Vol, 28 No. 1 Jan-Feb, 2022

DOS TIMES

A diagrammatic comparison of DMEK and hemi-DMEK graft preparation. Note that while preparing the hemi-DMEK grafts, donor tissue is not
trephined. Hence, more endothelial cells are available and a single donor tissue can be used to harvest two grafts.

determine Descemet side of the graft, which is a crucial step of plane and only then SF6 is injected using a 3 ml syringe. The
DMEK or PDEK.[17] This technique also helps to visualize graft bubble must occupy 90% of the anterior chamber volume. This
orientation, apposition, folds in graft or fluid interface. Moving can be achieved by inserting a bubble with peripheral meniscus
the tip of endo-illuminator around the limbus tangentially, gives just 0.5-1 mm shy of limbus. Utmost care must be taken to avoid
excellent depth perception. inadvertent entry of SF6 behind the iris.
Techniques to unroll the DMEK graft
Air-pump assisted DSEK or DMEK This step is crucial to achieve correct graft orientation with
Classically, manual air insufflation using air injection from 30 G posterior endothelial side. Stromal Marking with gentian
syringe to provide tamponade intra-operatively for 10 minutes violet S-stamp has been used most commonly. Use of endo-
and massage to corneal surface to remove interface fluid is done. illuminators or handheld slit lamps has also gained popularity
Vitreo-retinal surgical system can also be used following this air recently. However, unrolling the graft may still be challenging.
injection to provide continuous air pump to maintain IOP at 30 The most desirable condition is a loose scroll, so called ‘‘lazy
mm Hg for 15 minutes with occasional spikes of 50 mm Hg.[18] graft” which opens with just a few taps. However, in most cases,
Then this air is exchanges with Balanced salt solution and a re- the scroll is not so “lazy” and opens endothelium-up, this can
sidual air bubble of desired diameter is left in anterior chamber be checked by Moutsouris sign (when the graft is in double roll,
post-operatively. This technique ensures excellent tamponade to a tip of canula is inserted between them, if it appears blue, the
facilitate graft adherence. graft is in correct orientation). To open a stubborn scroll Dapena
with Dirisamer manoeuvre can be applied where a small air
Trochar Anterior Chamber Maintainer (TACM) bubble between a partially unfolded scroll is injected and then
An anterior chamber maintainer (ACM) is a very commonly two cannulas are used for unfolding.[21] Once, most of the graft is
used device amongst anterior segment surgeons. A new unfolded with a few small folds, Bubble bumping manoeuvre is
technique which amalgamates benefits of trochar canula and applied, after air injection in AC, gentle taps on corneal surface
ACM has recently been devised for air -fluid infusion in DSEK/ can unfold rest of the small folds.
DMEK.[19] This trochar has a shorter blade to avoid damage to
structures of AC and is inserted 1 mm away from limbus at 45 Need for Rebubbling
degree angle parallel to limbus and then rotated to enter just Rebubbling of AC is indicated in cases where more than 30%
above the iris plane and flush of canula is visible, then, trochar is of graft area is detached, or progressive detachment seen on
removed. The long, angulated scleral tunnel prevents any leakage follow-up visits with diffuse corneal edema. It can be done on slit
and stent of canula can be attached to infusion line. lamp using a 27G canula attached to a 43 inch IV tubing coupled
with a 5 ml syringe.
Use of 20% SF6 gas
Air injections provide a short duration of tamponade and in True Endothelial Cell (TenCell) Transplantation
cases, where a longer duration of tamponade is desired, 20% This novel technique transfers donor endothelial cells with
SF6 gas can be introduced in AC after complete unscrolling of only a Descemets carrier after host cornea is prepared by
graft.[20] The eye should no longer be hypotonos before injecting descemetorrhexis, no stromal roughening is required. A
the gas, so the BSS infusion is directed towards the pupillary

www.dosonline.org/dos-times 51
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

Tappin’s endothelial canula (Figure 3) is used to avoid donor Corneal Endothelial Reconstruction with Bioengineered
tissue scrolling and the donor sheet is transferred after making Cell Sheet
an 8 mm corneal incision.[22] This incision can either be sutured This technique is being studied in animal models and its
or a sutureless surgery with bioadhesive glue or photochemical success might pave a way of clinical transplantation of corneal
keratodesmos can be performed. endothelial cell on bioengineered sheets like spherically curved
gelatin hydrogel sheet (SCGS) prepared by the dehydrothermal
Figure 3 : Tappin’s endothelial canula with central port. Air is injected cross-linking method.
through the port to achieve donor endothelial cell sheet apposition to host Endothelial Cell Activation
cornea. ROCK is a serine/threonine protein kinase that is activated by
Rho and forms Rho/ROCK complex that regulates a variety
of cellular functions, such as cell proliferation, differentiation,
migration, contraction, and apoptosis. In 2009, it was found
that the use of a selective ROCK inhibitor, Y-27632, enhanced
corneal endothelial cell proliferation, promoted adhesion onto
a substrate, and suppressed apoptosis. Ripasudil was approved
in Japan in 2014 in an eye drop form to increase the outflow
of the aqueous humor as a treatment for glaucoma and ocular
hypertension. It has also been used for treatment of corneal
endothelial decompensation in a case of FECD with promising
results in a clinical research. (Figure 4)

(a) Pre-treatment (b) Post-treatment

Figure 4 : (a) Pre-treatment case of Fuch’s endothelial dystrophy (b) Post-treatment cornea of the same patient after use of Ripasudil.

Conclusion 4. Rita Mencucci, Eleonora Favuzza et al. Ultrathin Descemet stripping
The field of endothelial keratoplasty is rapidly evolving and automated endothelial keratoplasty versus Descemet membrane
newer techniques are changing the way we tackle corneal endothelial keratoplasty: a fellow-eye comparison. EyeVis (Lond.).
endothelial pathologies. This evolving horizon of endothelial 2020;7:25.
keratoplasty is making the treatment of corneal blindness more
widely available and more efficacious. We are at the precipice of 5. Vajpayee, Rasik B. Modification in Descemet-Stripping Automated
great innovations in the field of corneal endothelial rehabilitation Endothelial Keratoplasty “Hitch Suture” Technique. Cornea. 2006;
and the best is yet to come. 25 (9): 1060-1062.

References 6. Jodhbir S Mehta, Yong Ming Por. Comparison of Donor Insertion
Techniques for Descemet Stripping Automated Endothelial
1. Barraquer JI. Special method s in corneal surgery. In: King H Jr, Keratoplasty. Arch Ophthalmol. 2008;126(10):1383-1388.
McTique JW, ed s. The Cornea World Congress. Washington, DC:
Butterworths; 1965:586-604. 7. Brissette A, Conlon R. Evaluation of a New Technique for Preparation
of Endothelial Grafts for Descemet Membrane Endothelial
2. Melles GR, Eggink FA, Lander F, et al. A surgical technique for Keratoplasty. Cornea. 2015; 34(5): 557-559.
posterior lamellar keratoplasty. Cornea.1998;17(6):618-626.
8. Matthew JD, Jennifer RN. Corneal Higher-Order Aberrations in
3. John T. Selective tissue corneal transplantation: A great step forward Descemet Membrane Endothelial Keratoplasty versus Ultrathin
in global visual restoration. Expert Rev Ophthalmol 2006;1:5-7. DSAEK in the Descemet Endothelial Thickness Comparison Trial: A
Randomized Clinical Trial. Ophthalmology. 2019;7:946-957.

9. Heinzelmann S, Maier P. Visual outcome and histological findings

DOS Times - Volume 28, Number 1, January-February 2022 52 www.dosonline.org/dos-times

DOS TIMES

following femtosecond laser-assisted versus microkeratome-assisted 20. Siebelmann, Sebastian, Lopez Ramos et al. Graft Detachment Pattern
DSAEK. Graefes Arch Clin Exp Ophthalmo. 2013;251:1979–1985. After Descemet Membrane Endothelial Keratoplasty Comparing Air
Versus 20% SF6 Tamponade, Cornea.2018;37(7):834-839.
10. Bachmann BO, Laaser K, Cursiefen C et al (2010) A method to
confirm correct orientation of descemet membrane during descemet 21. Liarakos VS, Dapena I, Ham L, van Dijk K, Melles GRJ. Intraocular
membrane endothelial keratoplasty. Am J Ophthalmol 149:922-925. Graft Unfolding Techniques in Descemet Membrane Endothelial
Keratoplasty. JAMA Ophthalmol. 2013;131(1):29–35.
11. Michael Straiko, Mark Terry, Julia Talajic, David Davis-Boozer;
Descemet’s Membrane Endothelial Keratoplasty (DMEK) : Over- 22. Tappin, M. A method for true endothelial cell (Tencell) transplantation
stripping the graft bed promotes donor adherence. Invest. Ophthalmol. using a custom-made cannula for the treatment of endothelial cell
Vis. Sci. 2013;54(15):3079. failure. Eye. 2007; 21:775–779.

12. Fogla R, Thazethaeveetil IR. A Novel Technique for Donor Insertion 23. Okumura N, Koizumi N, Kay EP, Ueno M, Sakamoto Y, Nakamura
and Unfolding in Descemet Membrane Endothelial Keratoplasty, S, Hamuro J, Kinoshita. The ROCK inhibitor eye drop accelerates
Cornea. 2021;40(8): 1073-1078. corneal endothelium wound healing. S nvest Ophthalmol Vis Sci.
2013; 54(4):2493-502.
13. Aparna S. Patel, Jeffrey M. Intraoperative Optical Coherence
Tomography–Assisted Descemet Membrane Endothelial Keratoplasty Corresponding Author:
in the DISCOVER Study: First 100 Cases. American Journal of
Ophthalmology.2020;210:167-173. Dr. Alok Sati, MS
Department of Ophthalmology
14. Sarah Pizzuto, Jessica Weant, Natalie A Afshari, David Eveleth; Army Hospital (R&R), Subroto Park, Dhaula Kuan, New Delhi.
Accelerated regeneration of corneal endothelium after Descemet’s
stripping mediated by the engineered fibroblast growth factor
TTHX1114. Invest. Ophthalmol. Vis. Sci. 2021;62(8):797.

15. Lam FC, Baydoun L, Dirisamer M, Lie J, Dapena I, Melles GRJ. Hemi–
Descemet Membrane Endothelial Keratoplasty Transplantation: A
Potential Method for Increasing the Pool of Endothelial Graft Tissue.
JAMA Ophthalmol. 2014;132(12):1469–1473.

16. Özlem Evren Kemer, Emine Esra Karaca. Evolving Techniques and
Indications of Descemet Membrane Endothelial Keratoplasty. Turk J
Ophthalmol. 2021;51:381-392.

17. Soosan Jacob, Amar Agarwal et al. Endoilluminator–assisted
transcorneal illumination for Descemet membrane endothelial
keratoplasty: Enhanced intraoperative visualization of the
graft in corneal decompensation secondary to pseudophakic
bullous keratopathy. Journal of Cataract & Refractive
Surgery.2014;40(8):1332-1336.

18. Jacob S, Narasimhan S. Air Pump–Assisted Graft Centration, Graft
Edge Unfolding, and Graft Uncreasing in Young Donor Graft Pre-
Descemet Endothelial Keratoplasty, Cornea. 2017 ;36(8):1009-1013.

19. Hayashi T, Oyakawa I, Kato N. Techniques for Learning Descemet
Membrane Endothelial Keratoplasty for Eyes of Asian Patients with
Shallow Anterior Chamber. Cornea. 2017;36(3):390-393.

www.dosonline.org/dos-times 53
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

Recent advances in Pharmacotherapy for
Glaucoma

Jatinder Singh Bhalla[1], MBBS, MS, DNB, MNAMS, Kanika Jain[2], MBBS, MS, DNB, Satender Kumar Singh[2], MBBS, MS,
Ashwini Kulkarni[3], MBBS, Thory Prakash[3], MBBS, DO
1. Consultant & Academic Incharge, Department of Ophthalmology, Deen Dayal Upadhyay Hospital, Hari Nagar, New Delhi.
2. Senior Resident, Department of Ophthalmology, Deen Dayal Upadhyay Hospital, Hari Nagar, New Delhi.
3. Junior Residents, Department of Ophthalmology, Deen Dayal Upadhyay Hospital, Hari Nagar, New Delhi.

Introduction can be prevented by early diagnosis and timely appropriate
Glaucoma is a chronic progressive optic neuropathy caused management. The mainstay of treatment lies in strict IOP
by a group of ocular conditions, leading to damage of optic control primarily by medical management.[2,7] Multiple factors
nerve with functional loss of vision, the most common and aid poor adherence and failure in management of glaucoma
modifiable risk factor being raised intra-ocular pressure i.e. lack of education about the disease, poor communication
(IOP).[1] It is a leading cause of irreversible blindness and the between patient and doctor, lifelong follow-up, timely and
second leading cause of blindness worldwide.[2,3] Estimated repetitive evaluations, complex and multi-drug therapy, side
global burden of glaucoma is 76 million in 2020 and expected to effects of the glaucoma medications along with the preservatives
increase upto 111.8 million by 2040 majorly affecting the Asian used in them and financial constraints.[2,8,9]
and Africans.[2,4] Most common is open angle glaucoma (OAG) It is necessary to understand and assess the benefit-risk ratio
accounting for 70 percent of all the glaucoma.[2,5] of medical management to achieve the target pressure without
Axons of retinal ganglion cells (RGC) are damaged leading to hampering the health-related quality of life (HRQL) and im-
an early apoptosis irreversible vision loss.[6] As the disease is prove patient adherence. Hence the need for more research and
mostly asymptomatic it is often very late when the diagnosis is introduction of newer drugs/newer delivery agents with mild or
made. Permanent visual disability due to glaucoma although no side effects, better IOP lowering and neuroprotection.

