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6.2 Pathophysiology ofDiabetic Retinopathy
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a
Fig. 6.13 Fundus photograph of a patient with diabetic
retinopathy, with suspected NVD (a, blue arrow). On the
en-face optical coherence tomography angiography
b
c
(OCTA), the new vessels on the optic nerve head appear
as ne arborizing vessels (red arrows), at the level of deep
capillary plexus (b) as well as the outer retina (c)
a
Fig. 6.14 Fundus photograph showing old central retinal
vein occlusion with collaterals on the optic disc (a, blue
arrow). On the en-face optical coherence tomography
angiography (OCTA), the collaterals on the optic nerve
b
c
d
head appear as dilated looping vessels (red arrows) at the
level of supercial (b) and deep (c) capillary plexus. They
are not appreciated at the level of the choriocapillaris (d)
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6 New Vessels ontheOptic Disc andElsewhere intheRetina
The S-OCTA is a non-invasive tool to monitor
the regression of new vessels. These are seen to
start regressing as early as 1week after the rst
session of pan-retinal photocoagulation [72].
Following the en-face OCTA, intravitreal injection of bevacizumab was seen to decrease the
blood ow area and cause progressive regression
of NVD starting within 24h that was maintained
for at least 1month [73]. The presence of NVE of
more than four-disc diameters and the forwardlocated NVE growing into the vitreous on the SS
OCTA can predict the occurrence of vitreous
haemorrhage. However, NVE that lie at on the
retina and do not grow into the vitreous had a low
risk of such haemorrhages [74]. For patients less
than 45years of age, increasing blood urea nitrogen and smoking are independent risk factors for
the progression of brovascular proliferation in
PDR [75].
6.2.11 Automated Detection ofNew
Vessels inDiabetic
Retinopathy
There are two main mechanisms by which vision
may be lost in patients with diabetes, the most
common being collection of uid in/or under the
neurosensory retina, causing a swelling of the
macular area called diabetic macular oedema,
which is responsible for moderate visual loss.
The second, although less common, is the development of NVE that ruptures to cause preretinal
haemorrhages or the NVD that causes vitreous
haemorrhage. Both may cause sudden and severe
loss of vision. Till the patient loses vision, diabetic retinopathy remains asymptomatic. Fundus
screening has been practiced for several decades,
either manually by ophthalmologists or using tele
screening using non-mydriatic cameras.
However, it has not signicantly reduced unnecessary blindness from diabetic retinopathy. In the
last 15years or so, there has been intense focus
on the development of articial intelligent strategies to automatically detect lesions of diabetic
retinopathy, such as retinal microaneurysms/dot
hemorrhages, retinal vessel calibre changes, or
detection of NVE/NVD for prompt referral of the
patient for detailed evaluation and timely treatment. Several features of the new vessels on the
optic disc, such as the number, thin calibre, convoluted, irregular, and randomly directed, have
low contrast and, if elevated above the surface,
may be blurred, have been used to develop an
automated detector [76].
6.2.12 Chronic Kidney Disease
andDiabetic Retinopathy
Diabetes affects the micro and macro vessels of
all organs. Besides affecting the eyes, diabetes
targets the kidneys, peripheral nerves, and cardiovascular system. Nearly one third of patients
with diabetes will develop chronic kidney disease
(CKD) that begins as asymptomatic albuminuria,
shows a progressive decline in the glomerular ltration rates, and nally turns into an end-stage
kidney disease (ESRD) requiring renal replacement therapy. Diabetes is the most common
cause of ESRD.The glomerular capillary changes
in the kidneys mimic the changes happening in
the retinal capillaries, as discussed above, including the deposition of extracellular matrix proteins
leading to the thickening of the endothelial basement membrane and loss of foot plates of the
podocytes. These highly specialized pericytes
wrap around the endothelial cells on the side of
the urinary pole. Thickening of the basement
membrane leads to a breach in the cell-to-cell
communication between the endothelial cells and
the podocytes. The podocytes expressing VEGF
are responsible for endothelial turnover and normal functioning. The endothelial cells in the kidney are fenestrated (unlike in the retinal
capillaries) and provide for the glomerular ltration barrier that usually prevents the passage of
proteins into the ltrate. Changes due to diabetes
lead to progressive apoptosis of the podocytes
and the endothelial cells leading to albumin
excretion [77]. There is an increased deposition
of extracellular matrix from the mesangial cells
due to non-enzymatic glycation of proteins leading to nodular glomerular sclerosis, the pathology dening lesions of the diabetic kidney
disease (Kimmelstiel-Wilson disease) [78].
