, extrafoveal
polyps of PCV were treated with thermal laser
photocoagulation. However, it led to extensive
scarring if BVN was also included in the treatment. Moreover, it did not prevent recurrences of
exudation or haemorrhages. A selective combina-
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7 Subretinal/Submacular Haemorrhage
tion of laser photocoagulation of extrafoveal polyps combined with anti-VEGF therapy
hasimproved visual acuity and choroidal thickness [54]. Before the advent of anti-VEGF therapy, photodynamic therapy (PDT) with
intravenous verteporn for PCV was a popular
treatment modality. However, the initial promising results could not be sustained in the longterm studies, and nearly half of the eyes had a
recurrence by the third year of follow-up.
Recurrences led to poorer outcomes [55].
Complications of PDT such as the RPE rip, even
with half uence PDT [56] and choroidal infarction, although rare, were a cause of concern,
especially if the initial visual acuity was good
[57]. Although the anti-VEGF therapy alone can
close the polyps in less than 40% of eyes and
needs multiple injections, it is much safer than
PDT and thermal laser. Several randomized controlled trials have compared intravitreal antiVEGF agents such as ranibizumab or aibercept
alone versus only PDT or anti-VEGF agents
alone vs anti-VEGF agents combined with rescue
therapy with PDT [54]. In the Planet trial, 85% of
patients treated with intravitreal aibercept did
not need rescue therapy with PDT [58]. However,
the signicant advantage of combining PDT with
intravitreal ranibizumab is a very high closure
rate of the polyps as well as a reduction in the
number of injections. Despite the higher incidence of inammation with intravitreal brolucizumab, compared to the aibercept, it yielded
better visual outcomes in Japanese eyes with
PCV.More than 2/3 of the eyes that were given
brolucizumab monotherapy did not require more
frequent injections than every 12 weeks [59].
Choroidal vascular hyperpermeability, as seen in
ICG studies, rather than the choroidal thickness,
as measured on SS-OCT, appears to be a better
predictor of the outcome of both the anti-VEGF
monotherapy andthe combination therapy [60],
in sharp contrast to an earlier observation that a
lower subfoveal choroidal thickness was a better
predictor than the choroidal vascular permeability [61].
7.11 Treatment ofMassive
Submacular Haemorrhage
Massive submacular haemorrhage (MSH) is at
least three times more common in PCV eyes
than in nAMD eyes [62]. When followed for up
to 10years, nearly 30% of eyes with PCV, especially those with multiple grape-like polyps,
may develop MSH causing immediate and
severe loss of the central vision (Fig. 7.12).
They also dened any submacular haemorrhage
as signicant if its largest diameter was >1-optic
disc diameter (DD) but <4 DD and massive if it
was >4 DD [63]. The anti-VEGF therapy alone
or in combination with PDT is protective of
MSH compared to when PDT alone is used for
treating PCV (Fig.7.13). Apart from the PCV
and the AMD, rupture of the retinal arterial
macroaneurysms and trauma may also result in
sub-macular haemorrhage. The prolonged presence of blood under the retina may have toxic
effects (iron toxicity) on the photoreceptors
besides the tractionexerted by the shear forces
of the contracting brin content of the clot that
limit the visual outcome of SMH in its natural
course. Earlier attempts to surgically remove the
AMD brovascular complex and the blood clots
stripped the overlying RPE resulting in photoreceptor degeneration and permanent loss of central vision. Heriot rst demonstrated the
successful clinical use of intravitreal tissue plasminogen activator (tPA) and long-acting expansile peruoropropane (C3 F8) gas injection,
followed by prone positioning to displace the
blood clot from the submacular space [64].