Newer pharmacological agents

Pharmacological Agents Neurotrophic Agents

Innovative hypotensive drugs Antioxidative agents Neuroprotective Agents • Intravitreal GFs
• Memantine (CNTF, BDNF, NGF, GDNF)
• ROCK inhibitors • Ginkgo biloba extract • Topical NGF
• A1 receptor agonist • Resveratrol • Slow releasing implants
• SiRNA • Alpha-lipoic acid • Gene therapy (viral/non-
• Cannabinoids • Alpha luminol
• Latrunculin derivatives • Staniocalcine 1 viral vectors)
• BkCa ionic channel • Peptidomimetic ligands

modulators of TrKA
• Newer prostaglandin

analogues

A. Innovative hypotensive drugs contractility, proliferation, and apoptosis.[2] Rho‑associated
- ROCK inhibitors (RHO kinase inhibitors): The colied coil‑forming protein kinase (ROCK) regulates the actin-
Rho family consists of guanosine triphosphate‑binding protein myosin proteins that promote cellular contraction in smooth
which plays a vital role in regulating cell shape, motility, muscle and also promotes the production of extracellular matrix

DOS Times - Volume 28, Number 1, January-February 2022 54 www.dosonline.org/dos-times

DOS TIMES

proteins which are responsible for anchoring of cells to their the aqueous outflow resistance.
substrate. The trabecular meshwork (TM) cells’ contains smooth b) Improving optic nerve perfusion
muscle like properties and the resistance to aqueous drainage c) Retinal ganglion cell (RGC) protection and
is controlled by the contraction of cells of TM and production neuroprotection
of extracellular matrix components. ROCK inhibitors block d) Promoting RGC axon regeneration
the TM cell contraction and decrease the production of the e) As an anti-fibrotic agent in glaucoma surgery
extracellular matrix substance hence increasing the aqueous f) Increasing cell adhesion and proliferation of corneal
outflow thus reducing the IOP.[10] Mechanism of action of Rho endothelial cells thus helps in preservation of
kinase inhibitors is as follows: corneal endothelial cells and slowing of apoptosis
a) Decreasing IOP by causing relaxation of the smooth g) Anti inflammatory properties
muscle cells in the trabecular meshwork, thus the

Compound Mechanism of IOP Lowering Dosing Adverse Events Market Status
Ripasudil Action
Rho kinase 2.6 mmHg at trough; Twice daily Conjunctiva l hyper- Available in Japan as
inhibitor 3.7 mmHg at peak emia (75%); blepharitis Glanatec (Ripasudil
(21%); allergic conjunc- 0.4%, Kowa Compa-
Netarsudil Rho kinase − 3.3 to − 5.0 mmHg Once daily tivit is (17%) ny, Ltd,
inhibitor and (ROCKET-1); Conjunctiva l hyper- Nagoya, Aichi, Japan)
NET − 3.3 to − 4.6 mmHg emia (50–53%); since 2014 Available
(ROCKET-2) conjunctival hemor- in India as Ripatec
rhage (13%); corneal (Ripasudil 0.4%)
Netarsudil+ Fixed drug Additional Once daily verticillata (9%) Ajanta pharma
Latanoprost combination, − 1.9 Available in the
Rho kinase mmHg vs. Conjunctiva l hyper- USA as Rhopressa
inhibitor+NET+ latanoprost; emia (40%) (netarsudil 0.02%,
PG analogue additional − 2.6 Aerie Pharmaceu-
mmHg vs. netarsudil ticals, Bedminster,
NJ, USA) since 2017
Available as Netalo in
Delhi
RHOPRESSA can
be made available
Mumbai, Kolkata,
Hyderabad, Chennai,
Ahmedabad, Delhi,
Bangalore and Pune
by Indian Phar-
ma Network after
fulfilling the legal
requirement (if
applicable)
Recent FDA
approval (2019)
in the USA as Rocla-
tan™ (Netarsudil
0.02% / latanoprost
0.005%), Aerie
Pharmaceuticals

Table 1 : Rock Inhibitors: Overview

• Ripasudil (Figure 1) - was approved in Japan for the has the International Union of Pure and Applied Chemistry (IU-
treatment of glaucoma and ocular hypertension (OHT) in Sep- PAC), name being 4-fluoro-5-(((2S)-2-methyl-1,4-diazepan-1-
tember 2014. Ripasudil, also known as K-115 from various clin- yl)sulfonyl)isoquinoline. It has shown to lower IOP within two
ical trials, with the chemical formula of C15H18FN3O2S and hours of instillation, and was proven to do so consistently over

www.dosonline.org/dos-times 55
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

a period of a full year. Phase 1 and phase 2 clinical trials (Mono
drug), demonstrated Ripasudil (0.4%) twice daily provided re-
duction of 2 to 4.4 mmHg of IOP from the baseline.[11-13] Phase
3 trial demonstrated Ripasudil (0.4%) when used along with
Timolol Maleate (0.5%) twice daily gave an additional lowering
in IOP of 0.9 to 1.6 mmHg. The most common side effect was
conjunctival hyperemia which was observed in all the phases of
clinical trial.[14]

Figure 2 : Netarsudil 0.02% eye drops

Figure 1 : Ripasudil 0.4% eye drops

• Netarsudil (Figure 2,3)- It is a Rho kinase inhibitor Figure 3 : Netarsudil 0.02% eye drops by aerie pharmaceuticals
and norepinephrine transporter (NET) inhibitor which was ap-
proved in 2017 in a 0.02% concentration, as a one drop per day
for use in United States of America for management of glauco-
ma and OHT. Netarsudil, known as AR-13503 in clinical trials,
has the chemical formula of C28H27N3O3 and has the IUPAC
name of (4-((1S)-1-(Aminomethyl)-2-(isoquinolin-6-ylamino)-
2-oxoethyl)pheny)methyl2,4- dimethylbenzoate. Netarsudil has
been shown to decrease IOP within two hours of instillation
and also to sustain this decrease for a 24-hour period after dos-
ing. It had a longer duration of action than few drugs in this
category.[15] Animal trials demonstrated additional decreased
aqueous humour production and decreased episcleral venous
pressure.[16,17] In a clinical trial of single daily dose Netarsudil
(0.01% and 0.02%) an average of 5.5 and 5.7 mmHg IOP low-
ering from the baseline was noted. Conjunctival hyperemia, in-
creased lacrimation were few side effects of the drug. The study
concluded that if used with Latanoprost 0.005% it provided good
results. Also, the drug showed better results in patients with low-
er mean IOP from the baseline.[18]

DOS Times - Volume 28, Number 1, January-February 2022 56 www.dosonline.org/dos-times

DOS TIMES

The Rho Kinase Elevated IOP Treatment trials 1 and 2 (ROCK- - Adenosine receptor agonist (Figure 5): Various
ET-1 and ROCKET-2), phase three clinical trials, investigated physiological and biochemical pathways in the body are
safety and effectiveness relating to Netarsudil and Timolol in a facilitated through G protein‑coupled adenosine receptors.
sample of patients with elevated IOP. In a double-masked, rand- Secretion of matrix metalloproteins (MMP) in the endothelial
omized non-inferiority clinical trial, Netarsudil once a day and cells of TM is stimulated by these receptors leading to shrinkage
twice a day, produced significant lowering from baseline IOP, of cell volume and extracellular matrix remodeling, ultimately
which was non-inferior to Timolol (ROCKET-1 and 2) only in facilitating the conventional aqueous outflow.[2] Trabodenoson
patients with a baseline IOP < 25 mmHg. (INO8875) (Inotek Pharmaceuticals, USA) is a highly selective
In summary, netarsudil is likely most effective as an adjunctive adenosine A1 receptor agonist that causes an upregulation of
agent for patients already using other classes of IOP-lowering protease A and matrix metalloproteinase-2 (MMP-2) in target
medications and may be helpful as a first-line therapy for pa- cells. A phase 2 study on patients with POAG and OHT of
tients with normal tension glaucoma, as it has been shown to be Trabodenoson reported that it was well tolerated by the study
more effective for patients with lower baseline IOPs. group at a dose of 500 micrograms twice daily with no systemic
• Netarsudil 0.02% has been used in a fixed-dose combi- side effects. The average IOP lowering was 4.1 mmHg.[19]
nation (FDC) with Latanoprost 0.005%. This fixed-dose combi- - Small interference RNA (siRNA): siRNA are small
nation was recently approved by the US FDA in 2019 as Rocla- nucleotides that are able to interfere with mRNA translation
tan™ (PG324) (Aerie Pharmaceuticals) (Figure 4). In a phase II protein. Bamosiran is a naked double stranded siRNA, it acts
clinical trial over 28 days, this FDC was statistically superior to as a gene silencer and blocks the beta-2 adrenergic receptor
either of the two drugs alone. The FDC has significant increased thus decreases the aqueous production by the ciliary body. As
IOP lowering of -1.9 mmHg compared with Latanoprost and − the drug gets absorbed very quickly in the anterior chamber, no
2.6 mmHg compared with Netarsudil alone. In the Mercury 1 systemic absorption of the topical drug has not been reported
and Mercury 2 trials, patients were randomized to the FDC Ro- yet.[21] Phase 1 clinical have shown that 600 µg/eye/day of the
clatan™, Latanoprost 0.005%, and Rhopressa (netarsudil 0.02%), Bamosiran was well tolerated with 20% IOP reduction from
all dosed daily. Roclatan™ was superior to Latanoprost by 1.5–2.4 baseline. Few animal studies have also reported neuroprotective
mmHg and superior to Rhopressa by 2.2–3.3 mmHg across all properties as well.[10]
time points. A multicenter randomized placebo controlled parallel design
phase 2 trial of 89 patients revealed that 300 µg/eye/day caused
Figure 4 : Rocklatan Ophthalmic solution-Fixed dose combination of statistically significant IOP reduction and was well tolerated
Netarsudil 0.02% with Latanoprost 0.005% by 80% of the patients and only one serious complication of
hyponatremia was noted.[22]
- Cannabinoids: They not only reduce IOP but also pos-
sess neuroprotective properties as well.[10] The presence of can-
nabinoid receptor 1 was seen in the TM and ciliary epithelium.
They have a direct effect on the ciliary process and dilating blood
vessels contributing to its property of altering aqueous humor
dynamics. They also induce COX-2, PG E2 and MMP 1,3 and 9
expression adding to IOP reduction properties.[23]
- Nitrogen Mono-oxide (NO) donors: Nitric oxide
using cGMP initiates a series of events causing structural and
functional changes leading to overall relaxation of TM and
inner wall of Schlemm’s canal.[24] Latanoprostene bunod
(0.0024%) (LBN) (Figure 6) is a nitrous oxide donating
compound which is metabolized in situ and converted to
latanoprost acid and butanediol mono nitrate, a NO donating
species. It causes lowering of IOP by dual action of increasing
the uveoscleral outflow and causing the relaxation of TM and
SC leading to increased drainage of aqueous humor. Various
studies comparing the efficacy of LBN (0.024%) with Timolol
Maleate (0.5%) have been done. Studies like LUNAR and
APOLLO demonstrated that once daily dose of LBN (0.024%)
was not inferior to Timolol Maleate 0.5% and was well tolerated.
Another study VOYEGAR concluded that LBN 0.024% had
better IOP reduction than Latanoprost (i.e. 1mmHg more
than Latanoprost). Some newer drugs NCX 667 (Nicox) and

www.dosonline.org/dos-times 57
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

NCX 470 are also in the pipeline and undergoing animal being-conjunctival hyperemia (17.7%), growth of eyelashes
trial.[25-29] Overall, the adverse effect profile was found to be (16.2%), eye irritation (1105%), eye pain (10%) and increased in
similar to that of prostaglandin analogues, the most common iris pigmentation (9%).

Modulate aqueous humor
formation

Modulate outflow facility Adenosine / Adenosine Increase blood flow and
receptors system recovery of retinal function, and

neuroprotection

Modulate ion transport Modulate intraocular pressure
Figure 5 : Mechanism of action of Adenosine receptor agonist[20] Both values were significantly lower than treated baseline IOP
(p < 0.001).[31] Tumbocon JA et al. reported preservative free Taf-
luprost (0.0015%) to be safe and effective IOP lowering agent
in routine clinical setup. The study was conducted in 329 eyes
of 177 patients. Most common diagnosis was POAG (34.9%),
followed by primary angle-closure (PAC) glaucoma post-laser
iridotomy (24.0%), PAC post- laser iridotomy (15.5%), OHT
(14.6%), secondary glaucoma (6.7%), and normal-tension glau-
coma (4.3%). Mean IOP change at month 3 was 6.18 mmHg
(SD 4.06), a 26.37% reduction (p<0.001) and IOP reduction was
sustained throughout the study period. Conjunctival hyperemia
was noted in 15% patients in the study.[30]

Figure 6 : Vyzulta (Latanoprostene Bunod 0.024%) ophthalmic solution

- Newer Prostaglandin Analogues Figure 7 : Saflutan (Tafluprost 0.0015%) ophthalmic solution
1. Tafluprost 0.0015% (Figure 7): The mechanism of
action is same as that of Latanoprost and other drugs in this
class, but it has prostanoid FP-receptor affinity which is 12 times
greater than Latanoprost.[30] A study by Hommer et al. was done
in 544 patients to evaluate the efficacy and tolerability of pre-
servative free Tafluprost 0.0015%. The subjects were on antiglau-
coma drugs and Tafluprost was used as an adjunct therapy or
in combination with pre-existing treatment. The study found
that preservative free Tafluprost 0.0015% caused significant re-
duction in IOP from baseline. In 79.5% eyes IOP ≤ 18 mmHg
was achieved. An overall reduction of IOP in all patients (N =
544) from 19.4 +/- 5.0 mmHg at baseline to 15.7 +/- 4.1 mmHg
after 4 to 6 weeks and to 15.3 +/- 3.5 mmHg after 12 weeks.