ab
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There is strong evidence that patients with
diabetic retinopathy have concurrent diabetic
kidney disease [79, 80]. On the other hand,
patients with DM and CKD also show a strong
association with diabetic retinopathy [81]. In a
prospective 8-year study, high baseline ACR
(>30 mg/g), low eGFR (<60 mL/min/1.73 m2),
and serum creatinine were associated with the
development of PDR. At the same time, high
ACR was also associated with the development
of diabetic macular oedema [82]. Abnormal renal
functions predict the presence of signicant nonperfusion of the retina and vice-versa [83].
Retinal non-perfusion areas on ultra-wide FA in
patients with type 2 DM were associated with the
high urinary albumin creatinine ratio, creatinine
levels, and the estimated glomerular ltration
rate (eGFR). As imaged on the OCTA, retinal
non-perfusion areas also showed a negative correlation with the eGFR [84]. Extensive capillary
non-perfusion is also associated with the progression of CKD [85, 86] and may also dene the
outcomes of CKD [87].
6.3 Other Causes ofNew Vessels
ontheRetina
While diabetic retinopathy is the most signicant
and the most common cause of the development
of pathological retinal new vessels on the retina,
several other retinal diseases may lead to blindness from the development of pathological new
vessels on the retina, including the retinopathy of
prematurity, sickle cell retinopathy, retinal vein
occlusions (Fig.6.15), and inammations of the
retinal veins (Fig.6.16).
6.3.1 Retinopathy ofPrematurity
(ROP)
6.3.1.1 Historical Perspective
More than 75years ago, an ever-increasing number of surviving babies born prematurely led to
the recognition of a bilateral blinding condition
called retrolental broplasia (RLF), so named
because of a white reex behind the crystalline
lens caused by massive intraocular brosis. Terry
saw this in 12% of preterm babies with a birth
weight of 1360 g or less. He also observed no
white reex in some babies up to 8weeks after
birth, discounting the prevalent theory that the
RLF represented the persistence of the hyaloid
artery and persistent tunica vasculosa lentis. At
times, the eyes even got enucleated for an incorrect diagnosis of retinoblastoma [88–91].
Owens and Owens [92] followed babies with
birth weights less than 2000g and described in
detail for the rst time the earliest retinal changes
that led to RLF.The earliest change was retinal
vein dilatation, tortuosity of both retinal veins
Fig. 6.15 Fundus photograph (a) showing macular
branch retinal vein occlusion. Fluorescein angiography
from another patient with upper temporal retinal vein
occlusion showing NVEs (red arrows) and areas of capillary non-perfusion (blue arrows) (b)
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Fig. 6.16 NVD (black
arrow) and NVE (blue
arrows) in a case of
retinal vasculitis
6 New Vessels ontheOptic Disc andElsewhere intheRetina
and arteries, followed soon by the appearance of
a grey membrane with numerous vessels that,
between the second and the fth month of birth,
ended up with a picture consistent with RLF [92].
6.3.1.2 Role ofOxygen
Supplementation
The turn of the twentieth century had seen
increasing use of oxygen supplementation to deal
with acute respiratory distress that was common
in preterm babies. The use of oxygen supplementation undoubtedly led to increased survival of
premature babies. However, it coincided with an
ever-increasing number of bilateral blind infants
due to massive brovascular proliferation behind
the crystalline lens, termed retrolental broplasia
(RLF). In the early 1950s, diametrically, opposite
views were held of whether the over or the underuse of oxygen was responsible for the RLF till
Ashton [93], through his experiments on kittens
up to 12 days of age, demonstrated complete
obliteration of the retinal blood vessels on exposure to high concentration (70–80%) of oxygen.
