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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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9 Retinal Vascular Occlusions
Fig. 9.9 Complete occlusion of a major (lower temporal)
branch retinal vein (a) seen as a sheathed (black arrow)
vessel (a). Fluorescein angiography (b) shows extensive
the macula, and leakage of uid from dilated (telangiectatic) capillary bed and/ microaneurysms
and the presence of the cystoid macular oedema
(CME).
areas of retinal capillary non-perfusion (blue arrows) and
neovascularization of the optic disc (NVD, red arrow)
untreated eyes versus 60% who had undergone a
grid laser photocoagulation in the area of macular oedema [36]. The persisting macular oedema
does not follow a zonal distribution and collects
in the centre of the macula. Spontaneous resolution in up to 40% of the affected eyes may restore
9.3.6 Consequences
andComplications ofBRVO
near-normal visual acuity [33]. Clinical diagnosis of macular vein occlusion, especially if the
patient presents late, may pose a challenge to dif-
9.3.6.1 Macular Oedema inBRVO
andTreatment Strategies
By 3 months of the onset, most of the retinal
haemorrhages get absorbed by the usual phagocytic mechanisms and depending upon the
amount of uid leakage from the broken/decompensated endothelial cell barrier and the capacity
of the collateral vessels to drain it, the macular
oedema may resolve or continue to persist. By
and large, visual acuity improves spontaneously
in BRVO eyes without any intervention, but
improvement beyond 20/40 visual acuity is
uncommon [26, 27]. In the natural course, the
median time to resolve macular oedema was
18 months in the macular vein occlusion and
21months for the major BRVO [33]. In terms of
visual improvement, in the branch vein occlusion
study, a multicentric controlled trial, there was
spontaneous improvement >20/40in 34% of the
ferentiate it from diabetic retinopathy. Notably,
the veins follow a strict quadrantic pattern, and
the haemorrhages and the microaneurysms,
unlike the macular oedema, are strictly limited to
the affected quadrant above or below the horizontal raphe, as the case may be. In diabetic retinopathy, the microaneurysms and haemorrhages do
not follow this rule and are seen across the horizontal raphe. One notable exception is the formation of hard exudates in the BRVO.If the oedema
persists, hard exudates may be seen deposited in
a circinate pattern around the site of persisting
retinal oedema from the decompensated capillary
bed and microaneurysms and cross the horizontal
raphe. The formation of microaneurysms is a risk
factor for the development of refractory macula
oedema [37]. In the BRVO eyes with macular
oedema and increased subfoveal choroidal thickness, elevated levels of VEGF and IL-8 were seen
9.3 Branch Retinal Vein Occlusion
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as predictors of good outcomes following antiVEGF therapy [38]. Optical coherence tomography (OCT) is used to diagnose and monitor
macular oedema (Central retinal thickness, CRT).
Additionally, the OCT may show some structural
alterations, including disorganization of the internal retinal layers (DRIL) and disruptive changes
in the photoreceptors and the external limiting
membrane that may limit visual improvement
following therapeutic interventions.
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. They 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. Visual improvement and reduction in CRT,
the usual parameters to monitor the response,
have shown more signicant results with the use
of pharmacotherapy compared to laser gird therapy [39, 40]. A more recent Cochrane review of
randomized controlled trials has endorsed the
recommendations of the earlier studies that compared to no treatment or treatment with grid laser
photocoagulation, treatment with any of the antiVEGF agents or depot corticosteroids was more
effective in improving visual acuity, the CRT,
and quality of life up to 12months. Compared to
corticosteroids, anti-VEGF agents are more
effective. However, there is evidence that steroids lead to high intraocular pressure and cataract formation [41]. Although highly effective,
these injections have increased the burden on
patients and care providers. Macular laser photocoagulation can reduce the number of intravitreal injections [42].
9.3.6.2 Retinal Neovascularization
ofRetina andVitreous
Haemorrhage inBRVO
In patients with BRVO, one of the major visionthreatening complications is the development of
the retinal new vessels (RNV) and subsequent
leakage from these to cause vitreous haemorrhage. Complete occlusion of a major branch
retinal vein is complicated by the development of
variable areas of retinal capillary non-perfusion
that lead to overexpression of vascular endothelial growth factor (VEGF) (Fig.9.9). There is no
strict denition of how much area of nonperfusion area (NPA) will lead to the formation
of new vessels and when these new vessels will
develop. Such patients must be followed regularly to look for these RNV over several months.