DOS Times - Volume 28, Number 1, January-February 2022 58 www.dosonline.org/dos-times

DOS TIMES

2. Unoprostone (Figure 8): IOP-lowering docosanoid isopropyl (PF-04217329) is EP2agonist. ONO-9054 has dual ac-
and belongs to the family of lipid IOP-lowering agents. It is tion of being an EP3 agonist and FP receptor agonist.
commercially available as Unoprostone Isopropyl (0.012%)
ophthalmic solution. According to new research it acts on BK B. Antioxidants
channels which, upon activation cause cell hyperpolarization. Under stressful conditions like OHT/glaucoma there are mi-
Endothelin-1 (ET-1) in the TM induce contractility of cells cro-alterations in the blood ocular barrier as well as there is
which is mediated via glutamate-associated increase in intra- transient and prolonged ischemia this results in release of in-
cellular Ca2+. Through BK channel activation, unoprostone flammatory factors and free radicals which further leads to glau-
is believed to block this increase in intracellular Ca2+ in TM comatous neurodegeneration. The free radicals generated may
cells leading to increased trabecular meshwork outflow and IOP directly or indirectly damage the astrocytes and muller cells of
reduction.[32] Unoprostone typically lowers IOP by 10%–25% the retina further causing NMDA receptor hyperactivity sec-
from baseline, with a duration of effect of 2–5 hours.[33] Sponsel onded by retinal ganglion cell cytotoxicity. Mitochondrial dys-
et al[34] compared the IOP-lowering and hydrodynamic effects of function induced due to ischemia may also lead to RGC viabil-
Unoprostone and Latanoprost in 25 patients with OAG or OHT. ity. Reducing the oxidative stress could be helpful in achieving
After one month of therapy, both agents produced significant neuroprotection. Antioxidants like alpha-luminol, Ginkgo bilo-
reductions in IOP and increased pulsatile ocular blood flow, al- ba extracts, Resveratrol, Stanniocalcine-1 and alpha-lipoic acid
though the changes seen with Latanoprost were nearly two-fold have been evaluated in mouse models, proving to be effective in
greater than those seen with Unoprostone, which was statisti- RGC protection.[23]
cally significant. Nordmann et al[35] conducted double-masked, C. Neuroprotective agent (Memantine)
randomized trial of 556 patients with glaucoma or OHT receiv- It is a receptor antagonist for NMDA and acts by blocking the
ing either Unoprostone, Betaxolol, or Timolol twice daily for 6 exocytotoxic process mediated by glutamate.[36] It prevented
months, found similar mean diurnal IOP-lowering efficacy be- retinal ganglion cell loss in animal trials but in human trials the
tween Betaxolol and Unoprostone. results were not very satisfying when compared to the placebo
When used as adjunct therapy with Timolol it has shown to pro- group.[23]
vide an additional 2-3 mmHg fall in IOP.
D. Neurotrophic agents
Figure 8 : Rescula (Unoprostone 0.15%) ophthalmic solution
CiliaryNeurotrophicFactor(CNTF),BrainDerivedNeurotrophic
Prostanoid Receptor Agonist Factor (BDNF) Neurotrophic Factors, Neuronal Growth Factor
Recently EP2, EP3 receptors have emerged as new targets of (NGF) and the Glial cell line-Derived Neurotrophic Factor
interest for IOP lowering. These cause relaxation of endotheli- (GDNF) are produced by cells within the retina. In chronic
al cells in the Schlemm’s canal, facilitating uveoscleral outflow. conditions the intrinsic growth factors are not enough and can
They also increase convectional outflow by acting on the trabec- be administered via exogenous route.[23] intravitreal injections
ular meshwork, decreasing cell contractility and collagen depo- of 5 micrograms of BDNF and 2 µg of CNTF have reduced the
sition. DE-117 (Santen Pharmaceutical, Japan) and Taprenepag death of RGC in animal models by 8 and 22% respectively after
1 month, but the effect was not sustained and the need of
repetitive inject was required. Another study reported that
topical administration of NGF QID for 7 weeks increases the
density of ganglion cells by 37%. Functional improvements
detected with electroretinography, visual evoked potentials
and computerized visual field is doubtful as it was carried out
in small number of patients and in the absence of a control
group.[37-39] The gene therapy approach to elevate endogenous
retinal production of neurotrophic factors prevents the
undesirable complications and problems associated with the
in vivo delivery, showing good efficacy in pre-clinical trials.
Furthermore, research is required for development of this
approach to get desirable results with minimal side-effects.[40]
Newer Drug delivery systems
Conventional glaucoma therapy may be associated with many
constraints such as issues of compliance, availability, cost of
therapy, ocular side effects of the drugs or preservatives in them,
difficulty in sustained IOP control for 24 hours. In an effort to
circumvent these challenges, several new alterative medication
delivery systems have been studied.

www.dosonline.org/dos-times 59
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

1. Intracameral Sustained Release Implants to vasodilatation and not inflammation) and miosis, both of
which tended to diminish as the implant degraded over time.
- Bimatoprost Intracameral Implant (Figure 9) The implant appears to have increased efficacy in reducing IOP
Durysta (Allergan plc, Dublin, Ireland) has received FDA ap- as compared to topical therapy probably related to implant
proval for humans with OAG and OHT in March 2020. It is a achieving a 4,400 fold higher drug concentration in iris-ciliary
400 X 1100 micron rod shaped implant, supplied pre-load- body. It may also cause long lived anatomic or physiological re-
ed for intracameral injection in a 28G customized applica- modeling of outflow pathway that persists after the drug is no
tor. The bioerodible implant contains 10ug of Bimatoprost longer present. This might explain why in phase I/II and III
which is released in a steady sustained fashion for 3-4 months. human clinical trials, 28-36% of patients still had not required
This implant is well tolerated and visible only on goniosco- topical IOP lowering rescue medication or implant retreatment
py in inferior angle. Bimatoprost associated effects included 2 years after a single administration of implant even though the
dose related mild to moderate conjunctival hyperemia (due implant was depleted of drug long ago.[41-43]
- Travoprost Intracameral Implant
iDose Travoprost (Figure 10): Developed by Glaukos (San
Clemente, CA, USA) is an indwelling depot device to provide
sustained release of Travoprost to the anterior segment for pe-
riods of 6 months or longer. It is implanted by ab interno pro-
cedure placed in tandem with phacoemulsification. It is 1.8mm
X 0.5mm titanium implant designed to be anchored within
trabecular meshwork. It is currently recruiting patients for
phase III trials and interim results have been reported from a
double masked phase II clinical trial in human patients where-
by patients receiving it experienced 32-33% IOP reduction at 1
year.[44,45]

Figure 9 : Durysta- Bimatoprost intracameral implant

Figure 10 : idose Travoprost intracameral implant

ENV515: Developed by Envisia Therapeutics (Morrisville, NC, is to be placed in fornix and circumferentially contacts the
USA), is a biodegradeable intracameral Travoprost implant. It conjunctival surface. It contains 13mg of Bimatoprost which
was found to be well-tolerated, and rests stably in the inferior diffuses directly into the tear film. In a 6 month phase II clinical
angle. In human clinical trials, a single implant lowered IOP study of patients with OAG or OHT, the mean reduction of
by 25% over 11 months with no loss of efficacy during this IOP was comparable between eyes receiving the ring and a
period.[46,47] placebo non drug loaded device combined with 0.5% Timolol
eye drops BD. Mucoid discharge is the most common side effect
- Bimatoprost Topical Ring Insert (Figure 11) followed by conjunctival hyperemia, punctuate keratitis and
Developed by Allergan (Irvine, CA, USA), it is a preservative pruritis.[48]
free flexible ring ranging from 24-29mm in diameter which

DOS Times - Volume 28, Number 1, January-February 2022 60 www.dosonline.org/dos-times

DOS TIMES

Figure 11 : Bimatoprost topical ring insert

- Travoprost Punctal Plugs (Figure 12) been incorporated in contact lenses for sustained drug delivery.
OTX-TP intracanalicular Travoprost implant by Ocular These also have been tried as an adjuvant to glaucoma drainage
Therapeutix (Bedford, MA, USA) are placed into inferior devices to decrease fibrosis.
nasolacrimal canaliculus that releases drug to the ocular surface
via an inferior punctum for 2-3 months. However, it was not
found to be superior to Timolol in phase IIB clinical trials and
didn’t reach its primary endpoint in phase III human clinical
trials.[49,50]

- Contact Lens Based Drug Delivery
Silicon hydrogel soft contact lenses loaded with nanoparticle
thereby the drug diffuses from lens into tear fil increasing bi-
oavailability potential by 50% as against topical formulations
(1-5% bioavailability). Silicon hydrogel soft contact lenses con-
taining Timolol elutes the drug for more than a month in animal
models.[51]

Figure 13 : Timoptic XE, a Ph sensitive hydrogel formulation of Timolol
that turns from a solution to gel when it comes in contact with cations
in tear film, thereby enhancing the drug delivery to the ocular surface-
Nanoparticle based technology.

Figure 12 : Travoprost punctal plugs Conclusion
Glaucoma is the leading cause of irreversible blindness severely
- Nanoparticles affecting the quality of life. Its timely diagnosis and management
These are 10-1000nm sized bioinert, biodegradeable and mu- is even more difficult due to lifelong treatment and poor
coadhesive polymers that serve as the vehicles for drug delivery. patient adherence. Various drugs for glaucoma management
Timoptic XE (Figure 13), a Ph sensitive hydrogel formulation in the pipeline are undergoing trial few of which have shown
of Timolol that turns from a solution to gel when it comes in promising results either as monotherapy, adjunct therapy or in
contact with cations in tear film, thereby enhancing the drug de- combination with older drugs. These results have provided a
livery to the ocular surface.[52] Nanoparticle technology has also ray of hope that glaucoma management wouldn’t be a tedious
process for the patient and improvement in compliance to
treatment can be seen. Many novel drug delivery approaches

www.dosonline.org/dos-times 61
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

are in development with the aim to improve the effectiveness of venous pressure in Dutch belted rabbits. J Ocul Pharmacol Ther.
therapy, patient adherence, and elimination of issues associated 2015;31:146e151.
with traditional self administered drops. However, long term
trials are definitely the way forward to establish the safety and 17. Sit AJ, Kazemi A, McLaren JW, et al. The effects of Netarsudil
efficacy of these modalities incorporating the cost-benefit ratio ophthalmic solution on aqueous humor dynamics in humans. Invest
of these. Ophthalmol Vis Sci. 2017;58:2112.

References 18. Bacharach J, Dubiner HB, Levy B, et al. Double-masked, randomized,
dose-response study of AR-13324 versus latanoprost in patients with
1. Sihota R, Tandon R. Parson’s disease of the eye. 22nd edition. New elevated intraocular pressure. Ophthalmology. 2015;122:302e307.
Delhi: Reed Elsevier India Private Limited;2015.
19. Myers JS et al. Twice daily dose of Trabodenoson may lower IOP in
2. Kadambi SV, George R. Newer drugs in glaucoma management. glaucoma patients. J Ocul Pharamcol Ther.2016.
TNOA J Ophthalmic Sci Res 2017;55:134-9.
20. Zhong Y, Yang Z, Huang WC, et al. Adenosine, adenosine receptors
3. Quigley HA, Broman AT. The number of people with glaucoma and glaucoma: An updated overview. Biochimica et Biophysica Acta
worldwide in 2010 and 2020. Br J Ophthalmol 2006;90:262‑7. (BBA) - General Subjects, Volume 1830, Issue 4, April 2013, Pages
2882-2890.
4. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY, et al.
Global prevalence of glaucoma and projections of glaucoma burden 21. Martínez T, González MV, Roehl I, Wright N, Pañeda C, Jiménez
through 2040: A systematic review and meta‑analysis. Ophthalmology AI, et al. In vitro and in vivo efficacy of SYL040012, a novel siRNA
2014;121:2081‑90 compound for treatment of glaucoma. Mol Ther 2014;22:81‑91.

5. Feldman RM, Cioffi GA, Liebman MJ et al. Current Knowledge 22. Gonzalez V, Palumaa K, Turman K, et al. Phase 2 of bamosiran
and Attitudes Concerning Cost- Effectiveness in Glaucoma (SYL040012), a novel RNAi based compound for the treatment of
Pharmacotherapy: A Glaucoma Specialists Focus Group Study; increased intraocular pressure associated to glaucoma. Investigative
Clinical Ophthalmology 2020:14 729–739 Ophthalmology & Visual Science April 2014, Vol.55, 564.

6. Devalla SK, Liang Z,Pham TH, et al. Glaucoma management in the 23. Nuzzi R and Tridico F. Glaucoma: Biological trabecular and
era of artificial intelligence Br J Ophthalmol 2019;0:1–11. neuroretinal pathology with perspectives of therapy innovation and
preventive diagnosis. Front. Neurosci. 2017 11:494.
7. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein
M,et al. Reduction of intraocular pressure and glaucoma progression: 24. Gabelt BT, Kaufman PL. Production and flow of aqueous humor. In:
Results from the early manifest glaucoma trial. Arch Ophthalmol Levin LA, Nilsson SFE, Ver Hoeve J, et al, eds. Adler’s Physiology of
2002;120:1268‑79. the Eye. 11th ed. St. Louis: Mosby Elsevier; 2011:274–307.

8. Gibbons FM, Berlin MS, and Toteberg-Harms M. Influence of 25. Weinreb RN, Sforzolini BS, Vittitow J, et al. Latanoprostene bunod
new treatment modalities on adherence in glaucoma. Curr Opin 0.024% versus timolol maleate 0.5% in subjects with open-angle
Ophthalmol 2019, 30:104–109 glaucoma or ocular hypertension: the APOLLO study. Ophthalmology.
2016;123:965–973.
9. Schwartz GF, Quigley HA. Adherence and persistence with glaucoma
therapy. Surv Ophthalmol 2008;53 Suppl 1:S57‑68 26. Medeiros FA, Martin KR, Peace J, et al. Comparison of Latanoprostene
bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma
10. Bucolo C, Platania CBM, Drago F et al. Novel Therapeutics in or ocular hypertension: the LUNAR study. Am J Opthalmol.
Glaucoma Management. Current Neuropharmacology, 2018, 16, 2016;168:250–259.
978-992.
27. Weinreb RN, Ong T, Sforzolini S, for the VOYAGER study group.
11. Tanihara H, Inoue T, Yamamoto T, et al. Phase 1 clinical trials A randomised, controlled comparison of latanoprostene bunod and
of a selective Rho kinase inhibitor, K-115. JAMA Ophthalmol. latanoprost 0.005% in the treatment of ocular hypertension and open
2013;131:1288e1295. angle glaucoma: the VOYAGER study. Br J Ophthalmol. 2015;99:738–
745.
12. Tanihara H, Inoue T, Yamamoto T, et al. Phase 2 randomized
clinical study of a Rho kinase inhibitor, K-115, in primary open- 28. Bastia E, Impagnatiello F, Ongini E, et al. Repeated dosing of NCX
angle glaucoma and ocular hypertension. Am J Ophthalmol. 667, a new nitric oxide (NO) donor, retains IOP-lowering activity in
2013;156:731e736. animal models of glaucoma. Invest Ophthalmol Vis Sci. 2017;58:2106.

