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1.1.1 Rationale of PDT in PCV

Although a lot of work has been done on the role of
PDT in PCV, the sequence of events leading to resolution of disease is not
clearly understood. PDT with verteporfin utilises selective endothelial uptake
of photo activated compound into PCV lesions.(80) Dilated choroidal vessels and interconnecting BVN may
behave like CNV. PDT may cause selective thrombosis in abnormal choroidal
polypoidal lesions and BVN, leading to resolution of exudation and haemorrhage
from the lesions.(81) The smaller the vessel calibre and higher the
deformity of vessels, more is the effect of PDT.(80) This may translate into higher effect on polyps rather
than BVN as these have smaller deformable vessels than BVN.


1.1.2 Mechanism of action

PDT uses a benzoporphyrin derivative, verteporfin
which act as a photo sensitizer.(82) When injected intravenously, verteporfin gets
concentrated in endothelial cells of abnormal choroidal vessels. Low-density
lipoprotein receptors enhances selective targeting of vascular endothelial
cells.(82) Diode laser in the presence of verteporfin cause
endothelial-bound intra-luminal photo-thrombosis in these abnormal vessels.
This leads to occlusion and subsequent resolution of exudation. Also choroidal
vascular remodelling is being reported to occur after PDT.(83) Even without the presence of low-density lipoprotein
receptors, application of laser along with verteporfin might be adequate enough
to cause a non-selective transient choroidal vascular occlusion.(84) This would result in stagnant flow and thrombosis of
the abnormal choroidal vessels.

1.1.3 Standard protocol

Baseline FFA, ICGA, and OCTA are performed to
determine the location and size of the polypoidal lesions, as well as
interconnecting BVN. The greatest linear dimension (GLD) of the lesion
including the polyps and BVN is determined. As per the protocol followed in the
Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study, verteporfin
infusion (dose 6 mg/m2) is performed over 10 minutes.(85) 15 minutes after starting verteporfin infusion, diode
laser (689 nm) is applied for duration of 83 seconds with light dose of 50J/cm2.
Patients are advised to avoid sun exposure and to wear sunglasses for 3 days following
the procedure.

FFA and ICGA are repeated at 3 months after PDT to
determine polyp and BVN regression. PDT can be repeated if polyp regression is
incomplete or recurrence of polyp occurs later on follow up.

Visual and angiographic outcomes Short term

Following PDT, abnormal choroidal vessels undergo
remodelling, exudates get absorbed and polyps regress, leading to improvement
in visual acuity. Stable or improved vision in short term (upto 1 year) has
been reported to be achieved in 80% to 95% of cases in majority of the studies.(86–92) Mean visual improvement of 1.3 to 2.4 lines is
reported in upto half of the cases.(86–88) Mean treatment episodes in these studies ranged from
1.9/year to 2.9/year. 

The short term angiographic outcome is also favourable
with PDT. Absence of FFA leakage was achieved in 74% and 91% eyes at 1 year as
reported by Akaza et al.(89) and Chan et al. respectively.(87) Complete regression of polyps could be achieved in
around 78% to 95% of cases.(87,89,90,92) However, BVN showed no to little change and persisted
in majority of eyes. Recurrence of polyps at the end of 1 year is uncommon and
reported in upto 4.5 to 5.7% eyes.(87,89)       
Long term

New or recurrent PCV lesions may develop during
long-term follow-up. After 1 year, recurrence of polyps has been noted in 43.9%
to 77% eyes after PDT.(88,93,94) In a prospective study of 43 eyes followed over 3
years by Akaza et al, BVN enlargement occurred in 55.8% eyes.(94) In this study, all eyes had poorer final BCVA as
compared to baseline BCVA likely due to evolving foveal retinal and RPE atrophy
from recurrent exudation. This highlights the importance of long-term follow-up
for recurrence of PCV following PDT. Retreatment should be performed when new
symptoms occur due to recurrence of polyps and exudative changes.

1.1.5 Complications

The most common reported complication of PDT for PCV
is subretinal hemorrhage, estimated to be around 10% to 30%.(67,95,96) Hirami et al reported most of the hemorrhage to
develop within 1 month after PDT.(67) Despite the subretinal hemorrhage, visual acuity was
maintained in majority of eyes. Subretinal bleed can also breakthrough into the
vitreous cavity and lead to poorer outcome.(67,95) Larger lesion size, larger laser spot size and
leaking polyps are the common risk factors for post PDT bleeding.(67) Other complications of full fluence PDT include
massive suprachoroidal hemorrhage, RPE tears and micro rips, choroidal
ischaemia, RPE atrophy, secondary CNV, and fibrous scarring.(56,97)

1.1.6 Alternative treatment protocols

Reduced fluence or half dose PDT may be useful to
prevent adverse effects of full fluence PDT.