The presence of retinal haemorrhages in the acute
stage of BRVO does not allow precise estimation
of the NPA. Performing FFA, a somewhat invasive technique, has been a standard technique for
detecting NPA upon resolution of retinal haemorrhages. More recently, articial intelligence (AI)
techniques using deep learning algorithms have
shown that AI can accurately measure the NPA
[43]. In a prospective natural history study, new
vessels elsewhere (NVE) and new vessels on the
optic disc (NVD) were seen to develop at 9% and
8% by 12 months and 15% and 10% by
36 months, respectively [44]. In a multicentric
controlled trial (BVOS) study, 22% of the
untreated eyes with BRVO developed RNV compared to 12% of those that underwent prophylactic laser scatter argon laser photocoagulation.
Most of those who developed either RNV or vitreous haemorrhage had at least a 5-disc area of
capillary non-perfusion. In the untreated BRVO,
37% of the non-perfused versus 11% of the perfused and in the laser-treated group, 19.2% of the
non-perfused versus 6.7% of the perfused retina
developed either RNV or vitreous haemorrhage
(Fig.9.10). Re-evaluation of the perfused cases,
which developed these complications, revealed
that these patients had developed non-perfusion
in the course of follow-up, or the non-perfusion
was present but missed on evaluation of the photographs. The study strongly recommended that
BRVO eyes should be treated after they develop
RNV, as 12% of those prophylactically treated
versus only 9% of those treated after the development of RNV went on to develop vitreous haemorrhage [45]. A severe contraction of the visual
elds corresponding to the Laser photocoagulation treated sector led to a strong recommendation that laser photocoagulation is done after the
development of the RNV [46].
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Fig. 9.10 A case of untreated lower temporal BRVO (a) developed vitreous haemorrhage and brovascular prolifera-
tion as a complication (b)
9 Retinal Vascular Occlusions
9.4 Epidemiology ofCentral
Retinal Vein Occlusion
(CRVO)
The prevalence and incidence of CRVO in the
population is at least 1/sixth that of the BRVO.In
a population-based study (the Beaver Dam eye
study), the prevalence of CRVO was 0.1%, and
the ve-year incidence was 0.2%, respectively
[24]. When the same population was revisited, the
15-year incidence of CRVO was 0.5%. Retinal
vascular occlusions (RVO) accounted for 12% of
the causes of severe vision loss (<20/200) over
15 years in this population [25]. In pooled data
from different regions of the world, the estimated
prevalence of CRVO in persons above the age of
30 years was seen to vary with ethnicity, from
0.88in Whites, 0.37in Black, 0.74in Asians, and
1.01 per 1000 population in the Hispanic population. It is estimated that nearly two million people
worldwide suffer from CRVO [26, 27].
9.4.1 Risk Factors forCRVO
In the 15-year incidence and prevalence study of
RVO (The Beaver dam eye study), the signicant
risk factors for CRVO, apart from age, included
glaucoma, history of diabetes, and use of digoxin
and barbiturates. Other risk factors include diabe-
tes, lipid abnormalities, smoking, and hyperhomocysteinemia. Resistance of activated protein
C, factor 5 Leiden mutation, and a genetic mutation in prothrombin has been reported mainly in
younger patients with CRVO.However, inconsistent results do not merit any tests for screening
these factors [47, 48].
9.4.2 Pathogenesis ofCRVO
The central retinal vein (CRV) exits the eye
through the optic nerve head, which shares the
adventitial sheath with the central retinal artery.
A morphometric study has shown that compared
to the CRA, the CRV has a reduced perimeter and
lumen and acquires a ‘D’ shape compared to the
circular shape of the CRA [49]. Because of these
notable anatomical limitations, the CRV gets narrower in the lamina cribrosa and has a higher
ow. Higher intraocular pressure also leads to
further compression of the RV in the lamina
cribrosa. Further, in patients with arteriolosclerosis, hardening of the central retinal artery wall
compresses the CRV leading to turbulence and
endothelial injury and the formation of a thrombus just posterior to the lamina cribrosa [50, 51].