13. Tanihara H, Inoue T, Yamamoto T, et al. Intra-ocular pressure- 29. Antipolis S. Nicox provides clinical and regulatory update for NCX
lowering effects of a Rho kinase inhibitor, ripasudil (K-115), over 470 for IOP lowering. January 24, 2017. Available at: http://www.
24 hours in primary open-angle glaucoma and ocular hypertension: nicox.com/newsmedia/ nicox-provides-clinical-regulatory- update-
a randomized, open-label, crossover study. Acta Ophthalmol. ncx-470-iop-lowering-2/. Accessed April 10, 2020
2015;93:e254ee260.
30. Tumbocon JA, Macasaet AM. Efficacy and safety of tafluprost 0.0015%
14. Tanihara H, Inoue T, Yamamoto T, et al. Additive intraocular – retrospective analysis of real-world data from the Philippines. Clin
pressure-lowering effects of the rho kinase inhibitor ripasudil (K- Ophthalmol. 2019;13:1627-1634.
115) Combined with timolol or latanoprost: a report of 2 randomized
clinical trials. JAMA Ophthalmol. 2015;133:755e761. 31. Hommer A, Mohammed Ramez O, Burchert M, Kimmich F. IOP-
lowering efficacy and tolerability of preservative-free tafluprost
15. Sturdivant JM, Royalty SM, Lin C-W, et al. Discovery of the ROCK 0.0015% among patients with ocular hypertension or glaucoma. Curr
inhibitor netarsudil for the treatment of open-angle glaucoma. Bio org Med Res Opin. 2010 Aug;26(8):1905-13.
Med Chem Lett. 2016;26:2475e2480.
32. Fung DS, Whitson JT. An evidence-based review of unoprostone
16. Kiel JW, Kopczynski CC. Effect of AR-13324 on episcleral isopropyl ophthalmic solution 0.15% for glaucoma: place in therapy.
Clin Ophthalmol. 2014 Mar 10;8:543-54.

DOS Times - Volume 28, Number 1, January-February 2022 62 www.dosonline.org/dos-times

DOS TIMES

33. Camras CB, Alm A. Initial clinical studies with prostaglandins and 46. Navratil T, Garcia A, Tully J. Preclinical evaluation of ENV515
their analogues. Surv Ophthalmol. 1997;41(Suppl 2):S61–S68. (Travoprost) intracameral implant- clinical candidate for treatment of
glaucoma targeting six month duration of action. Invest Ophthamol
34. Sponsel WE, Paris G, Trigo Y,et al. Comparative effects of latanoprost Vis Sci.2014;55:3548-13548.
(Xalatan) and unoprostone (Rescula) in patients with open-angle
glaucoma and suspected glaucoma. Am J Ophthalmol. 2002;134:552– 47. Navratil T, Garcia A, Verhoeven RS, et al. Advancing ENV515
559. (Travoprost) intracameral implant into clinical development: non
clinical evaluation of ENV515 in support of first time in human phase
35. Nordmann JP, Mertz B, Yannoulis NC, et al. for the Unoprostone 2a clinical study. Invest Ophthamol Vis Sci.2014;55:3548-13548.
Monotherapy Study Group- EU A double-masked randomized
comparison of the efficacy and safety of unoprostone with timolol and 48. Brandt JD, Sall K, DuBiner H, et al. six month intraocular pressure
betaxolol in patients with primary open-angle glaucoma including reduction with a topical bimatoprost ocular insert: results of a phase
pseudoexfoliation glaucoma or ocular hypertension. 6-month data. II randomized controlled study. Ophthalmol 2016;123:1685-94.
Am J Ophthalmol. 2002;133:1–10
49. Diehl KA, Bowden AC, Knudsen D. Bandage contact lens retention in
36. Hare, W. A., and Wheeler, L. Experimental glutamatergic dogs- a pilot study. Vet Ophthalmol.2019;22:584-90.
excitotoxicity in rabbit retinal ganglion cells: block by memantine.
Invest. Ophthalmol. Vis. Sci. 2009; 50, 2940–2948. 50. Lin MM, Ciolino JB, Pasquale LR. Novel glaucoma drug delivery
devices. Internatl Ophthalmol Clin 2017;57:57-71.
37. Ko ML, Hu DN, Ritch R, et al. The combined effect of brain-derived
neurotrophic factor and a free radical scavenger in experimental 51. Jung HJ, Abou- Jaoude M, Carbia BE, Plummer C, Chahan A.
glaucoma. Invest. Ophthalmol. Vis. Sci. 2000; 41, 2967– 2971. Glaucoma therapy by extended release of timolol from nanoparticle
loaded silicone-hydrogel contact lenses. J Control Release 2013.
38. Ko ML, Hu DN, Ritch R, et al. Patterns of retinal ganglion cell
survival after brain-derived neurotrophic factor administration in 52. Weng Y, Liu J, Jin S, Guo W, Liang X, Hu Z. Nanotechnology based
hypertensive eyes of rats. Neurosci. Lett. 2001; 305, 139– 142. strategies for trearment of ocular disease. Acta Pharmaceutica Sinia
B.2017;7:281-91.
39. Lambiase A, Aloe L, Centofanti M, et al. Experimental and clinical
evidence of neuroprotection by nerve growth factor eye drops: Corresponding Author:
implications for glaucoma. Proc. Natl. Acad. Sci. U.A.S. 2009;106,
13469–13474. Dr. Jatinder Singh Bhalla, MBBS, MS, DNB, MNAMS
Consultant & Academic Incharge, Department of Ophthalmology
40. Nafissi N, Foldvari M. Neuroprotective therapies in glaucoma: I. Deen Dayal Upadhyay Hospital, Hari Nagar, New Delhi.
Neurotrophic factor delivery. WIREs Nanomed. Nanobiotechnol.
2016; 8, 240–254.

41. Allergan, Inc., Irvine CA (US), Robinson MR, Burke JA, Schiffman RM,
Ghebremeskel AN. Intracameral sustained release therapeutic agent
implants. US Patent application publication no.: US2020/0121593 A1
April 23,2020.

42. Shen J, Robinson MR, StrubleC, Attar M. Nonclinical pharmcokinetic
and pharmacodynamic assessment of Bimatoprost following a single
intracameral injection of sustained- release implants. Trans Vis Sci
Tech. 2020;9:20.

43. Seal JR, Robinson MR, Burke J, Benjamin M, Coote M, Attar
M. Intracameral sustained release Bimatoprost implant delivers
Bimatoprost to target tissues with reduced drug exposure to oo-target
tissues/ J Ocul Pharmacol Ther.2019;35:50-7.

44. Dick HB, Schultz T, Gertse RD. Miniaturization in glaucoma
monitoring and treatment: a review of new technologies that require
a minimal surgical approach. Ophthalmol Therapy.2019;8:19-30.

45. Mitch Ibach O. Travoprost eluting drug delivery device shows pomise.
Optometry Times.2019;11-9.

www.dosonline.org/dos-times 63
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

Multimodal Imaging in Polypoidal
Choroidal Vasculopathy : An Integrated
Approach to Diagnosis

Lalit Verma, MD, Ritesh Narula, MS, Yusra Asad, MS
Centre for Sight, New Delhi.

Abstract: Polypoidal choroidal vasculopathy (PCV) is an important cause of visual loss in the elderly and although
it is considered as a subtype of neovascular AMD type I, it may not always respond adequately to the conventional
anti-VEGF therapy. An accurate and timely diagnosis of PCV, thus, becomes paramount. This article describes risk
factors, epidemiology, diagnostic criteria and features of PCV on various imaging modalities such as spectral-domain
optical coherence tomography (SDOCT), indocyanine green angiography (ICGA), fluorescein angiography (FA),
OCT- angiography and multicolor imaging. Treatment options for PCV include focal laser therapy, verteporfin
photodynamic therapy, anti-VEGF monotherapy and combination therapy, and treatment of each patient needs to
be customized on case to case basis. 

Introduction Cigarette smoking is the most consistent risk factor both in
typical AMD and PCV.[14-17] Studies also report females having a
Polypoidal choroidal vasculopathy (PCV) is an important lower risk for both typical AMD and PCV.[16,18] Also, higher body
cause of visual loss in the elderly, and is characterized by the mass index and raised serum levels of C-reactive protein were
presence of polypoidal or aneurysmal lesions with or without a known to increase the risk for both typical AMD and PCV.[14,16,19]
branching vascular network (BVN) in the choroidal vasculature In terms of ocular risk factors, a hyperopic shift was observed
as seen on indocyanine green angiography (ICGA).[1] Although both in typical AMD and PCV compared with the controls.[14]
it is considered to be a subtype of neovascular AMD type I, However, the association with the other systemic factors such
significant variations in the epidemiologic, clinical, imaging as diabetes mellitus, hypertension, hyperlipidemia, stroke, and
features and natural history between PCV and typical AMD coronary artery disease were inconsistent.
have been reported.[2,3] The main genetic risk factors for both PCV and neovascular
Epidemiology and Risk Factors AMD include polymorphisms in CFH and HTRA1 genes,
and they might interact with other additional genetic and
PCV is seen more commonly in pigmented races, that is, environmental factors such as smoking status.[20-22]
Asians and African-Americans compared to Caucasians. The
prevalence of PCV among patients diagnosed with neovascular Clinical Characteristics
AMD is as high as 24.5% to 54.7% in the Chinese and Japanese
population, respectively, 49% in the Taiwanese and 24.6% in the PCV often presents as serous or hemorrhagic pigment ep-
Korean populations compared to 4% to 9.8% in Caucasians.[4-10] ithelial detachment (PED) with or without subretinal
The mean age at presentation ranges between 60 and 72 years,[11] hemorrhage.[23,24] PCV can be clinically classified into quies-
earlier than that for AMD.[12] In a study by Anantharaman et cent, exudative, or hemorrhagic types. In quiescent PCV, there
al.,[13] the mean age in the Indian population was 61.06 years is an absence of intraretinal fluid, subretinal fluid, or retinal
(41–80), comparable to other published reports.[11] Interestingly, or subretinal hemorrhage. Quiescent PCV is asymptomat-
PCV is more commonly seen in males in the Asian population, ic and is usually identified incidentally or in the fellow eye of
whereas in Caucasians it is more common in females (75%).[11] PCV patients. Exudative PCV presents with exudation owing
PCV is seen bilaterally in 21%–55% Caucasian population, but to leakage from active polyps and/or BVN but without hemor-
<20% Asians have bilateral disease.[11] The study on the Indian rhage, along with serous pigment epithelial detachment (PED),
population also revealed a male predilection with M:F ratio of subretinal fluid, subretinal lipid exudation, and thickening of
1.4:1 and bilateral involvement in 17.8% of patients.[13] the neurosensory retina with intraretinal fluid. Hemorrhag-
The locations of polyps also vary among the Asians and ic PCV is characterized by subretinal or sub-retinal pigment
Caucasians. The polyps are seen in the macular region in 92% of epithelium (RPE) hemorrhage with or without exudation.[25]
Asians, with an even distribution of polyps in the macular and (Figure 1) The hemorrhage can vary in size and can sometimes
peripapillary location among the Europeans.[11] be massive covering the entire macula and can even result in
breakthrough vitreous hemorrhage.[1]

DOS Times - Volume 28, Number 1, January-February 2022 64 www.dosonline.org/dos-times

DOS TIMES

beneath the Bruch’s membrane can be seen in the early phase of
ICGA.[30] (Figure 2) A study by Cheung et al., evaluated fundus
camera-based and confocal scanning laser ophthalmoscope-
based ICGA systems and found that both systems were able
to detect >80% of PCV, however, the confocal scanning
laser ophthalmoscope (CSLO) is superior in detecting the
BVN.[31] Although ICGA plays an important role in the diagnosis
of PCV, it is invasive, time-consuming, and requires specific
equipment, which may not be available in some ophthalmology
clinics or hospitals. Other alternative imaging modalities might
be useful to help in differentiating PCV from neovascular AMD
or other retinal diseases.[1]

Figure 1 : A) Small orange subretinal nodule (blue arrow) seen in a case of
PCV without the presence of any serous or hemorrhagic PED (quiescent).
B) Large serous PEDs along with some intraretinal exudation with small
areas of subretinal and sub-RPE hemorrhage. C) Intraretinal exudation
(blue arrow) seen disproportionate to the size of serous PED in a case of
PCV. D) Large areas of subretinal hemorrhage sparing the macula along
with the presence of subretinal and intraretinal fluid.