Earlier, experimental studies on subretinal blood
had shown that intravitreal tPA led to clot lysis
within 24h [65] albeit partially [66, 67]. In one
of the earliest clinical studies, complete displacement of SMH was seen when intravitreal
tPA was combined with pneumatic displacement of the submacular blood by prone positioning [68]. Given its potentialfor toxicity, the
dose of intravitreal tPA was suggested to be limited to 50 mcg [69]. Currently, however, most
surgeons use 25 mcg of tPA. To facilitate a
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a
b
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Fig. 7.12 Massive submacular haemorrhage (a) from a PCV causing immediate and severe loss of central vision in an
88-year-old man. OCT showed a dense hyperreectivity in the subretinal and sub-RPE layers (b)
quicker displacement of the blood clot,subretinal
tPA (25mcg) and air (0.4mL) with a microneedle combined with small gauge vitreous surgeryfollowed by overnight prone positioning
led to 100% displacement of the blood clot [70,
71]. Since the primary cause of the SMH is
either a PCV or nAMD, compared to the expansile gas and intravitreal rtPA (recombinant tissue
plasminogen activator), better outcomes were
seen if simultaneous anti-VEGF was also used
[72, 73]. The initial fears that bevacizumab may
get cleaved or get functionally inactivated by
the action of tPA were unfounded [74].
Although the initial studies had used intravitreal tPA [68], there were unfounded concerns that
intravitreal tPA may not cross the retina, and a
trendto perform small gauge vitreous surgery and
deliver subretinal tPA began. While subretinal
rtPA may be more effective in the complete displacement of the clot, serious complications such
as vitreous haemorrhage and retinal detachment
are higher with the PPV approach [75–77].
Moreover, a small, randomized study that compared the efcacy of intravitreal tPA vs PPV with
subretinal tPA combined with intravitreal bevacizumab and expansile gas found both techniques
to be equally effective [78]. Similar results were
found in a more recent study where three techniques were compared: intravitreal bevacizumab
and expansile gas with intravitreal rtPA vs PPV
with subretinal tPA or intravitreal rtPA combined
with bevacizumab and expansile gas (Fig.7.14)
[79]. Combining PPV with subretinal rtPA,
aibercept, and intraocular air yields better outcomes regardingthe subsequentlyreduced frequency of the need for anti-VEGF agents [80]. A
novel approach may be to perform PPV, subretinal rtPA, and intravitreal anti-VEGF, followed by
positioning the patient to ensure a gravitational
settlement of the blood [81]. Vitreous haemor-
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a
b
ef
Fig. 7.13 (a–d): A 47-year-old woman presented with
recurrent massive subretinal haemorrhages in both eyes.
She was diagnosed with PCV and underwent photodynamic therapy (PDT) with Visudyne elsewhere. The right
eye at presentation showed extensive retina atrophy due to
PDT, residual hard exudates, large PED and residual
blood (a). FFA showed transmission defects due to retinal
atrophy and a large PED (b, c). Shortly thereafter, she pre-
rhage as a major complication was seen in nearly
18% of eyes following the use of rtPA and gas
injection for extensive MSH, especially in eyes
sented with a fresh massive submacular haemorrhage (d),
for which she received intravitreal bevacizumab. (e, f):
She was followed for several years with intravitreal antiVEGF therapy as and when required. Six years after the
presentation, she resolved most of the haemorrhages (e).
OCT shows a thumb-like PED with hyperreectivity in its
lumen with a shadow effect (a residual sub-RPE haemorrhage) and residual hard exudate (f)
through haemorrhage may go up to 30% in
patients who are smokers, have a larger area, and
have a thicker MSH [83].
with PCV [82]. The incidence of this break-
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a
c
Fig. 7.14 Same patient as in Fig. 7.12 shows a partially
gas-lled eye one week (a) and 2weeks (b) after undergoing vitreous surgery with subretinal tPA combined with
b
ranibizumab and expansile gas. OCT showed partial resolution of the submacular haemorrhage (c)
7.12 Other Causes ofSubmacular
Haemorrhage
Apart from the common causes of submacular
haemorrhages discussed above, some severe systemic or local diseases may present as submacular haemorrhage. See Boxes 7.3 and 7.4.
Box 7.3 Systemic Associations of
Submacular Haemorrhage
1. Acute promyelocytic leukaemia may
present with intraretinal haemorrhages
and choroidal effusions [84] but at
times, may present as haemorrhagic
retinal detachment [85].
2. Spontaneous occurrence of subretinal
haemorrhage may be the presenting
sign of very high blood pressure in
young patients [86].
3. Metastatic choroidal lesions especially
renal cell carcinoma.
Box 7.4 Ocular Causes of Submacular/
Subretinal Haemorrhages
1. Age-related macular degeneration
2. Polypoidal choroidal vasculopathy
3. Rupture of retinal arteriolar macroan-
eurysm [87].
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