Reduced Fluence PDT (RFPDT): Light energy of 25 J/cm2 (instead of 50J/cm2) is
given for 83 s (300 mW /cm2) after 6 mg/m2 verteporfin
injection. Decreased incidence of subretinal hemorrhage has been reported
by Yamashita et al(98) and Sen et al(99) following RFPDT, although it was combined with
intravitreal anti- VEGF injection. However, a high rate of BVN persistence was
reported by Ricci et al. with this approach.(100)

Half dose PDT: Dose of verteporfin is reduced to half (3mg/m2)
with standard fluence of light energy (50J/cm2). Wong et al found
that half-dose PDT combined with ranibizumab was highly successful in treating
single small polyp PCVs, but it appeared to be less effective if there were BVN
and/or multiple polyps were present.(101)


Anti-VEGF agents

1.2.1 Role of VEGF in PCV

VEGF may play an important role in the development of
PCV. Its increased expression has been found in excised CNV specimens in the
vascular endothelial cells and RPE cells in PCV eyes by Matsuoka et al.(102) Also elevated levels of VEGF and PEDF have been found
in aqueous samples of patients with active PCV by Tong et al.(39) PEDF and VEGF may modulate the formation of subfoveal
fibro-vascular membranes. Therefore, it is believed that anti-VEGF therapy may
play a potential role in the treatment of PCV.

1.2.2 Effect of anti-VEGF therapy

The anti-permeability property of anti-VEGF agents
probably plays a role in reducing the exudation from abnormal choroidal vessels
and polyps, thereby decreasing the subretinal fluid and preserving vision.(103–111) In most of the studies done for evaluating their
role, 3 monthly injections were followed with as needed intravitreal anti-VEGF
injection. Their safety and tolerability is proved in these studies over
variable follow up, ranging from 3months to 2years.(104,105,111) They cause resolution of subretinal haemorrhage,
decrease in macular oedema and stabilisation of vision in 80% to 100% of the

Conbercept is the most recent anti-VEGF agent used in
the management of PCV.(112) Similar to Aflibercept, it also binds to all isoforms
of VEGF-A, PLGF and VEGF-B. But its affinity is higher than all other anti-VEGF
agents. Safety and efficacy of both 0.5mg and 2mg dose of Conbercept have been
shown in a retrospective study of PCV patients from the landmark AURORA study.(112)


1.2.3 Limitations of anti-VEGF

Polyps and BVN persist in majority of eyes despite repeated
injections of anti-VEGF agents. In short term studies, Lai et al. and Kokame et
al. reported persistence of polyps in 100% eyes treated with Bevacizumab and 67%
eyes treated with Ranibizumab respectively. Chhablani et al. reported
persistence in 33% eyes treated with Bevacizumab at 9 months follow up. In a
large prospective study done over 2 years using Ranibizumab, Hikichi et al.
found that polyp resolution occurred in 40% and 25% eyes at 1 year and 2 year
respectively. BVN on the other hand persisted in all eyes at 1 year and increased
in size at 2 year follow up.

While using Aflibercept, Hosokawa et al. reported
polyp regression in 77% eyes at 6months, which is greater than reported using
other agents. In a large retrospective study over 1 year, Yamamoto et al. noted
polyp regression in 55% eyes but BVN regressed in size in only 13.4% eyes. In
another retrospective study over 1 year duration, Hara et al. noted polyp
resolution in 66% eyes at 3 months and additional resolution in 13.8% eyes at 1
year. However polyps recurred at 1 year in 26% eyes which had complete
resolution at 3 months. In a prospective study (EPIC) by Kokame et al. with
follow up of 6 months, polyp regression was noted in 67% and BVN regression only
in 4.8% eyes.(113)

Incomplete regression of polyps has also been observed
with the use of most potent anti-VEGF agent Conbercept in PCV.(112) Complete regression was noted in only 56.5% of
patients in 0.5-mg group and 52.9% of those in 2.0-mg group in this study.