Diagnosis of PCV Figure 2 : FFA (left) and ICGA (right) frames of a case of PCV showing
a very early appearance of branching vascular networks on ICGA with
Diagnostic Criteria: There are 2 diagnostic criteria based on polypoidal lesions (blue arrow) appearing at the ends of BVN in early
ICGA established for PCV: the Japanese Study Group of PCV frames and persisting through the late frames. Dilated choroidal vessels
and the EVEREST study group.[26-29] can also be noted. Corresponding FA shows mottled hyper fluorescence
in early frames with leakage on late frames. Note the difference in the size
Japanese Study Group Guidelines of leakage on FFA as compared to the size of lesions and affected area on
ICGA.
Definite PCV: Elevated orange-red lesions on fundus
examination, and/or Polypoidal lesions on ICGA.
Probable PCV: Only abnormal BVN seen on ICGA or recurrent
hemorrhagic or serous RPE detachments, or both, without
features of definite PCV.
EVEREST criteria (Based on Confocal Scanning Laser
Ophthalmoscopy)

Focal hyperfluorescent lesions appearing before 6 minutes on
ICGA, plus at least 1 of the following:
1. BVN on ICGA
2. Pulsatility on dynamic ICGA
3. Nodular appearance when ICGA viewed stereoscopically
4. Hypofluorescent halo on ICGA
5. Orange subretinal nodule on colour photograph (CFP)
6. Associated massive submacular haemorrhage (>4 disc
areas)
Indocyanine Green Angiography(ICGA)

This is the gold standard for diagnosis of PCV as also seen by
the diagnostic criteria defined above. Single or multiple vascular
aneurysmal lesions along with branching vascular networks

www.dosonline.org/dos-times 65
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

Spectral Domain Optical Coherence OCT Angiography
Tomography(SDOCT) OCT angiography (OCTA) is a relatively new non-invasive
Characteristics of PCV on SDOCT include features of polyp- imaging tool that allows visualization of retinal and choroidal
oidal lesions such as sharply peaked PED, ‘thumb-like’ protru- vasculature by detecting blood flow inside the vascular lumen
sions, PED notch, hyperreflective ring underneath PED with a through segmentation of images into different layers without
hyporeflective lumen, and feature of BVN: the double layer sign the use of angiographic dye.[32] Several studies have compared
(a thin separation between the RPE and Bruch membrane) with the use of OCTA and ICGA in the detection of polyps and BVN
thickened choroid (often >300um) and sometimes focal cho- and have shown ICGA to be comparable or slightly superior
roidal excavation.[1] (Figure 3) Presence of such features should to OCTA in the detection of BVN.[33-35] Although polyps with
alert a clinician to the possibility of PCV even in populations cluster-like structures and flow signals within the polypoidal
where PCV prevalence is low or ICGA is not performed rou- lesions could be detected on OCTA, the sensitivity of OCTA
tinely. In addition to assisting the diagnosis of PCV, SD OCT is in the detection of polyps was lower.[34,35] Possible reasons for
also useful in monitoring the changes in subretinal fluid, PED, an incomplete detection rate of polypoidal lesions with OCTA
or both after therapy. The presence of subretinal fluid and intra- are signal attenuation from overlying structures and low blood
retinal fluid are markers of active exudative activity and often flow speed within the polyps.[1] Therefore, with the present
correlate to areas of leakage on fluorescein angiography (FA).[1] technology, OCTA is unable to replace ICGA in the assessment
of PCV.
Figure 3 : A) SD-OCT scan of a PCV patient demonstrating a Fluorescein Angiography
sharply peaked PED (blue arrow) with the presence of subretinal Owing to the sub-RPE location of PCV lesions, FA commonly
fluid and intraretinal exudation. B) Notched PED (blue arrow) on demonstrates that the majority of PCV eyes will have an occult
SD-OCT which was later found to be corresponding to the location choroidal neovascularization (CNV) pattern of leakage and only
of a polyp on ICGA. C) Multiple PEDs with the presence of a a small proportion will have a classic CNV leakage pattern on
hypo reflective lumen (blue arrow) on the undersurface of a PED. FA.[36,37] Compared with the features on CFP and SD-OCT, FA
D) Small PED with a hypo reflective lumen along with the presence of the features have relatively lower accuracy in differentiating PCV
‘double layer’ sign (blue arrow). from neovascular AMD or CSC.[38]
Furthermore, greater leakage with fluorescein dye, compared
with ICGA, makes the lesions of PCV visualized on FA appear
larger than those visualized on ICGA. (Figure 2) Therefore,
if FA is used as guidance for the use of PDT in PCV, an
unnecessarily larger spot size may be applied.[39] However, FA
may be superior to ICGA for detecting and monitoring leakage
of BVN.[1]
Multicolour Imaging
Multicolor imaging is a novel imaging modality in which
reflectance images from 3 different wavelengths are obtained
simultaneously.[40] The combination of 3 reflectance images
results in a pseudo-color image. A study by Tan et al has
evaluated the features of PCV on multicolor imaging and results
demonstrated that polypoidal lesions were most clearly seen
on infrared reflectance (IR) images, in which they appear as
dark gray oval lesions with distinct margins.[41] On multicolor
composite images, polypoidal lesions appear as dark green oval
lesions. For BVNs, they appeared as mottled gray areas on IR
imaging and were seen less frequently compared with polypoidal
lesions.[41] Another study compared the use of multicolor imaging
and CFP in detecting PCV lesions and results suggested that
both investigations were comparable in the detection of PCV
lesions and multicolor imaging may therefore be considered as
an alternative to CFP.[42]
Management of PCV
The provision of optimal treatment for PCV patients is largely
dependent on the accurate diagnosis of PCV and differentiation

DOS Times - Volume 28, Number 1, January-February 2022 66 www.dosonline.org/dos-times

DOS TIMES

of PCV from other macular diseases. ICGA remains the gold Administration for the treatment of neovascular AMD based on
standard in the diagnosis of PCV, while SD-OCT is useful to findings from the phase 3 HAWK and HARRIER studies.[69] In a
determine the activity of PCV as shown by the presence of subanalysis of the HAWK study which evaluated the treatment
SRF, intraretinal fluid, and/or PED. On some occasions, the outcomes of Japanese participants with PCV, robust BCVA gains
polypoidal lesions might not be visible at the initial clinical or were observed across all treatment arms, confirming the efficacy
ICGA assessments, and PCV is only diagnosed during the later of anti-VEGF monotherapy using brolucizumab and aflibercept
course of the disease process. Therefore, in neovascular AMD for both typical neovascular AMD and PCV patients.[70]
cases non-responsive to anti-VEGF therapy, ICGA should Combination Therapy
be repeated to reassess the patients for a possible diagnosis of
PCV. After decades of research, currently, a wide spectrum of The EVEREST-I study was the first randomized controlled
treatment options are available for the treatment of PCV. trial in PCV that compared the efficacy and safety of IVT-R
Focal Laser Therapy monotherapy, PDT monotherapy, and combination therapy with
IVT-R and PDT in 61 patients.[27] The primary endpoint was
Focal laser long has been used to ablate extrafoveal and polyp regression based on ICGA results at month 6. The results
extramacular polyps identified on ICGA.[43-49] Stabilization or demonstrated PDT alone or combined with IVT-R achieved
even improvement of vision has been described in these reports. a significantly higher polyp regression rate (71.4% and 77.8%,
However, limitations include scarring and recurrence. respectively) compared with IVT-R monotherapy (28.6%).
Verteporfin Photodynamic Therapy(vPDT) Despite the lower polyp closure rate, IVT-R monotherapy
achieved higher visual gain than PDT monotherapy (9.2 letters
The use of vPDT as monotherapy showed less favorable long vs. 7.5 letters), although the difference was not statistically
term visual outcomes with other concerns including the per- significant.
sistence of the BVN[50,51] and rare incidences of complications, EVEREST-II compared IVT-R monotherapy with combination
including subretinal hemorrhage, choroidal infarction, and RPE therapy of IVT-R plus PDT at baseline,[71] whereas PLANET
tear.[52-56] Modifications to the settings of PDT, like a limitation compared IVT-AFL monotherapy with or without rescue PDT,
of spot size to include only active polyps, but not the BVN,[57] which was available after 3 months.[72] Both studies reported
and reduced-fluence PDT,[58,59] have been proposed to reduce the significant visual acuity gain in the anti-VEGF monotherapy
frequency of these rare adverse events. arms at 1 year (5.1 letters in EVEREST-II; 10.8 letters in
Anti-VEGF Monotherapy PLANET). Polyp closure rates were 34.7% (EVEREST-II) and
38.9% (PLANET).
Early studies suggested that despite a limited polyp regression In addition to combination therapy performed at baseline,
rate with anti-VEGF monotherapy (25%-40%),[60-63] anti-VEGF the deferred combination has been evaluated in the FUJISAN
monotherapy has favorable visual outcomes. Pivotal clinical study,[73] which compared the outcomes of initial or deferred
trials in typical neovascular AMD have shown that anti-VEGF PDT combined with IVT-R. The study reported similar BCVA
therapy has now superseded PDT as the first line of therapy.[64-66] and polyp closure outcomes at 1 year between patients with
The PEARL studies consisted of 2 open-label studies of PCV initial PDT and those with deferred PDT. With this approach,
using monthly IVT-R 0.5 mg (PEARL 1 study) or 2.0 mg more than half of the patients in the deferred arm (17 of 31
(PEARL 2 study). In both studies, significant improvement in patients) did not require PDT, although patients in this arm had
mean BCVA was accompanied by a reduction in subretinal significantly more injections (3.8 vs. 1.5 injections in addition to
hemorrhage, subretinal fluid, or both.[67] 3 loading doses).
The LAPTOP study is a phase 4 prospective, multicenter, Conclusion
randomized trial comparing the effect of PDT and intravitreal
Ranibizumab (IVT-R) in PCV using a pro re nata(PRN) Polypoidal choroidal vasculopathy, believed to be a subtype of
retreatment regimen. At both month 12 and month 24, patients neovascular AMD type I, could be an important cause of visual
in the IVT-R arm achieved better visual outcomes than patients loss in the elderly not responding to conventional anti-VEGF
in the PDT arm.[68] However, angiographic results were not therapy for AMD. It is seen more commonly in pigmented races
evaluated in these studies. as compared to Caucasians, along with a male predilection seen
Another anti-VEGF agent, aflibercept, also has been approved in Asians. It occurs at a younger age as compared to AMD with
for the treatment of typical neovascular AMD. The efficacy of cigarette smoking being the most risk factor for both.
intravitreal aflibercept (IVT-AFL) administered every 8 weeks Clinically, it presents as a serous or hemorrhagic PED with or
after 3 monthly loading doses in neovascular AMD has been without subretinal hemorrhage and can be either of quiescent,
demonstrated in the VIEW studies,[66] which compared the exudative or hemorrhagic type. The most definitive investigation
efficacy and safety of IVT-AFL and IVT-R in patients with for making a diagnosis of PCV is ICGA, however, the other
neovascular AMD among whom 29 eyes were confirmed to have noninvasive imaging modalities like OCT, OCTA, CFP can
PCV (33%). be of immense use for potential diagnostic features as also for
Brolucizumab was recently approved by the US Food and Drug following up of therapeutic benefit.

www.dosonline.org/dos-times 67
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

Treatment of PCV is mainly based upon correct diagnosis and and age-related macular degeneration in Chinese persons.
individual features on OCT and ICGA along with presenting Ophthalmology 2011; 118:846–852.
visual acuity and hence needs to be decided on an individual
basis. Although intravitreal anti-VEGF are currently the 16. Kikuchi M, Nakamura M, Ishikawa K, et al. Elevated C-reactive
mainstay of treatment, combination therapy with vPDT can be protein levels in patients with polypoidal choroidal vasculopathy
of benefit on case to case basis depending upon the availability and patients with neovascular age-related macular degeneration.
and accessibility to ICGA and verteporfin and bearability of the Ophthalmology 2007; 114:1722–1727.
burden of multiple injections.
17. Laude A, Cackett PD, Vithana EN, et al. Polypoidal choroidal
References vasculopathy and neovascular age-related macular degeneration:
same or different disease? Prog Retin Eye Res 2010; 29:19–29.
1. Cheung CMG, Lai TYY, Ruamviboonsuk P, Chen SJ, Chen Y, Freund
KB, Gomi F, Koh AH, Lee WK, Wong TY. Polypoidal Choroidal 18. Meng Q, Huang L, Sun Y, et al. Effect of high-density lipoprotein
vasculopathy: definition, pathogenesis, diagnosis, and management. metabolic pathway gene variations and risk factors on neovascular
Ophthalmology. 2018;125(5):708–724. age-related macular degeneration and polypoidal choroidal
vasculopathy in China. PloS One 2015; 10:e0143924.
2. Wong CW, Yanagi Y, Lee WK, et al. Age-related macular degeneration
and polypoidal choroidal vasculopathy in Asians. Prog Retin Eye Res. 19. Hong T, Tan AG, Mitchell P, Wang JJ. A review and meta-analysis of
2016;53:107-139. the association between C-reactive protein and age-related macular
degeneration. Surv Ophthalmol 2011; 56:184–194.
3. Cheung CM, Li X, Mathur R, et al. A prospective study of treatment
patterns and 1-year outcome of Asian age-related macular 20. Liang XY, Chen LJ, Ng TK, Tuo J, Gao JL, Tam PO, et al. FPR1
degeneration and polypoidal choroidal vasculopathy. PLoS One. interacts with CFH, HTRA1 and smoking in exudative age-related
2014;9(6):101057. macular degeneration and polypoidal choroidal vasculopathy. Eye
(Lond) 2014;28:1502–10.
4. Liu Y, Wen F, Huang S, Luo G, Yan H, Sun Z, et al. Subtype lesions
of neovascular age-related macular degeneration in chinese patients. 21. Ng TK, Liang XY, Lai TY, Ma L, Tam PO, Wang JX, et al. HTRA1
Graefes Arch Clin Exp Ophthalmol. 2007;245:1441–5. promoter variant differentiates polypoidal choroidal vasculopathy
from exudative age-related macular degeneration. Sci Rep.
5. Maruko I, Iida T, Saito M, Nagayama D, Saito K. Clinical 2016;6:28639.
characteristics of exudative age-related macular degeneration in
Japanese patients. Am J Ophthalmol. 2007;144:15–22. 22 Fan Q, Cheung CMG, Chen LJ, Yamashiro K, Ahn J, Laude A, et al.
Shared genetic variants for polypoidal choroidal vasculopathy and
6. Chang YC, Wu WC. Polypoidal choroidal vasculopathy in Taiwanese typical neovascular age-related macular degeneration in East Asians.
patients. Ophthalmic Surg Lasers Imaging. 2009;40:576–81. J Hum Genet. 2017;62:1049–55

7. Byeon SH, Lee SC, Oh HS, Kim SS, Koh HJ, Kwon OW, et al. Incidence 23. Sho K, Takahashi K, Yamada H, Wada M, Nagai Y, Otsuji T, et al.
and clinical patterns of polypoidal choroidal vasculopathy in Korean Polypoidal choroidal vasculopathy: Incidence, demographic features,
patients. Jpn J Ophthalmol. 2008;52:57–62. and clinical characteristics. Arch Ophthalmol. 2003;121:1392–6.