Notably, retinal vascularization in human babies
is only complete once they attain a weight of
2000g. Unlike human full-term newborn babies,
the kitten does not develop complete retinal vascularization till 3weeks of age and mimics the
retina of preterm human babies [93]. On being
shifted to the ambient air, the obliterative phase
was followed by a disorderly and profuse proliferative phase of the retinal vessels that grew into
the vitreous cavity. Ashton speculated that the
release of a hypoxic factor from the anoxic retina
is responsible for the vasoproliferative phase
[94]. Simultaneously, similar conclusions were
reached by Patz [95], who showed on histopathology the development of endothelial proliferation, budding of the new vessels through the
ILM, and retinal haemorrhages in several animal
models of oxygen toxicity. Patz recommended
monitored use of oxygen with frequent measurements of oxygen tension [95]. Patz [96], after an
extensive review of the clinical and experimental
evidence, concluded that long-duration unmonitored high concentration of oxygen was the signicant risk factor for the development of RLF.
6.3.1.3 Classication ofROP
Nearly 35 years after, Owens and Owens [92]
rst described the clinical stages of the disease
that ultimately caused RLF an international classication of retinopathy of prematurity (IC ROP)
was developed with an intent to bring about uniformity in reporting epidemiological data and
treatment outcomes in various stages of the ROP
[62]. The term ROP was preferred over the RLF
that had been used previously but represented
only stage 5 of the ROP.The retina was divided
into three zones to indicate the location of the
ROP changes. The innermost zone, zone I, was
the area within a circle, centred on the optic disc,
with a radius twice the distance between the centre of the optic disc and the centre of the macula;
zone II was the retina between the outer boundary of zone I and a circle tangent to the nasal ora
serrata and the zone III was the temporal crescent
beyond the outer limit of zone II (Later a poste-
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Fig. 6.17 Schema of the right eye (RE) and left eye (LE)
showing zone borders and clock hour sectors used to
describe the location of vascularization and extent of the
retinopathy. Solid circles represent borders of zones I
through III, and dotted circles represent borders of posterior zone II (2-disc diameters beyond zone I). A hypothetical example of examination ndings is shown in LE,
representing approximately three clock hours of stage 1
rior zone II was added that lay two-disc diameter
beyond the outer boundary of zone I). Each zone
was further divided into 12 clock hours (30°
each) to show the circumferential spread of the
pathology (Fig.6.17). Stage 1 was dened as a
demarcation line marking the junction of the vascularized and avascular retina. In stage 2, this
demarcation line developed a volume and was
seen as a ridge. Stage 3 was dened by the
development of pathological extra-retinal brovascular proliferation on the ridge that lay perpendicular to the retina. Initially, stage 4 was
dened as the development of any retinal detachment, either tractional or exudative. More
recently, in the third edition of the IC-ROP, stage
disease in zone II (note single line on drawing to document the presence of stage 1 disease). (Reproduced with
publishers’ permission from Chiang et al. International
Classication of Retinopathy of Prematurity, Third
Edition. Ophthalmology. 2021 Oct;128(10):e51-e68.
https://doi.org/10.1016/j.ophtha.2021.05.031. Epub 2021
Jul 8. PMID: 34247850)
4 was modied into Stage 4A, a peripheral retinal
detachment not involving the fovea, and Stage
4B, when involving the fovea. In stage 5, there is
a total tractional retinal detachment; if the optic
disc is visible, it is stage 5A, and if the optic disc
is not visible due to the retrolental brous membrane, it is stage 5B.
Furthermore, if there was a signicant dilatation and tortuosity of the retinal vessels, it is
labelled a Plus disease. The pre-plus disease is
only vascular dilation without sufcient tortuosity. The plus disease should be assessed only in
zone I vessels. Plus disease often has vascular
dilation on the iris, rigid iris, and vitreous haze
([97]; see Box 6.2).
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Box 6.2 Classication of Retinopathy of
Prematurity
Zone I Retinal area within a circle centred on the
optic disc and of a diameter twice the distance
between the optic disc’s centre and the macula’s
centre
Zone II Retinal area between the boundary of
zone I in a circle tangent to the nasal ora serrata
Posterior Zone II Two-disc diameters beyond the
boundary of zone 1
Zone III Temporal crescent
The circumferential extent of retinopathy is
measured in clock hours. Each clock hour is 30°.