From these studies, it can be determined that  in eyes presumed to have AMD where response
to anti-VEGF therapy is suboptimal, diagnosis should be reconsidered and PCV
should be ruled out on ICGA.(114)

1.2.4 Choice of anti-VEGF treatment

No studies have proved the superiority of a particular
anti-VEGF agent in PCV. Cho et al. did a retrospective review to compare the
effect of intravitreal ranibizumab and bevacizumab in 121 PCV eyes followed
till 12 months.(115) They found no significant difference in visual
improvement, reduction in CMT, and regression of polyps between the groups.
Polyps regressed only in 23.3% and 24.2% of eyes in ranibizumab and bevacizumab
groups respectively.

Aflibercept carries certain advantages over
Bevacizumab and Ranibizumab like greater binding affinity for VEGF, longer intravitreal
half-life, and capacity to antagonize additional factors such as PLGF. A few
studies have examined the role of Aflibercept in PCV patients who developed
tachyphylaxis to Ranibizumab and advocated switching to Aflibercept in cases
refractory to other agents.(116,117)

1.2.5 Indications of anti-VEGF

Anti-VEGF agents may be useful in eyes with exudative
changes and polyps with minimal or no activity.(81) They may also be considered in cases where polyps are
not clearly visible in ICGA and therefore PDT cannot be undertaken. In these
cases, the polyps might be visualised in repeat imaging after resolution of
subretinal fluid and/or macular hemorrhage.


Combination therapy of PDT and anti-VEGF agents

1.3.1 Rationale of combination

The combination therapy uses together the thrombotic
property of PDT and anti-permeability property of anti-VEGF agents to cause
regression of polypoidal lesions and reduce subretinal exudation respectively.(72) PDT alone has some limitations like subretinal hemorrhage
and up regulation of VEGF which causes secondary CNV formation and PCV
recurrence. Anti-VEGF agents used alone have low polyp regression rates and
negligible effect on BVN. However, if used along with PDT these can probably suppress
the pro angiogenic activity and result in lesser complications than PDT
monotherapy alone. 

1.3.2 Effect of combination therapy

Numerous studies have found superior results with
combination therapy than monotherapy alone.(75,104,118–121) The landmark study among these is EVEREST study. It
was a multicenter ICGA-guided RCT of 61 symptomatic treatment naive PCV cases treated
with verteporfin PDT monotherapy, 0.5 mg ranibizumab monotherapy, or a
combination of these treatments. Both combination therapy and PDT monotherapy
were superior to ranibizumab monotherapy in polyp regression at 6 months (77.8%
vs. 71.4% vs. 28.6% respectively).(75) Also the combination therapy had most favourable BCVA
and retinal thickness at the end of 6 months.

In a retrospective study of 146 PCV eyes by Gomi et
al., polyp resolution and recurrence rates were similar with combined PDT and
bevacizumab treatment compared with PDT monotherapy.(118) But combined therapy group had significantly faster
visual recovery and better final visual outcome than the monotherapy group at
all visits till 12 months. In another retrospective study comparing combination
therapy with ranibizumab monotherapy in 57 cases by Saito et al, combination
group had better vision gain at 2 years as compared to PDT alone (+2.63 line versus
?0.16 lines).(120) Combined therapy group did not develop any subretinal
hemorrhage compared to 25% patients in the PDT group. Combination therapy also
reduced the number of PDT sessions over 24 months as compared to PDT alone (1.4
versus 2.6).


1.3.3 Limitations of combination therapy

The benefits of treatment with combination therapy are
short lived. The initial visual improvement starts to diminish after 6 to 12
months and final visual improvement at 2 years is not significantly better than
baseline.(122–124) It is believed by some authors that the synergistic
effect of combination therapy gets reduced if PDT application is performed days
after anti-VEGF injection (half life of the drug).

The combined therapy does not fare well in terms of
visual gain in already treated eyes with PDT. In a study of 27 cases who had
received PDT monotherapy prior to combination treatment, Tomita et al reported
that the mean BCVA deteriorated from baseline at 12 months.(125)

BVN tends to persist following combination treatment
as well. BVN may also enlarge over time despite treatment and cause recurrence
of polyps at their terminal ends.(126)

The optimal protocol is also not defined for
combination treatment with variable drugs and/or regimen used in most of the
studies. Also the full fluence PDT carries inherent side effects which can be
reduced with RF-PDT as seen in a few small case series.(127,128) In this regard large RCT needs to be done to evaluate
the non-inferiority and/or benefits of RF-PDT over FF-PDT.