8. Lafaut BA, Leys AM, Snyers B, Rasquin F, De Laey JJ. Polypoidal 24. Yannuzzi L, Sorenson J, Spaide R, Lipson B. Idiopathic polypoidal
choroidal vasculopathy in caucasians. Graefes Arch Clin Exp choroidal vasculopathy (IPCV) Retina. 1990;10:1–8.
Ophthalmol. 2000;238:752–9.
25. Koh AH, Chen LJ, Chen SJ, Chen Y, Giridhar A, et al. Expert PCV
9. Ladas ID, Rouvas AA, Moschos MM, Synodinos EE, Karagiannis Panel. Polypoidal choroidal vasculopathy: Evidence-based guidelines
DA, Koutsandrea CN, et al. Polypoidal choroidal vasculopathy and for clinical diagnosis and treatment. Retina. 2013;33:686–716.
exudative age-related macular degeneration in Greek population. Eye
(Lond) 2004;18:455–9. 26. Japanese Study Group of Polypoidal Choroidal Vasculopathy.
[Criteria for diagnosis of polypoidal choroidal vasculopathy]. Nippon
10. Scassellati-Sforzolini B, Mariotti C, Bryan R, Yannuzzi LA, Giuliani Ganka Gakkai Zasshi. 2005;109(7): 417-427.
M, Giovannini A, et al. Polypoidal choroidal vasculopathy in Italy.
Retina. 2001;21:121–5. 27. Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety of
verteporfin photodynamic therapy in combination with ranibizumab
11. Imamura Y, Engelbert M, Iida T, Freund KB, Yannuzzi LA. Polypoidal or alone versus ranibizumab monotherapy in patients with
choroidal vasculopathy: A review. Surv Ophthalmol. 2010;55:501–15. symptomatic macular polypoidal choroidal vasculopathy. Retina.
2012;32(8):1453-1464.
12. Sho K, Takahashi K, Yamada H, Wada M, Nagai Y, Otsuji T, et al.
Polypoidal choroidal vasculopathy: Incidence, demographic features, 28. Tan CS, Ngo WK, Chen JP, et al. EVEREST study report 2: imaging
and clinical characteristics. Arch Ophthalmol. 2003;121:1392–6. and grading protocol, and baseline characteristics of a randomised
controlled trial of polypoidal choroidal vasculopathy. Br J Ophthalmol.
13. Anantharaman G, Ramkumar G, Gopalakrishnan M, Rajput A. 2015;99(5):624-628.
Clinical features, management and visual outcome of polypoidal
choroidal vasculopathy in Indian patients. Indian J Ophthalmol. 29. Cheung CM, Laude A, Wong W, et al. Improved specificity of
2010;58:399–405. polypoidal choroidal vasculopathy diagnosis using a modified
EVEREST criteria. Retina. 2015;35(7):1375-1380.
14. Woo SJ, Ahn J, Morrison MA, et al. Analysis of genetic and
environmental risk factors and their interactions in Korean patients 30. Spaide RF, Yannuzzi LA, Slakter JS, Sorenson J, Orlach DA.
with age-related macular degeneration. PLoS One 2015; 10:e0132771. Indocyanine green videoangiography of idiopathic polypoidal
choroidal vasculopathy. Retina 1995; 15:100–110.
15. Cackett P, Yeo I, Cheung CM, et al. Relationship of smoking and
cardiovascular risk factors with polypoidal choroidal vasculopathy 31. Cheung CM, Lai TY, Chen SJ, et al. Understanding indocyanine
green angiography in polypoidal choroidal vasculopathy: the group
experience with digital fundus photography and confocal scanning

DOS Times - Volume 28, Number 1, January-February 2022 68 www.dosonline.org/dos-times

DOS TIMES

laser ophthalmoscopy. Retina 2014; 34:2397–2406. 49. Spaide RF, Yannuzzi LA, Slakter JS, et al. Indocyanine green
videoangiography of idiopathic polypoidal choroidal vasculopathy.
32. Spaide RF, Klancnik JM, Jr, Cooney MJ. Retinal vascular layers Retina. 1995;15(2):100-110.
imaged by fluorescein angiography and optical coherence tomography
angiography. JAMA Ophthalmol. 2015;133:45–50. 50. Byeon SH, Lee SC, Oh HS, et al. Incidence and clinical patterns
of polypoidal choroidal vasculopathy in Korean patients. Japan J
33. Tomiyasu T, Nozaki M, Yoshida M, Ogura Y. Characteristics of Ophthalmol. 2008;52(1):57-62.
polypoidal choroidal vasculopathy evaluated by optical coherence
tomography angiography. Invest Ophthalmol Vis Sci. 2016;57:324– 51. Wakabayashi T, Gomi F, Sawa M, et al. Marked vascular changes of
30. polypoidal choroidal vasculopathy after photodynamic therapy. Br J
Ophthalmol. 2008;92(7):936-940.
34. Takayama K, Ito Y, Kaneko H, Kataoka K, Sugita T, Maruko R, et al.
Comparison of indocyanine green angiography and optical coherence 52. Lo Giudice G, De Belvis V, Piermarocchi S, et al. Acute visual loss and
tomographic angiography in polypoidal choroidal vasculopathy. Eye. chorioretinal infarction after photodynamic therapy combined with
2016;31:45–52. intravitreal triamcinolone. Eur J Ophthalmol. 2008;18(4):652-655.

35. Chan SY, Wang Q, Wang YX, Shi XH, Jonas JB, Wei WB. Polypoidal 53. Chan WM, Lam DS, Lai TY, et al. Photodynamic therapy with
choroidal vasculopathy upon optical coherence tomographic verteporfin for symptomatic polypoidal choroidal vasculopathy:
angiography. Retina. 2018;38:1187–94. one-year results of a prospective case series. Ophthalmology.
2004;111(8):1576-1584.
36. Gomi F, Sawa M, Mitarai K, Tsujikawa M, Tano Y. Angiographic
lesion of polypoidal choroidal vasculopathy on indocyanine green and 54. Akaza E, Yuzawa M, Matsumoto Y, et al. Role of photodynamic
fluorescein angiography. Graefes Arch Clin Exp Ophthalmol 2007; therapy in polypoidal choroidal vasculopathy. Jpn J Ophthalmol.
245:1421–1427. 2007;51(4):270-277.

37. Chaikitmongkol V, Khunsongkiet P, Patikulsila D, et al. Color 55. Kim SW, Oh J, Oh IK, Huh K. Retinal pigment epithelial tear
fundus photography, optical coherence tomography, and fluorescein after half fluence PDT for serous pigment epithelial detachment in
angiography in diagnosing polypoidal choroidal vasculopathy. Am J central serous chorioretinopathy. Ophthalmic Surg Lasers Imaging.
Ophthalmol 2018; 192:77–83. 2009;40(3):300-303.

38. Chaikitmongkol V, Kong J, Khunsongkiet P, et al. Sensitivity and 56. Klais CM, Ober MD, Freund KB, et al. Choroidal infarction
specificity of potential diagnostic features detected using fundus following photodynamic therapy with verteporfin. Arch Ophthalmol.
photography, optical coherence tomography, and fluorescein 2005;123(8):1149-1153.
angiography for polypoidal choroidal vasculopathy. JAMA
Ophthalmol 2019; 137:661–667. 57. Jeon S, Lee WK, Kim KS. Adjusted retreatment of polypoidal choroidal
vasculopathy after combination therapy: results at 3 years. Retina.
39. Gomi F, Sawa M, Mitarai K, et al. Angiographic lesion of polypoidal 2013;33(6):1193-1200.
choroidal vasculopathy on indocyanine green and fluorescein
angiography. Graefes Arch Clin Exp Ophthalmol. 2007;245(10):1421- 58. Yamashita A, Shiraga F, Shiragami C, et al. One-year results of
1427. reduced-fluence photodynamic therapy for polypoidal choroidal
vasculopathy. Am J Ophthalmol. 2010;149(3): 465-471.
40. Graham KW, Chakravarthy U, Hogg RE, Muldrew KA, Young IS,
Kee F. Identifying features of early and late age-relate4d macular 59. Yamashita A, Shiraga F, Shiragami C, et al. Two-year results of
degeneration: a comparison of multicolor versus traditional color reduced- fluence photodynamic therapy for polypoidal choroidal
fundus photography. Retina 2018; 38:1751–1758. vasculopathy. Am J Ophthalmol. 2013;155(1): 96-102.

41. Tan CS, Ting DS, Lim LW. Multicolor fundus imaging of polypoidal 60. Hikichi T, Higuchi M, Matsushita T, et al. Factors predictive of
choroidal vasculopathy. Ophthalmol Retina 2019; 3:400–409. outcomes 1 year after 3 monthly ranibizumab injections and as-
needed reinjections for polypoidal choroidal vasculopathy in Japanese
42. Tan ACS, Yanagi Y, Cheung GCM. Comparison of multicolor imaging patients. Retina. 2013;33(9):1949-1958.
and color fundus photography in the detection of pathological findings
in eyes with polypoidal choroidal vasculopathy. Retina 2019; [Epub 61. Ogino K, Tsujikawa A, Yamashiro K, et al. Intravitreal in- injection of
ahead of print]. ranibizumab for recovery of macular function in eyes with subfoveal
polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci.
43. Yannuzzi LA, Sorenson J, Spaide RF, Lipson B. Idiopathic polypoidal 2013;54(5):3771-3779.
choroidal vasculopathy (IPCV). Retina. 1990;10(1):1-8.
62. Matsumiya W, Honda S, Kusuhara S, et al. Effectiveness of intravitreal
44. Yuzawa M, Mori R, Kawamura A. The origins of polypoidal choroidal ranibizumab in exudative age-related macular degeneration (AMD):
vasculopathy. Br J Ophthalmol. 2005;89(5): 602-607. comparison between typical neo- vascular AMD and polypoidal
choroidal vasculopathy over a 1 year follow-up. BMC Ophthalmol.
45. Yannuzzi LA, Freund KB, Goldbaum M, et al. Polypoidal choroidal 2013;13:10.
vasculopathy masquerading as central serous chorioretinopathy.
Ophthalmology.2000;107(4):767-777. 63. Kang HM, Koh HJ. Long-term visual outcome and prognostic factors
after intravitreal ranibizumab injections for polypoidal choroidal
46. Uyama M, Wada M, Nagai Y, et al. Polypoidal choroidal vasculopathy: vasculopathy. Am J Ophthalmol. 2013;156(4):652-660.
natural history. Am J Ophthalmol. 2002;133(5):639-648.
64. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular
47. Lee JH, Lee WK. Choroidal neovascularization associated with focal age-related macular degeneration. N Engl J Med. 2006;355(14):1419-
choroidal excavation. Am J Ophthalmol. 2014;157(3):710-718. 1431.

48. Lafaut BA, Leys AM, Snyers B, et al. Polypoidal choroidal vasculopathy 65. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus
in Caucasians. Graefes Arch Clin Exp Ophthalmol. 2000;238(9):752- verteporfin for neovascular age-related macular degeneration. N Engl
759. J Med. 2006;355(14):1432-1444.

www.dosonline.org/dos-times 69
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

66. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF 73. Gomi F, Oshima Y, Mori R, et al. Initial versus delayed photodynamic
trap-eye) in wet age-related macular degeneration. Ophthalmology. therapy in combination with ranibizumab for treatment of polypoidal
2012;119(12):2537-2548. choroidal vasculopathy: the Fujisan Study. Retina. 2015;35(8):1569-
1576.
67. Kokame GT, Yeung L, Teramoto K, et al. Polypoidal choroidal
vasculopathy exudation and hemorrhage: results of monthly Corresponding Author:
ranibizumab therapy at one year. Int J Ophthalmol. 2014;231(2):94-
102. Dr. Yusra Asad, MS
Centre for Sight
68. Oishi A, Miyamoto N, Mandai M, et al. LAPTOP study: a 24-month B5-24, Safdarjung Enclave, New Delhi.
trial of verteporfin versus ranibizumab for polypoidal choroidal
vasculopathy. Ophthalmology. 2014;121(5): 1151-1152.

69. Dugel PU, Koh A, Ogura Y, et al. HAWK and HARRIER: Phase 3,
multicenter, randomized, double-masked trials of brolucizumab for
neovascular age-related macular degeneration. Ophthalmology 2020;
127:72–84.

70. Jaffe G. Sub-group analysis of Japanese polypoidal choroidal
vasculopathy patients in the HAWK study. Presented at Americal
Academy of Ophthalmology 2019 Annual Meeting Retina Subspecialty
Day.

71. Koh A, Lai TYY, Takahashi K, et al. Efficacy and safety of
ranibizumab with or without verteporfin photodynamic therapy for
polypoidal choroidal vasculopathy: a randomized clinical trial. JAMA
Ophthalmol. 2017;135(11):1206-1213.

72. Lee WKIT, Ogura Y, et al. Efficacy and safety of intravitreal aflibercept
for polypoidal choroidal vasculopathy in the PLANET study: a
randomized clinical trial. JAMA Ophthalmol. 2017.

DOS Times - Volume 28, Number 1, January-February 2022 70 www.dosonline.org/dos-times

DOS TIMES

Recent Advances in Retinal Imaging

Karthikeya R[1], MD, Vinod Kumar[2], MD, FRCS
1. Associate Consultant, Centre for Sight, New Delhi.
2. Additional Professor, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi.

Retinal imaging has improved by leaps and bounds in the last better than SDOCT. Longer wavelength also are scattered
2 decades. From the use of standard 30 degrees fundus camera less by the RPE. This leads to the choroid and suprachoroidal
to the present-day multimodality imaging of retina with the structures being seen very well on the OCT, even in heavily
convenience of imaging over 200 degrees of retina with a single pigmented Indian eyes. On an SSOCT scan, it is not
click, the advancements have been truly pathbreaking and have uncommon to see even the retro-orbital fat, especially in
opened up a new era in ophthalmology. myopic eyes. (Figure 1a).