The cumulative clock hours mean the total of the
clock hours
Stage 1: Demarcation line between the
vascularized and non-vascularized retina
Stage 2: The demarcation line has a volume and is
seen as a ridge
Stage 3: Pathological extraretinal new vessels
perpendicular to the ridge
Stage 4A: Tractional or exudative retinal
detachment not involving the macula
Stage 4B: Retinal detachment involving the macula
Stage 5A: Total retinal detachment, but the optic
disc is visible
Stage 5B: Total retinal detachment, the optic disc
is not visible
Preplus disease: Dilatation of retinal vessels in
zone I
Plus disease: Dilatation and tortuosity of retinal
vessels in zone I
Chiang etal. [97]
6 New Vessels ontheOptic Disc andElsewhere intheRetina
6.3.1.4 Threshold ROP
Given the uncertainty of the progression or a
spontaneous regression of the ROP, the prethreshold ROP was dened as any stage of ROP
in zone I, or stage 2 (ridge) in zone II with plus
disease or stage 3 (extra retinal new vessels) in
Zone III.The threshold ROP was considered the
stage that, if left untreated, had a 50% risk of
developing blindness. Threshold ROP was
dened as stage 3 disease in eight cumulative or
ve contiguous clock hours in zone 1 or 2 with
plus disease [98] (Figs.6.18).
6.3.1.5 Early Treatment ofROP
In the natural history study of the CRYO-ROP, it
was seen that pre-threshold eyes with specic
characteristics progressed in 66.4% versus 15.5%
in eyes without those features. The treatment
strategy was revised to treat (mostly laser photocoagulation, but even cryotherapy was allowed)
the high-risk pre-threshold eyes designated as
type 1 ROP. These characteristics were zone I,
any stage with plus disease or stage 3 without
plus disease; zone II, stage 2 or 3 with plus disease. Disease severity less than type 1 was
labelled type 2, and careful follow-up of these
eyes was recommended. With the early treatment
of the type 1 ROP, the 9-month unfavourable
ab
Fig. 6.18 Retinopathy of Prematurity (ROP) Stage 3. A
6-week-old infant, born prematurely at 30weeks of gestation, showing stage 3 ROP in zone 2 posterior in both eyes
(a and b). (Images courtesy of Dr. Simar Rajan Singh.
Post Graduate Institute of Medical Education and
Research, Chandigarh)
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Fig. 6.19 Aggressive Retinopathy of Prematurity
(AROP). A 4-week-old infant, born prematurely at
28weeks of gestation, showed features of AROP in Zone
1 with avascular loops and at neovascularization in both
structural outcomes reduced from 15.6 to 9.1%
[99]. At 6years, the type 1 ROP-treated eye had
signicantly better visual (25.1% vs 32.8%) and
structural outcomes (8.9% vs 15.2%). However,
there was no benet of treatment on visual and
structural outcomes in type 2 ROP eyes. Notably,
52% of the untreated eyes with type 2 ROP
showed spontaneous regression.
6.3.1.6 Aggressive ROP (A-ROP)
Previously dened as Aggressive posterior ROP
(AP-ROP), Infants <1000 g birth weight or
<28weeks GA risk developing an aggressive disease seen in zone I or posterior zone II and do not
follow the usual stages of progression. Clinically,
it is characterized by forming vascular loops at
the junction of the vascular and avascular retina
rather than having a line or a ridge. There are no
retinal capillaries in between the vascular loops.
It is accompanied by a signicant plus disease.
These eyes tend to develop at new vessels along
the retina’s surface and are frequently associated
with preretinal and vitreous haemorrhages. The
blood vessels may have a brush re appearance
and quickly progress into stages 4 and 5 [100].
Recognizing that the rapidly progressive ROP
eyes (a and b). (Images courtesy of Dr. Simar Rajan
Singh. Post Graduate Institute of Medical Education and
Research, Chandigarh)
may not always be limited only to the posterior
zones I and II and may also be seen in infants
much higher in weight or GA, the nomenclature
of AP-ROP has been revised to Aggressive-ROP
(A-ROP) in the third edition of IC-ROP [97]
(Fig.6.19).