1.4. Comparison of PDT and anti-VEGF

1.4.1 EVEREST study

The landmark EVEREST study concluded that PDT is more
effective than intravitreal Ranibizumab in achieving polyp regression (71.4%
vs. 28.6%; P < 0.01).(75) The visual outcome was not significantly different in the two groups; however it was better in the ranibizumab monotherapy group than in the PDT monotherapy group (mean change in BCVA, 7.5 ± 10.6 PDT, and 9.2 ± 12.4 ranibizumab). 1.4.2 LAPTOP study As the visual outcomes were not significantly superior with any of the treatment arms in the EVEREST study, LAPTOP study was undertaken to address this issue. It was a prospective multicenter RCT of 93 treatment naive PCV patients comparing PDT versus Ranibizumab. At 12 months, intravitreal ranibizumab was superior to PDT monotherapy in achieving visual gain.(95) In PDT arm, 17.0% achieved visual acuity gain, 55.3% had no change, and 27.7% had visual acuity loss. These were 30.4%, 60.9%, and 8.7%, respectively in the ranibizumab arm, significantly better than the PDT arm (p value= 0.039). Both the treatment options reduced the retinal thickness significantly. The results were reciprocated at 24 months as well.(129) From these studies, it can be concluded that although PDT can efficiently induce regression of polypoidal lesions, the same may not be implied to the visual outcome. 3 monthly injections followed by as-needed injections of ranibizumab can achieve better final visual outcomes than PDT alone.   1.5 Thermal laser photocoagulation Thermal laser photocoagulation has been used in several studies for the treatment of extrafoveal symptomatic PCV.(12,130,131) These have used either argon green (514 nm) laser or double-frequency neodymium-doped yttrium aluminium garnet (Nd: YAG) or diode (532 nm) laser. The laser can be applied to the polyps as well as any associate BVN detected in ICGA. Feeder vessel identification on ICG video-angiography can help in precise target identification and treatment.(132) Significant visual improvement is reported with near complete regression of peripapillary polyps and significant regression in macular polyps.(12) However, the treated area develop a chorioretinal scar and causes scotoma. Other limitations are recurrent or persistent exudation from the polypoidal lesion, RPE tears, worsening of or development of new subretinal or sub-RPE hemorrhage, and secondary CNV. For these reasons, the outcomes are less favourable in sub-foveal lesions. Therefore thermal laser photocoagulation is reserved for symptomatic PCV with lesions located far away from the fovea.   1.6 Triamcinolone acetonide A few authors have evaluated the role of intravitreal or subtenon triamcinolone acetonide (TA) in PCV.(133–136) It is believed that TA decreases the size of polyps and reduces exudation.  It also decreases the severity of choriocapillaris occlusion if used along with PDT.(134) Following trans-tenon retro bulbar injections of 12mg TA, Okubo et al. noted reduction in the size of the polyp and complete resolution of SRF.(133) Nakata et al compared PDT monotherapy with a combination therapy of PDT, intravitreal bevacizumab and intravitreal TA (triple therapy) and found visual gain in significantly higher number of eyes in triple therapy arm at 24 months (41.7% vs. 12.5%).(135) Triple therapy arm also had reduced retreatment rates and post-treatment vitreous hemorrhage than PDT monotherapy arm. On the other hand, Lai et al found no visual improvement but rather increased risk of cataract formation and ocular hypertension with additional intravitreal TA in PCV eyes treated with PDT.(136) Therefore till further large scale studies demonstrate its efficacy and safety in PCV, TA should not be used as a routine treatment.     2.    Surgical management for submacular hemorrhage PCV often presents with recurrent extensive submacular hemorrhage.(137) The retinal imaging (FFA and ICGA) cannot be of much help in such situations and therefore appropriate timely management with PDT is delayed. Subretinal or sub RPE blood damages the retinal photo-receptors by nutritional deprivation, iron toxicity, and mechanical shearing effect.(137) Hence its early removal is justified to prevent permanent visual loss. The surgical treatment for massive submacular hemorrhage (>4 disc area) in PCV is also unclear. Published techniques in
literature include pneumatic displacement with intra-vitreal gas alone or in
combination with adjuncts like intra-vitreal recombinant tissue plasminogen
activator (r- tPA)/ anti-VEGF agent.(137–139)

Pneumatic displacement can be tried within 10 to 14
days of onset of bleed. Either sulphur hexafluoride (SF6) or perfluoropropane
(C3F8) gas can be used for this purpose followed by prone position for 2 weeks
duration. Not only intravitreal gas displaces the subretinal bleed, it also hastens
the absorption of sub RPE bleed by pressure effect.(139) In ideal situations, the bleed gets displaced in 1 or
2 weeks and FA/ICGA can then be performed. Thrombosed polypoidal lesions do not
require further treatment and patient can be monitored for resolution of bleed.
However, if leakage is present in presence of active polypoidal lesions, PDT
with or without anti-VEGF agents can be performed.