Swept Source Optical Coherence Tomography Figure 1 : A: SSOCT scan of the macula in a high myope showing retina,
thinned out choroid, sclera and even the retro-orbital fat (white arrow).
No single technology in the last couple of decades has brought as SSOCT can also image under a dense hemorrhage (which
much changes in our understanding, management and outcomes
of retinal diseases as has the optical coherence tomography usually lead to shadowing on SDOCT). This allows us
(OCT). It has given us anatomic understanding, pathogenetic visualization a) into hematomas caused by a retinal artery
insights, a close look into the natural history of diseases and macroaneurysm, for e.g, and b) under subretinal or sub-
has been a reliable indicator of therapeutic response in a vast RPE bleed in cases of Age-related macular degeneration
majority of retinochoroidal diseases. (AMD). This can be very useful when a surgical intervention
OCT technology has evolved through many generations from is planned in these cases.
the earliest time-domain OCT with long acquisition times and The longer wavelength also translates to greater depth
rudimentary axial resolution to the spectral domain (SD-) OCT of resolution. Clinically this results in good visibility of
with faster acquisition and improved resolution to the currently choroid and sclero-choroidal junction and simultaneous
available swept source OCT (SSOCT)[1] which has very high visualization from vitreous body to sclero-choroidal
speed image acquisition and many other advantages. junction in a single scan. (Figure 1b)
SSOCT is considered superior to other SDOCT platforms for
the following reasons:
1. Higher scanning speed: Upto 100000 A-scans per second

can be acquired using regular commercially available
SSOCT machines. This is twice as much as a regular SDOCT
used in the clinic. There are also prototypes in development
with higher than 100000 A-scans/sec, called as the multi
megahertz OCT systems.
Higher scan speed translates into more B scans per second,
higher volume scans and higher signal to noise ratio (SNR).
Clinically this translates into larger scan area, better resolved
images, more details per scan and lesser artefacts. There are
commercially available SSOCT platforms that can capture
an OCT of 23×20mm with a single click and scans that can
be montaged up to 31×27mm!
Higher scanning speeds also means more volume data
which means better OCT Angiography (OCTA) data (See
below)
2. Longer wavelength laser: The laser used for acquisition of
images is also different. With a longer wavelength of 1040-
1060nm, the laser used in SSOCT can penetrate deeper
through retinal pigment epithelium (RPE) (and even
through significant media opacities like cataract and mild
vitreous vhemorrhage) and can image sub-RPE features

www.dosonline.org/dos-times 71
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

Figure 1 : B: SSOCT scan (in Enhanced Vitreous Visualization mode Figure 2 : A: SSOCT scan of the macula in a patient with CSC showing
available on the DRI OCT Triton platform) showing vitreous (white focal choroidal thickening (white arrow heads) underlying RPE and
arrow), posterior precortical vitreous pocket, retina, choroid and sclera neurosensory detachments. The choroid is less thick in other regions.
(black arrow), all in good focus, in a single scan.

Imaging Choroid on Oct Figure 2 : B: SSOCT scan in a patient with VKH syndrome showing
Ability to image the choroid non-invasively has been another diffuse choroidal thickening (white arrow heads).
break through event in the imaging of retina. Conventionally
and anatomically outside of retina, but functionally and Optical Coherence Tomography Angiography
pathophysiologically closely related to many retinal diseases, Optical Coherence Tomography Angiography (OCTA) is
examination of the choroid through OCT has provided another useful recent addition into our armamentarium of
invaluable insights into disease pathophysiology and has retinal imaging modalities which gives a quick, non-invasive,
significantly changed our understanding of numerous diseases. dye less and ‘depth resolved’ angiographic data of the retina. It
For example, while the outer choroid is selectively dilated in has been a significant research tool and, with improvements, is
pachychoroid spectrum, it is diffusely dilated in inflammatory slowly integrating itself as a routine retinal imaging modality
disorders like Vogt-Koyanagi-Harada syndrome. (Figure 2a used in everyday patient care.
and 2b) Conventional fluorescein angiographies (FA), as opposed to
Choroidal OCT can be obtained either on SDOCT platform
as enhanced depth imaging OCT (EDI-OCT) or with swept
source OCT without any additional maneuvers. The ease
and clarity SSOCT provides to choroidal imaging makes it
the platform of choice for clinical as well as research work on
choroid.[2] Some SSOCT platforms can provide automated
choroidal thickness maps within the early treatment diabetic
retinopathy study (ETDRS) subfields. Additionally, SSOCT is
superior in the imaging of eyes with pathologic myopia.
Limitations of SSOCT
Cost is the single most important limiting factor for the use
of SSOCT. Also, many of the analytic algorithms used in the
SSOCT are not approved for clinical use which has limited its
use in many setting where medical devices are tightly regulated.
There is also mild loss of axial resolution as compared to SDOCT
due to the longer wavelength used in the imaging.

DOS Times - Volume 28, Number 1, January-February 2022 72 www.dosonline.org/dos-times

DOS TIMES

OCTA, are not depth resolved, in the sense that the images There are four distinct capillary plexuses in the retina: The
we visualize during the study are a composite of the vascular superficial capillary plexus (SCP), the middle (or intermediate)
functions of the various layers of capillaries as well as the capillary plexus (MCP), the deep capillary plexus (DCP) and
fluorescein blockers and accumulators that are present in the the radial peripapillary capillary plexus (RPCP). The SCP,
field and do not permit visualization or assessment of individual MCP, and the DCP delimitate the foveal avascular zone (FAZ)
components (capillary plexus or vascular network). that is round- or oval-shaped in healthy eyes. OCTA can delimit
OCTA is produced by a “motion contrast” that is generated each of these plexuses and identify abnormalities individually in
when a B scan is repeated in the same section. In simple words, each of them.
when OCT B-scan is repeated in a given section multiple times Uses Of OCTA
over different time points, the scan should essentially be the • Detection of Choroidal Neovascular Membrane (CNVM),
same except the changes brought about by the mobile compo-
nents of the tissue which is the RBCs in the blood vessels. The especially in cases with difficulty in interpretation of FA
changes between the two B scans in measured and constructed images such as chronic central serous chorioretinopathy
as the vascular tree. Various algorithms are used on various plat- (CSC), myopic CNVM, macular telangiectasia, choroidal
forms (Eg: SSADA by Angiovue (Optovue, Fremont, CA, USA), osteoma, secondary CNVMs in cases of macular dystro-
OMAG by Cirrus (Zeiss Inc, Germany), OCTRA by DRI OCT phies etc. (Figure 3)
Triton, (Topcon, Tokyo, Japan) etc) to arrive at this angiographic
data from the raw OCT data without using a dye.[3] The angio- • Detection and characterization of microvascular changes
gram thus created is also depth resolved and can provide lay- in vascular and nonvascular diseases of the retina. For eg:
er-by-layer information of the vascular architecture of the reti- Diabetic retinopathy (DR), Retinal dystrophies, systemic
na, in striking contradistinction to the conventional FA. cardiovascular disease etc.

Figure 3 : SSOCTA in a case of Macular telangiectasia type-2 with secondary CNVM. The CNVM is clearly see on the outer-retinal slab (white arrow).
Motion artefacts (Red arrow) and projection artefacts (yellow arrow head) are also noted in this scan.

Quantitative OCTA of non-perfusion in macula, distortion of foveal avascular zone
While qualitative detection of changes on OCTA are sufficient (FAZ) etc), evaluation and follow up of vascular retinal diseases
for clinical management of many conditions (for eg: presence (and many other research questions) require quantification of
or absence of CNVM in a doubtful case, presence or absence the features seen in OCTA. Many indices have been developed

www.dosonline.org/dos-times 73
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

over the last few years for this qualitative analysis. Broadly these VISTA algorithm etc) and
indices can be divided into those that are • 3D- perfusion indices (for more accurate estimation of
• FAZ related (area, circularity)
• Blood vessel caliber and density related (vessel density, perfusion)

perfusion density, vessel caliber, vessel tortuosity etc) These indices can be used to objectively measure the various
• Blood vessel branching related (fractal dimension, branch vascular parameters of the individual retinal capillary
beds.[4] For eg: the vascular density in the superficial capillary
point analysis, vessel complexity index etc) plexus is reduced in patients with DR, sickle cell retinopathy,
• Flow related (flow index, flow void, total retinal blood flow, glaucoma etc. (Figure 4)

Figure 4 : A typical OCTA report in a patient with DR showing custom slabs of segmentation on the left-hand side, the highlighted superficial slab
enlarged at the centre and the corresponding en-face scan at the right-hand top corner. At the right bottom corner are the auto-calculated vascular (red
circle) and FAZ (yellow circle) indices of the superficial slab. The lower central image shows a B-scan from the volume scan with the pink lines depicting
the limits of segmentation of the slab.

Wide-Field OCTA OCTA and Diabetic Retinopathy
Wide-field OCTA has overcome a significant limitation of
early versions of OCTA which was the limited field of view. Depth resolved feature of the OCTA provided invaluable
Earlier versions of machines with OCTA could only provide insights into common diseases such as DR and Age-related
OCTA data on a field of 3mmX3mm to upto 6mmX6mm macular degeneration (AMD). High resolution OCTA studies
which allowed assessment of perifoveal and macular retina on the retina of diabetic patients has led to some very interesting
and limited application of OCTA to diseases with peripheral discoveries.[6,7]
retinal implications. Advancement in the speed of acquisition It has been shown that FAZ is larger in not only patients with
and refinement in processing algorithms has led to introduction DR but also in patients with Diabetes without DR. Similarly,
of wider fields in OCT-A which in expanding the utility of vascular density is lower in patients with DR and Diabetes
OCTA and allowing earlier diagnosis of diseases. There is now without DR as compared to age matched individuals. Densities
evidence to suggest that widefield OCTA can detect proliferative in RPCP was also noted to be reduced in patients with DR and
DR (PDR) changes earlier in DR than clinical examination.[5] was found to be a significant risk factor for progression of DR.
(Figure 5) Also, diabetic changes were seen more frequently on the DCP
as compared to the SCP on OCTA. This was a finding which

DOS Times - Volume 28, Number 1, January-February 2022 74 www.dosonline.org/dos-times

DOS TIMES

was previously only suggested based on histopathological grading tool (because they are objective and continuous) of
examination and its reiteration on OCTA studies have validated diabetic retinopathy than the currently used clinical and imaging
the relevance of studying diseases on OCTA. criteria (which is subjective and categorical).[8]
There are suggestions that OCTA indices may be a more reliable

Figure 5 : A widefield OCTA (12mmX12mm) scan showing neovascularization at disc (red arrow head) and elsewhere (yellow arrow head) in a patient
with PDR.

Limitations of OCTA • Segmentation errors: Software mediated auto-segmentation
of B-scans is one of the backbones of OCTA technology
• OCTA does not identify leakage from blood vessels. Leakage and these segmentations are very reliable in eyes without
from blood vessel is an important indicator of neovascular retinal morphological changes. But the accuracy of seg-
and inflammatory activity. It is also an indicator of mentation goes down significantly with the presence of
functional breakdown of blood-ocular barrier. This morphological changes in the retina (for eg: macular ede-
information sometimes is critical in planning the ma, CNVM, exudation etc). Poor segmentation may lead to
management of a patient. For eg: Presence of abnormal abnormal or erroneous results.
blood vessels in the outer retina or the choriocapillaris layer,
whilst is certainly abnormal, may not necessarily warrant • Artefacts: Artefacts such as motion artefacts, projection
treatment since regressed CNVMs and disciform scars can artefacts, shadow artefacts are common and care needs
also show blood vessels in them. to be exercised to rule out these in an OCTA image.
(Figure 3)
• OCTA does not show transit times and vascular filling.
• OCTA detects flow: Slow flow may be missed in view of Fundus Autofluorescence Imaging

a very small decorrelation signal between B Scans. Swept Fundus autofluorescence (FAF) is a non-invasive imaging
Source OCTA (SSOCTA) has distinct advantages in this re- technique that gives us information on the health of the RPE.
gard since its higher speeds can allow multiple scans to be FAF is increasingly becoming popular and an essential tool in
used to generate a decorrelation signal and even low flow the multimodal imaging of retinal diseases.
lesions can theoretically be identified better on SSOCTA Autofluorescence signal in the fundus is produced by natural
platforms.

www.dosonline.org/dos-times 75
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

fluorophore substances present in the retina that has the to their inability to actively turn the lipofuscin over to the cho-
capacity of absorbing light at specific wavelengths (excitation roid. This leads to the pattern of absent FAF signal (hypoauto-
spectrum) and then releasing light at different wavelengths fluorescence) from dead/atrophic RPE cells (as in geographic at-
(emission spectrums). FAF imaging systems illuminate the rophy) and increased FAF signal (hyperautofluorescence) signal
retina with an excitation beam and then collect the emitted from dying/damaged/dysfunctional RPE cells (often surround-
autofluorescence from ocular fluorophores to form a brightness ing hypoautofluorescent areas like a cuff. (Figure 6)
map. Uses
Excitation wavelengths commonly used are in the blue region FAF is commonly used in the imaging of AMD (Drusen,
are the obtained image are referred to as short wavelength aut- Geographic atrophy, RPE rips), CSC, Retinal dystrophies
oflouorescence or blue autofluorescence. The fluorophore excit- (Figure 7) and monitoring drug toxicities etc. FAF is the method
ed by this wavelength is the lipofuscin. FAF images can also be of choice for the follow up of cases with GA, drug toxicities. FAF
obtained by exciting in the near-infrared region and the images can detect abnormalities not otherwise identified with clinical
thus obtained is referred to as Near-infrared autofluorescence. examination, color fundus photography, FA, spectral-domain
The fluorophore excited by this spectrum is the melanin. optical coherence tomography, and other techniques, and it
The natural fluorophore substance used for FAF imaging can identify signature phenotypes facilitating the diagnosis of a
commonly is the Lipofuscin. Lipofuscin is a heterogeneous wide variety of retinal disorders. Wide field autofluorescence (as
mixture formed from the metabolism of photoreceptor out- obtained by Optos) has shown use in evaluation of progression
er segments. This collects in the RPE Lysosomes with age. A of inherited retinal diseases, genotype-phenotype correlation
healthy RPE is capable of turning over the lipofuscin in the etc. among other uses.
lysosomes into the choroid for final elimination via the blood
stream. An abnormal or an RPE under stress loses this ability
to transfer lipofuscin into choroid and it starts accumulating
in the RPE lysosomes. Therefore, the distribution of lipofus-
cin reflects the overall health of the RPE and its alteration is
detected in various disease conditions. In healthy eyes, the lipo-
fuscin concentration is greatest in the posterior pole, is limited
in the fovea, and decreases toward the periphery. Dead, atro-
phic or metabolically inactive RPE cells will not contain any
lipofuscin due to secondary loss of overlying photoreceptors.
The dying, damaged or dysfunctional RPE cells will contain
more than average amount of lipofuscin in their lysosomes due

Figure 7 : Short wavelength autofluorescence (blue autofluorescence) in
a case of Stargardt disease. There is near confluent hypoautofluorescence
at the fovea suggestive of RPE and photoreceptor atrophy.
Hyperautofluorescent flecks (due to accumulation of A2E, a major
component of lipofuscin) are also visualized on this image admixed with
discrete areas of hypoautofluorescence which are the areas of flecks that
have subsequently undergone atrophy.