6.3.1.7 Cryoablation ofROP
In Japan, ROP had been treated with cryotherapy
for more than a decade before it prompted a randomized multicentric trial named ‘CRYO-ROP’
to evaluate the efcacy of cryotherapy of the nonvascularized peripheral retina in eyes with threshold ROP. The preliminary results reported at
3months of the treatment were highly promising
and showed an unfavourable outcome in 21.8%
of the treated eyes compared to 43% of the
untreated eyes, rmly establishing the role of
cryoablation [98]). The 15-year results of the
CRYO-ROP trial (2005) demonstrated that the
benecial effects in the treated eyes were maintained for at least 15years. Following cryoablation of the non-vascularized peripheral retina in
eyes with threshold ROP, 52% of the untreated
versus 30% of the treated eyes had adverse structural outcomes (partial or total retinal detachment
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6 New Vessels ontheOptic Disc andElsewhere intheRetina
involving the macula, or obscuration of the macula by retinal fold or media opacities due to cataract or corneal opacity) and adverse functional
outcomes (VA < 20/200) in 64.3% and 44.7%,
respectively [101].
6.3.1.8 Laser Photocoagulation
forROP
Although the trans-scleral application of cryotherapy of the avascular retina was efcacious, it
often required general anaesthesia in extremely
low birth weight babies, the procedure was timeconsuming, and the babies had spells of apnea,
bradycardia, or arrhythmias during the treatment.
In addition, too many local complications including marked conjunctival chemosis and even vitreous haemorrhage [102]. By then, laser
photocoagulation had already been established as
the standard of care for proliferative diabetic retinopathy. The availability of laser delivery through
indirect binocular ophthalmoscopes prompted
preliminary studies comparing the outcomes of
argon laser photocoagulation with the thenstandard- of-care cryotherapy. Laser ablation of
the peripheral avascular retina had a favourable
outcome in 94% of the eyes versus 75% with
cryoablation [102]. Soon after, Capone Jr etal.
[103] reported successfully using diode laser
photocoagulation in the zone I threshold
ROP.Since then, it has been realized that there is
more damage to the photoreceptor layer with the
diode laser and higher chances of over-treatment
because of less visible photocoagulation marks.
The majority of ophthalmologists, in any case,
possess a green laser. The odds of a favourable
outcome in the long term were almost seven
times higher with the laser compared to the cryotherapy. It rmly established laser photoablation
of the avascular retina as the standard of care in
threshold ROP [104–106].
6.3.1.9 Anti-VEGF Therapy forROP
As the role of the VEGF in the pathogenesis of
pathological neovascularization in ROP became
clearer, initial anecdotal cases were followed by
more extensive studies, including prospective
studies comparing the outcomes of the laser vs
the intravitreal anti-VEGF therapy [107, 108].
The intravitreal bevacizumab treatment allowed
for continued revascularization of the peripheral
retina, unlike the retinal ablation with laser/cryo,
which did not allow for further vascularization of
the peripheral retina. Furthermore, laser photocoagulation resulted in a lifelong contraction of the
peripheral visual elds [109]. In the beat—ROP
group study comparing intravitreal bevacizumab
(0.625mg in 0.025mL) with laser photocoagulation for zone I, stage 3+ROP and zone II posterior, stage 3 + ROP, the recurrence rates at
54weeks postmenstrual age (PMA) were highly
favourable for the intravitreal group at 6% vs
26% in the laser group and the difference was
still higher 6% vs 42% in the zone I disease [109].
However, the patients must be followed closely
until the peripheral retina is vascularized. In a
multicentric controlled trial, intravitreal ranibizumab (0.2mg) was also found to be better than
laser photoablation, with 80% of the eyes receiving ranibizumab 0.2mg till 24weeks of follow up were alive, with no active disease, no any
unfavorable structural abnormality, or no need
for any retreatment [110]. In type 1 zone I ROP,
combining laser photocoagulation (outside zone
I) with intravitreal bevacizumab resulted in better
anatomical results and fewer chances of myopia
[111]. However, unlike the classic cases of ROP
in zone I, aggressive posterior ROP (AP-ROP),
now re-dened as A-ROP treated alone with
intravitreal bevacizumab, had larger peripheral
non-perfusion areas on FA and higher recurrence
rates. Lower birthweight, prolonged hospitalization, and AP-ROP are signicant risk factors for
recurrence (~8% of patients) of brovascular
proliferation and disease in eyes treated with a
single injection of bevacizumab [112].