Histopathological studies of the eyes with CRVO
removed within a week to 10 years after the
occlusion have shown a fresh thrombus to a
9.4 Epidemiology ofCentral Retinal Vein Occlusion (CRVO)
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191
recanalized thrombus along with endothelial cell
proliferation in nearly half of the eyes and evidence of chronic inammation in the other half of
the eyes [52]. FFA studies show that blood ow is
present in the CRVO eyes by opening pre- existing
retinociliary channels. A more posterior site of
thrombus formation means the availability of
more channels to drain the blood resulting in a
non-ischaemic CRVO (ni-CRVO). However,
fewer collaterals are available if the thrombus
extends anteriorly, leading to an ischaemic CRVO
(iCRVO) [53]. According to Hayreh, most
iCRVOs begin as non-ischaemic and progress to
the ischaemic type. Even the Central Vein
Occlusion Study reported that many CRVO eyes
initially labelled indeterminate progressed to the
iCRVO, emphasizing the need for a thorough and
frequent examination, including the slit-lamp,
within the rst 4months after onset [29, 30].
9.4.3 Clinical Presentation
andClassication ofCRVO
Occlusion of the CRV leads to a highly variable
clinical picture in the acute phase, the consistent
feature being venous dilatation and tortuosity in
all four quadrants. The increased hydrostatic
pressure in the veins causes loss of the bloodretinal barrier resulting in uid leakage and
varying severity of haemorrhages from a few
scattered ones to massive haemorrhages in all
the quadrants of the retina (Fig. 9.11). These
Fig. 9.11 Extensive retinal haemorrhages are seen in all
four quadrants in central retinal vein occlusion (CRVO)
may be accompanied by optic disc oedema, macular oedema, and cotton wool spots. Hayreh rst
classied CRVO into two distinct entities,
venous stasis retinopathy (non-ischaemic) and
haemorrhagic (ischaemic) CRVO, with altogether different outcomes (Fig. 9.12) [54].
According to Hayreh, most of the iCRVOs begin
as non- ischaemic and progress to the ischaemic
type [53]. Even the Central Vein Occlusion
Study reported that many CRVO eyes that were
initially labelled indeterminate progressed to the
ischaemic type emphasizing the need for a thorough and frequent examination, including the
slit-lamp within the rst 4 months after onset
[29, 30]. Patients with iCRVO present with four
highly sensitive and specic functional tests,
namely the relative afferent pupillary defect in
the affected eye, visual acuity <20/400, contracted visual elds on the kinetic perimeter, and
subnormal amplitude (<60%) of the B wave on
ERG [55]. The two tests, namely the visual acuity and the subnormal ERG, have 97% sensitivity in the diagnosis of iCRVO. The two
morphological tests, the severity of retinal haemorrhages in all four quadrants on the fundus
examination and FFA, are less sensitive in the
acute stage to differentiate the ischaemic from
the ni-CRVO.In the acute stage of CRVO, blockage of the uorescence by retinal haemorrhages
assesses capillary non-perfusion areas misleading [53]. The presenting visual acuity (VA) in the
acute ni-CRVO presenting within 3 months of
the onset is >20/30in 40% of eyes and >20/60in
nearly 2/3 of eyes, whereas in the iCRVO VA is
<20/400 in 80% of eyes, and none having
>20/200. The eld defects in non-ischaemic
CRVO are only mildly affected in >90 of eyes
versus moderate to severe visual eld defects in
ischaemic CRVO [53]. In a signicant number of
eyes, haemorrhages and macular oedema will
resolve spontaneously in ni-CRVO.However, a
cilioretinal artery occlusion may rarely complicate the non-ischaemic more than the
iCRVO. Persistent macular oedema is another
sight-threatening complication. On the other
hand, ischaemic CRVO is complicated by the
development of anterior segment neovascularization with consequent neovascular glaucoma.