Chan et al. did a prospective interventional study of
6 PCV patients with extensive and thick submacular haemorrhage, which was
displaced pneumatically with intravitreal pure 0.4 ml C3F8.(137) This was later followed with PDT treatment at 1-2
weeks. A moderate visual gain was obtained in all patients with displacement of
bleed. No serious complications were noted at 1 year. Nayak et al. combined
intravitreal bevacizumab injection to pneumatic displacement in 3 eyes with PCV
related massive subretinal and sub RPE bleed and found that even sub RPE bleed
resolved with treatment.(139) Intravitreal r- tPA (50 to 100µg) is believed to
liquefy the subretinal clot and help in displacement of bleed.(138)

PCV patients have an increased risk of developing
vitreous hemorrhage after pneumatic displacement and intravitreal injection of
tissue plasminogen activator.(140) Other complications of the procedure include increase
in intraocular pressure, cataract in phakic eyes, and risk of infection,
iatrogenic retinal break, and retinal detachment.

Existing literature on the role of vitrectomy for subretinal
bleed in PCV is scarce.(141–143) Pars plana vitrectomy with a sub retinal
administration of r- tPA (50?g) and pneumatic displacement by intravitreal gas
with short-term facedown positioning can help in near complete displacement and
resolution of submacular bleeds. Furthermore, it also allows early treatment of
the polypoidal lesions by PDT with or without anti-VEGF injection. In a
prospective study of 20 patients with PCV and submacular hemorrhage who
received either subretinal tissue plasminogen activator (TPA) with vitrectomy
or intravitreal injection of TPA and gas, visual and anatomical results were
better in the vitrectomy arm.(143) Vitrectomy may also be needed in cases with
breakthrough vitreous hemorrhage, which may be de novo or following
intervention like PDT/ pneumatic displacement.

The technique of vitrectomy and subretinal injection
of r-tPA along with pneumatic displacement was described first by Haupert et
al. in wet AMD.(144) However, this technique
requires sequential treatment of the pathology after clearance of the bleed
rather than simultaneous treatment. Later Martel et al modified this technique
with subretinal injection of 0.4 ml of 12.5 µg/0.1 ml of rt-PA with bevacizumab
and air.(145) The subretinal air decreases the buoyancy of bleed
which facilitates its displacement and bevacizumab targets the underlying
pathology directly and simultaneously.

We routinely follow Martel’s technique for management
of submacular hemorrhage associated with PCV at out centre. 23 gauge vitrectomy
is followed by submacular injection of 0.4 ml r- tPA (12.5µg/0.1ml), 0.1ml
bevacizumab (2.5mg/0.1ml) and air (0.3ml). A 41G translocation needle is used
to create a localised neurosensory detachment over the subretinal bleed which
provides a potential space for the displacement of liquefied blood clot. 20%
SF6 is then injected into the vitreous cavity for tamponade and propped up
positioning is advised. The bleed usually gets displaced within week duration
with this procedure. No serious complications have been noted with the
procedure. The 41G needle creates a self sealing retinotomy and does not
increase the risk of rhegmatogenous retinal detachment and epiretinal membrane formation.



Practical management approach to PCV

Direct thermal photocoagulation may be considered for
extrafoveal symptomatic PCV lesions. For symptomatic juxtafoveal or subfoveal polyps,
full fluence or reduced fluence PDT with or without intravitreal anti-VEGF injection
should be considered. For symptomatic exudative changes without active polyps, anti-VEGF
monotherapy may be considered. Regardless of the treatment type, patients
should be monitored regularly with OCT, FFA and ICGA to assess the activity of
polyps, amount of subretinal exudation and to determine the need for
re-treatment. For refractory exudative lesions, a switch to a different
anti-VEGF agent may be effective.

For PCV with subretinal
hemorrhage larger than 4 disc area and presenting within 10-14 days of onset,
pneumatic displacement with intravitreal gas and tissue plasminogen activator can
be performed. Vitrectomy with subretinal injection of tissue plasminogen
activator may be considered as alternative in cases with massive subretinal
hemorrhage or breakthrough vitreous hemorrhage. Subsequently PDT with or
without anti-VEGF therapy can be performed in cases with active disease on
angiography. A long term follow up is required to identify complications of
treatment and early disease recurrence.

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