Prophylactic laser photocoagulation following
intravitreal injection in AP-ROP eyes minimized
the adverse anatomical outcomes [113]. There
are several advantages of using anti-VEGF therapy in type 1 ROP as the time to treat is much
shorter (these babies have very low birth weight),
there is no difference in the efcacy compared to
the laser photoablation, and there is no tissue
destruction or restriction of peripheral visual
elds and fewer chances of developing myopia.
While there are conicting results on the recur-
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rence rates of brovascular proliferation and the
need to retreat, the delay in vascularization of the
retina, especially in the zone I disease, requires
these babies to be closely followed up for as long
as 70weeks PMA till the vascularization is complete [114]. Plasma VEGF levels were reduced
one day following intravitreal ranibizumab therapy for ROP, but this effect was not seen after one
week [115]. In a dose de-escalation study, intravitreal bevacizumab as low as 0.002 mg led to
reduced plasma VEGF levels, and this effect was
still evident at 2 and 4weeks after the injection
[116]. Recent studies also suggest that most
babies receiving bevacizumab developed newonset systemic hypertension within a month of
the treatment [117].
Moreover, the long-term adverse impact of
VEGF suppression on organ development, primarily neurodevelopment, is unknown.
Therefore, this treatment may be restricted to
type 1 ROP in zone I or the posterior zone II
[114]. Nearly 8% of the ROP eyes, especially
those with a plus disease receiving anti-VEGF
therapy, may develop retinal detachment requiring pars plana vitreous surgery [118]. Informed
consent from the parents should be taken before
considering anti-VEGF therapy for these infants.
Advances in understanding the pathogenesis and
management have been recently reviewed, and
readers seeking greater details may refer to these
publications [119–121].
6.3.1.10 Screening Strategies forROP
Many treatment options that are now available
can achieve favourable and stable anatomical and
functional outcomes in more than 90% of ROP
babies. However, the window of opportunity to
treat them efcaciously is extremely narrow.
Hence, the key to success lies in the timely detection and recognition of babies at high risk of
developing ROP. Neonatal care has been relatively standardized in western countries but
shows wide variations across the world’s middle
and low-income regions. The major risk factors
besides preterm birth and low birth weight
include prolonged hospital stay due to comorbidities like infections, haemorrhages and the
need for blood transfusion, as well as notably
unmonitored oxygen ventilation.
In three of the most advanced countries with
well-developed neonatal care, preterm babies
with a mean gestational age (GA) of <26weeks
and a mean birth weight of <800 g developed
threshold 3+ or higher ROP whereas in the
middle- income and low-income countries where
the neonatal care may be less than optimal, babies
with 34 weeks GA and birth weight of even
2000g may develop it [122]. In most advanced
countries, the screening criteria are birth weight
<1500g and gestational age <34weeks [122]. In
the three multicentric trials of ROP in the US
from 1986 to 2013, there was a progressive
decline in the GA (28–27weeks) and birth weight
(954–864g) of preterm babies with ROP while
the prevalence remained stable. During this time,
there has been a steady improvement in obstetrical care, the use of antenatal corticosteroids,
human milk feeding, surfactants, and better oxygen monitoring, resulting in increased survival of
these babies [123]. In sharp contrast, in a retrospective study of 275 ROP eyes seen over
10 years in an Indian tertiary care centre, the
mean birth weight was 1534 g (range 1251–
2750 g), and the mean gestation period was
31weeks (range 26–35). Applying the US or the
UK screening criteria to this cohort would have
missed 17.6% and 22.6% of babies with threshold or worse ROP [124]. Similar conclusions
were reached in a prospective study in a South
India referral centre [125]. Thus, all countries
must develop criteria to include all ROP babies.