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9 Retinal Vascular Occlusions
Fig. 9.12 Fundus photographs and uorescein angiography of ischaemic CRVO (a, b) and non-ischaemic CRVO (c,
d)
Occlusion oftheCilioretinal
Artery (CLRA)
Retinal circulation is autoregulated, and therefore whenever there is a rise in the intravascular
hydrostatic pressure in the central retinal vein
and its tributaries, there is an automatic drop in
the high-pressure central retinal artery supply
system compared to the non-autoregulated, but a
low-pressure ciliary supply system of which the
cilioretinal artery (CLRA) is a branch. It is of
note that the venous drainage of the CLRA is
through the draining capillaries of the retinal
9.4.3.1 Complications ofCRVO:
veins, and these are met with a raised intracapillary pressure of the retinal venous system. Nearly
one third of normal people possess one or sometimes more CLRAs. During autonomic systemcontrolled nocturnal lowering of blood pressure,
a signicant drop in the blood pressure in the
CLRA may fail to overcome the raised intracapillary pressure (caused by the CRVO), thereby
causing either a haemodynamic or permanent
cessation of the blood supply via the CLRA
(Fig.9.13). These patients may complain either
of transient attacks of blurring of vision or may
nd their vision diminished on waking up in the
morning [56].
Haemodynamic occlusion of this phenomenon can be demonstrated on the FFA, as the
bolus of the dye moves back and forth in the
cilioretinal artery—a phenomenon given the
name of ‘dye front reciprocation’ [57, 58].
Notably, whether isolated or associated with
CRVO, cilioretinal artery occlusion is nearly
always associated with paracentral acute middle
maculopathy lesions [59].
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9.4 Epidemiology ofCentral Retinal Vein Occlusion (CRVO)
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Fig. 9.13 CRVO with cilioretinal artery occlusion seen as a pale island of opacication (black arrows) in the macula
(a). Fluorescein angiography shows the corresponding area (blue arrows) of non-perfusion (b)
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9.4.3.2 Complications ofCRVO:
Paracentral Acute Middle
Maculopathy
Paracentral acute middle maculopathy (PAMM)
lesions caused by capillary ischaemia in the
intermediate and deep capillary plexus can be
seen in ~5% of the cases with non-ischaemic
CRVO.This area of the retina is a watershed of
the oxygen and micronutrient supply between the
retinal and the choroidal circulation. It is thus
vulnerable to raised interstitial pressure in this
zone caused by the non-ischaemic CRVO [60]. A
plaque-like hyperreective band in the inner
nuclear layer on the spectral domain OCT characterizes the PAMM lesions (Fig. 9.14). On en
face OCT, the PAMM lesions due to CRVO
appear as areas of perivenular hyperreectivity
[60]. On fundus examination, these are seen as
perivenular opacication of the retina which
appears dark on near-infrared reectance imaging. While the cotton wool spots are whitestriated supercial lesions that follow the retinal
nerve bres course, the PAMM lesions are dull
grey and located deep in the retina [61]. It is
important to note that the perivenular fern pattern
of PAMM that starts in the deep capillary plexus
may be a harbinger of a branch or central retinal
artery occlusion requiring a stroke evaluation
[62]. Once the PAMM lesions resolve, they leave
behind thinning of the inner nuclear layer.
9.4.3.3 Complications ofCRVO:
Persistent Macular Oedema
Raised intravascular pressure in the CRVO leads
to a breakdown of the blood-retinal barrier and
increased uid leakage into the retina’s interstitial tissues. The increased pressure interferes
with the perfusion in the retinal tissues and
leads to a state of hypoxia and release of
hypoxia- inducible factor 1-alpha causing overexpression of the vascular endothelial growth
factor (VEGF). Discovered in 1989, the VEGF
is expressed in response to hypoxia and is a
potent endothelial cell-specic stimulant that
causes increased vascular permeability, endothelial cell proliferation, formation of new vessels, and recruitment of leucocytes [63].
Vascular endothelial growth factor (VEGF) was
found elevated in the ocular uids in the patients
with proliferative diabetic retinopathy and
CRVO [64, 65] and related with the severity of
the retinal vein occlusion [66]. Although initial
reports had found elevated VEGF levels in the
RVOs, it was unknown how much of the uid in
the interstitial uid is contributed by the
increased hydrostatic pressure or the cytokines
in the retina. The discovery of VEGF led to the
development of an antigen- binding protein
against VEGF (bevacizumab) and later a unique
antigen-binding fragment (ranibizumab), especially for intraocular use [67, 68]. Initial small
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9 Retinal Vascular Occlusions
c
Fig. 9.14 A case of non-ischaemic CRVO with perivenular opacication of the retina (yellow arrow) suggestive of
paracentral acute middle maculopathy (PAMM), as seen
on fundus photograph (a) and uorescein angiography
(b). OCT shows a plaque-like hyperreective band (blue
arrows) in the inner nuclear layer characterizing the
PAMM lesions (c)
controlled trials with 3-monthly injections of an
anti-VEGF agent, ranibizumab, led to remarkable improvement in the vision and the reduction in central retinal thickness irrespective of
the duration of the RVO (Fig.9.15).