The current screening guidelines by the American
Academy of Pediatrics and Ophthalmology suggest that all infants born with a birth weight of
<1500g or GA of <30weeks or any infant with
birth weight between 1500 and 2000g or GA of
>30weeks who have received oxygen even for
more than a few days or unmonitored oxygen or
received ionotropic support for hypotension
should be screened for ROP at postmenstrual age
of 31–34weeks [126]. Monitoring oxygen saturation (SpO2) using pulse monitors, setting low
and high saturation level alarms, maintaining
high levels of hygiene, washing the hands by the
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6 New Vessels ontheOptic Disc andElsewhere intheRetina
staff, and avoiding unnecessary blood transfusions are some measures that can help reduce the
incidence of ROP.All babies born in India with
gestational age < 34 weeks or birth
weight<2000g or babies with even higher birth
weight who have comorbidities, such as sepsis,
respiratory distress, intraventricular hemorrhages, and requiring cardiopulmonary support,
should be screened by an Ophthalmologist who
is trained to use binocular indirect ophthalmoscope and well versed with the identication,
classication, and documentation of the ROP
[127]. It can be supplanted with a Ret cam or a
similar ultra-wide angle fundus imaging camera,
which can be used by a trained nurse/nonphysician and use teleophthalmology to submit
the images to a remote centre for interpretation
and decision for treatment [128, 129]. By and
large digital imaging is as sensitive as the clinical
retinal examination; the latter may, however,
have an edge in evaluating for a zone 3 disease
and ROP stage 3 disease [130]. However, digital
imaging is a permanent record and can objectively document any ROP progression [131]. It is
recommended that screening should be done
from 25 to 30 days of birth or at discharge,
whichever is earlier. If the babies have comorbid
conditions or receive unmonitored oxygen, they
should be screened earlier. Most preterm babies
are still in the hospital at this time, and if they are
discharged, they should be called to the outpatient clinic for screening. They should be monitored weekly or even two weekly depending upon
the development and maturation of retinal vessels, and their progress should be documented on
the fundus imaging and the paper charts [126].
The follow-up screening should be done for all
babies who have been treated irrespective of
either the laser photocoagulation or with an intravitreal injection of bevacizumab till there is complete regression of ROP lesions or retinal
vascularization has reached the temporal periphery. As mentioned earlier, the babies receiving
bevacizumab or incomplete ablation with laser
photocoagulation may develop recurrence of plus
disease or brovascular proliferation later and
must be monitored closely. Babies need periodic
visual rehabilitation examinations and monitor-
ing of cognitive and other neural development
milestones until at least 5years of age [127].
6.3.2 Familial Exudative
Vitreoretinopathy (FEVR)
FEVR is a rare genetic disorder seen in children
with a high level of heterogeneity both in hereditary patterns and in clinical manifestations. The
clinical spectrum of the disease may vary from
asymptomatic family members who may show
only peripheral avascular retina to peripheral retinal neovascularization and brous proliferation,
prominent temporal retinal fold, vitreous hemorrhage, and exudative, tractional or rhegmatogenous retinal detachment. Compared to the normal
population, more non-branching vessels radiate
from the optic disc [132]. Narrowing the temporal vascular arcades with multiple branching and
straightening of the peripheral vessels gives it a
broom-like appearance. Temporal dragging of
the optic disc vasculature is highly characteristic.
The retinal periphery may show abnormal arteriovenous loops and a V-shaped avascular area in
the temporal meridian [133].
FEVR is classied into ve stages. Stage 1 is
avascular peripheral retina seen on FFA; stage 2
is avascular retina with peripheral neovascularization without exudation (2A) or with exudation
(2B); stage 3 is extramacular retinal detachment
without exudation (3A) or with exudation (3B),
stage 4 is retinal detachment involving macula
without exudation (4A) or with exudation (4B),
and stage 5 is total retinal detachment [134]
(Fig.6.20).
Mutations are known in at least ve genes that
play a critical role in the development of the retina and are detectable in nearly half of the
patients. The genes are NDP, an X-linked gene,
FZD4, LRP, TSPAN12 (all three autosomal dominant and recessive), and ZNF 408, an autosomal
dominant gene [135]. Most of the clinical features of FEVR may also be seen in ROP, and the
diagnosis gets compounded as some of the children with FEVR may have been born prematurely and have low birth weight. However, ROP
is a highly symmetric and aggressive disease
Соседние файлы в папке Библиотека им академика М.И. Перельмана