Moreover, there was some correlation with the
decreasing VEGF levels in the aqueous humour
[69], suggesting that VEGF was a major driver of
macular oedema and laid grounds for establishing the role of anti-VEGF therapy for the resolution of macular oedema, albeit for a short duration
(~1month) in both the BRVO and the CRVOs. It
has now been shown that anti-VEGF therapy
leads to decreased retinal venous pressure in eyes
with CRVO [70]. Several controlled clinical trials
have been done both with anti-VEGF agents, that
last about one month and intravitreal injections of
depot steroids (triamcinolone acetonide, 1 mg
Kenalog) or sustained-release dexamethasone
implants (Ozurdex) to overcome the increased
burden of the monthly injections [71] (Fig.9.16).
There is a signicant risk of cataract formation
and raised intraocular pressure with intravitreal
depot steroids. The anti-VEGF agents remain the
rst line of therapy for persistent macular oedema
in RVOs, with depot steroids being reserved only
for patients resistant to the anti-VEGF agents
[72]. Strong evidence for a treat and extend strategy has found favours as only ~8 injections were
required by 12 months and 13 by the end of
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Fig. 9.15 A 51-year-old man presented with sudden
visual loss in the left eye due to CRVO (a). He received
intravitreal injections of bevacizumab every four weeks.
24months [73]. However, most patients continue
to receive injections even after 5years [74] and
still require at least four injections per year at the
end of 8years [75]. However, the search for innovative drug delivery systems continues in an
attempt to reduce the treatment burden.
Note resolution of retinal hemorrhages at six weeks (b),
four months (c) and eight months (d)
lowed up regularly to look for early signs of INV
as a substantial number of even the ni-CRVO
may develop ischaemic CRVO when followed
for a long time. There is a sharp rise in the development of INV in the iCRVO eyes within
6months of the onset. Likewise, NVG, if it has to
develop, does so within 12months in 90% of the
9.4.3.4 Complications ofCRVO: Ocular
Neovascularization
Besides the irreversible loss of central vision, the
major complication of iCRVO is the development of neovessels in the iris (INV) and the angle
of the anterior chamber (ANV), ultimately leading to a painful blind eye due to neovascular
glaucoma. Patients with CRVO have to be fol-
cases [76]. The anti-VEGF agents, if used, may
delay the onset of INV in iCRVO but do not eliminate the occurrence of this complication [77].
The denitive treatment is pan-retinal photocoagulation to eliminate the hypoxic retina. It is
recommended that pan-retinal photocoagulation
be done after the development of INV since prophylactic photocoagulation does not prevent the
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9 Retinal Vascular Occlusions
a
b
c
Fig. 9.16 Nonischemic CRVO (a) in a 35-year-old
woman with macular edema on uorescein angiography
(b) and spectral domain OCT (c). She received intravitreal
triamcinolone 4mg. At the 18-week follow-up, there were
no retinal hemorrhages and visual acuity had improved to
6/6 (a), there was a signicant reduction in perifoveal
leakage (e) and no macular edema on OCT (f)
9.5 Inammatory Retinal Vein Occlusions
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Fig. 9.16 (continued)
a b
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Fig. 9.17 Massive iris neovascularization (INV) with
neovascular glaucoma in ischaemic CRVO (a). Five
months following antiglaucoma surgery and pan-retinal
occurrence of neovessels on the iris (Fig.9.17)
[76, 78].
As most patients with iCRVO have already
lost their central vision, whatever is left of the
peripheral eld of vision required for ambulation
also gets lost due to photocoagulation.
photocoagulation, there was complete regression of INV
with control of intraocular pressure (b)
9.5 Inammatory Retinal Vein
Occlusions
Several inammatory disorders may present
with inammatory occlusion of single or multiple retinal vein occlusions. In TB-endemic
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