Figure 6 : A wide-field FAF in a case of chronic CSC showing a ‘gravitational’ Wide Field Imaging
tract of altered autofluorescence signal. The area of hypoautofluorescence Traditional retinal imaging consisted of color photos and FAs on
indicates loss of RPE cells and the surrounding hyperautofluorescent area a 30 degree field which provided information only of the optic
indicates either chronic SRF and/or damaged/dying RPE cells. disc and central macula. Even on montage, the field of view
would increase to only about 75 degrees. Later investigations on
Diabetic Retinopathy have shown that about 50% of the lesions

DOS Times - Volume 28, Number 1, January-February 2022 76 www.dosonline.org/dos-times

DOS TIMES

in DR may lie outside of the 7 standard fields. In addition, many Many of the platforms also facilitate a multimodal imagining
diseases preferably affect the peripheral retina (for eg: Eales’ with inbuilt FA, Indocyanine green angiography (ICG), OCT
vasculitis), imaging and documenting which using traditional and FAF features.
modalities was near impossible. All these have been overcome An FA on a widefield angiogram is especially useful in
by the advent of widefield and ultrawide field (>200 degree) conditions such as Diabetic Retinopathy, Retinal vein occlusions
imaging of the retina.[9] (Figure 9), Vasculitis, ROP, FEVR, Retinal hemangioma,
The advantages of wide field imaging systems are: Posterior uveitis etc. Not only do these wide-field angiographies
• Panoramic view of retina and its pathology highlight peripheral pathologies that are otherwise unseen,
• Evaluation and documentation of peripheral pathologies they also allow visualization of angiography in the same phase
in all the areas which was difficult in the era before wide field
like Vasculitis, ROP etc. imaging. Small pupil capabilities and confocal SLO systems have
• Many widefield imaging systems allow non-mydriatic also contributed to superior quality images. In fact, wide field
study of DR is causing a paradigm shift in our understanding
contactless wide-angle imaging and of the disease. Today we know that a significant percentage of
• They are great research tools. patients in DR suffer from predominantly peripheral lesions and
also that these patients with predominantly peripheral lesions
Among the available wide field imagining systems, many of are four times more likely to progress into Proliferative DR as
them use pseudocolor/multicolor imaging i.e use of monochro- compared to those with only posterior lesions.
matic lasers (rather than white light) for color imaging. For eg: Widefield ICG has also led to massive shifts in our understand-
Optos (Optos Inc, Dunfermline, UK) uses a red laser of 633 ing of the behavior of choroid and various diseases affecting it.
nm and a green laser of 532 nm for creation of color images Our understanding of the choroidal circulation has undergone
(Figure 8). The advantage of using monochromatic laser reflec- a significant overhaul along with our knowledge on the patho-
tance to reconstruct color images is that these different wave- physiology of chronic diseases like CSC, PCV, AMD etc. Today
lengths of light penetrate the retinal surfaces to different depths CSC is being investigated as a primary choroidal outflow prob-
and demonstrate details at the various layers of the retina. This lem after the widefield ICG suggestion of the same.
brings out pathology better, even though the color of the lesions
may be altered/unnatural.

Figure 8 : An ultrawide field image of an eye with ocular albinism. Note Figure 9 : An ultrawide field FA in a case of CRVO showing macular and
the ability of this modality to image fundus anterior to the vortex vein extensive peripheral ischemia.
ampulla and the pseudocolor nature of the photographs.

Some of the widefield platforms also offer wide field OCT Limitations of Wide Field Imaging
(upto 23mm wide scans) allowing OCT scanning and Cost is the single most important limiting factor of this
subsequent anatomical understanding of lesions and diseases technology. There are other minor limitations such as distortion
far in the periphery. Widefield systems like Retcam have been of images, under representation of superior and inferior poles,
indispensable in the treatment of ROP at institute level and also obstruction by lashes etc, especially on the Optos platform.
at community level by making telemedical services possible. Another important limitation is the lack of definitions to be
Widefield autofluorescence are useful in evaluation and applied for wide field imaging. For eg: the limit of non-perfusion
characterization of inherited retinal degenerations and AMD.

www.dosonline.org/dos-times 77
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

necessary to call a central retinal vein occlusion is derived from history, genotype-phenotype correlation and prognostication
FA done on conventional camera on seven standard fields. This (Figure 10). In addition capillary morphology, vascular density,
limit of 10-disc areas cannot be applied on ultrawide field FAs arteriolar and venular architecture etc have also been studied in
which often show an ischemia many folds worse even in less various retinal and systemic vascular diseases.[10]
severe forms of vein occlusion. This may lead to over treatment
or incorrect prognostication. References
Adaptive Optics Retinal Imaging
1. Laíns I, Wang JC, Cui Y, Katz R, Vingopoulos F, Staurenghi G, et
OCT imaging provides an anteroposterior (axial) resolution al. Retinal applications of swept source optical coherence tomography
of upto 3-5 µm. But the maximum transverse resolution that (OCT) and optical coherence tomography angiography (OCTA). Prog
could be attained with the best of the OCT platforms (and Retin Eye Res. 2021;84:100951.
other imaging modalities included) could not be better than
25 µm. This is due to the inherent limitations in the optics of 2. Kishi S. Impact of swept source optical coherence tomography on
the human eye and the aberrations built there-in. By neutralizing ophthalmology. Taiwan J Ophthalmol. 2016 Jun 1;6(2):58–68.
these aberrations in the optical system of the eye, the transverse
resolution of the eye could be increased upto 2.5 µm which can 3. Spaide RF, Fujimoto JG, Waheed NK, Sadda SR, Staurenghi G.
make the visualization of the cone mosaic, the smaller capillaries Optical coherence tomography angiography. Prog Retin Eye Res. 2018
and other microscopic details in vivo in the macula possible. May 1;64:1–55.
Adaptive optics technology makes this possible with the use
of a wavefront sensor and deformable mirror to correct the 4. Yao X, Alam MN, Le D, Toslak D. Quantitative optical coherence
aberrations. This increases the lateral resolution and makes tomography angiography: A review. Exp Biol Med Maywood NJ.
microscopic retinal structures visible. 2020;245(4):301–12.
Adaptive optics is a research tool and has so far been used to
study the photoreceptor morphology, density, geometry in 5. Khalid H, Schwartz R, Nicholson L, Huemer J, El-Bradey MH, Sim
various inherited retinal diseases to understand their natural DA, et al. Widefield optical coherence tomography angiography for
early detection and objective evaluation of proliferative diabetic
retinopathy. Br J Ophthalmol. 2021;105(1):118–23.

6. Akil H, Karst S, Heisler M, Etminan M, Navajas E, Maberley D.
Application of optical coherence tomography angiography in diabetic
retinopathy: a comprehensive review. Can J Ophthalmol. 2019 Oct
1;54(5):519–28.

7. Borrelli E, Battista M, Sacconi R, Querques G, Bandello F. Optical
Coherence Tomography Angiography in Diabetes. Asia-Pac J
Ophthalmol. 2021 Feb;10(1):20–5.

8. Durbin MK, An L, Shemonski ND, Soares M, Santos T, Lopes M, et al.
Quantification of Retinal Microvascular Density in Optical Coherence
Tomographic Angiography Images in Diabetic Retinopathy. JAMA
Ophthalmol. 2017 Apr;135(4):370–6.

9. Kumar V, Surve A, Kumawat D, Takkar B, Azad S, Chawla R, et al.
Ultra-wide field retinal imaging: A wider clinical perspective. Indian
J Ophthalmol. 2021 Apr;69(4):824–35.

10. Zhang B, Li N, Kang J, He Y, Chen X-M. Adaptive optics
scanning laser ophthalmoscopy in fundus imaging, a
review and update. Int J Ophthalmol. 2017 Nov 18;10(11):1751–8.

Corresponding Author:

Figure 10 : Adaptive optics scan of the central 1.5 degree of the visual field. Karthikeya R, MD
The cone mosaic can be clearly visualized (white arrow) and capillary Associate consultant
(White arrow head) limiting the foveal avascular zone is also imaged in Centre for Sight, B5-24, Safdarjung Enclave, New Delhi.
this scan.

DOS Times - Volume 28, Number 1, January-February 2022 78 www.dosonline.org/dos-times

DOS TIMES

Biologics in the Treatment of Uveitis

Shalin Shah, MS, Rahul Mayor, DNB
Vitreoretina Services, Dr. Shroff ’s Charity Eye Hospital, New Delhi.

Abstract: The management of noninfectious uveitis is constantly evolving. A new “biologic era” in treatment began
after the effectiveness of tumor necrosis factor-alpha blocking drugs was demonstrated in rheumatologic inflamma-
tory diseases. The goal of specific immunomodulation with a biologic drug is to target inflammation at the molec-
ular level with a low rate of serious adverse events. The purpose of this review is to summarize current knowledge
of biologic drugs in the treatment of noninfectious uveitis by describing clinical studies and recent pharmacological
developments.

Uveitis is one of the leading causes of visual impairment status, review of immunization record, and consideration of
and is responsible for 5–20% of legal blindness in Western possible latent infections, such as tuberculosis and hepatitis B
countries and approximately 25% of blindness in the developing or C virus disease.[4] If there is a previous history of neoplasm,
world.[1,2] Local and systemic corticosteroids constitute the patients must be closely monitored for recurrence. Yates et
first‑line therapy for virtually all patients with noninfectious al. reported an increased risk of malignancy—mainly non-
uveitis. Prolonged corticosteroid use can produce toxic effects, melanoma skin cancer and non-Hodgkin lymphoma—in the
so corticosteroid‑sparing immunomodulatory therapies have patients with Noninfectious uveitis (NIU) who were treated
assumed an increasingly important role in the management with immunomodulatory therapy.[5] Long-term follow-up of the
of chronic ocular inflammation. However, these conventional Systemic Immunosuppressive Therapy for Eye Diseases cohort
therapies did not lead to satisfactory outcomes for some active showed no increased overall and risk-related cancer mortality for
uveitis, including the management of adverse effects.[3] The the most frequently used immunomodulatory drugs, including
implication of immune‑mediated inflammatory pathways in anti-TNF- α agents.[6]
uveitis and the explosion of biologic agents to treat rheumatic The treatment of uveitis with biologics generally requires
and other inflammatory‑mediated diseases have led to a wealth a multidisciplinary approach, with co-management by
of potential therapies, systemic and local, for uveitis. rheumatologists and other medical specialists. Children are
The aim of biologic therapy is to regulate the inflammatory typically comanaged with a pediatrician. Table 1 summarizes
process, potentially by offering more specific targeted the biologic drugs used to treat uveitis, including doses and side
suppression of immune effectors response that damage tissue. effects.
An extensive clinical evaluation is required before the initiation
of any immunomodulatory drug. Baseline blood cell count, In this review, the literature is summarized, describing current
and liver enzyme and creatinine tests should be performed, as assessments in the progressing fields, under headings that relate
well as an assessment of cardiovascular and endocrinological to the specific targets of these biologics.

Generic Name Specific Target Route Dosage Potential Side Effects
TNF inhibitor TNF‑α IV
SC 3-5 mg/kg loading at weeks 0, 2, Susceptibility to infections,
Infliximab and 6, then maintenance 3-10 mg/ including reactivation of
(Remicade) SC kg every 4-8 weeks (20 mg/kg tuberculosis, histoplasmosis,
(Infimab) maximum in children) hepatitis B, and fungal infection;
40 mg every 1-2 weeks (if body Hypersensitivity reactions;
Adalimumab TNF‑α weight, 30 kg; 20 mg every 2 weeks); demyelinating disease; lupus‑like
(Humira) loading doses of 80-160 mg are syndrome; malignancy;
(Exemptia) (Adfrar) recommended thromboembolic events; congestive
heart failure
Adults 50 mg weekly (may be
Etanercept (Enbrel) TNF‑α, β given 50 mg twice weekly for first 3
months for PSA); children 0.8 mg/
kg/week (max 50 mg/week)

www.dosonline.org/dos-times 79
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

Generic Name Specific Target Route Dosage Potential Side Effects
Golimumab TNF‑α SC
(Simponi) SC 50 mg SC monthly; except for UC
TNF‑α 200 mg at week 0, 100 mg at week 2,
Certolizumab IV, SC then 100 mg every 4 weeks
(Cimzia) SC 400 mg SC at weeks 0, 2, and 4, then
200 mg every 2 weeks or 400 mg
every 4 weeks

Anti‑interleukin therapies

Daclizumab T cells (IL‑2) 1-2 mg/kg every 2 or 4 weeks Hypersensitivity reactions;
(Zenapax) 100 mg daily headache; gastrointestinal upset
Injection‑site reaction; infections,
Anakinra (Kineret) IL‑1 receptor 4 mg/kg infusion over 1 hour every neutropenia especially if
4 weeks, can increase to 8 mg/kg concurrently used with
Tocilizumab IL‑6 receptor IV based on response TNF‑inhibitors
(Actemra) IV 500 or 1000 mg at week 0 and 2 Infections; neutropenia;
thrombocytopenia; transaminitis
Rituximab (Rituxan) B‑cells (CD20)
(Reditux) (Ristova) Infusion reactions severe
mucocutaneous reactions;
hypertension; bronchospasm;
progressive multifocal
leukoencephalopathy

Interferons SC 3-6 million IU/day tapering over 6 Injection site reaction, flu‑like
Interferon α‑2a IV months reaction, bone marrow suppression
(Roferon)
500 or 1000 mg at week 0, 2, 4 then Serious infections; allergic reactions;
Fusion protein of CTLA‑4 every 4 weeks (children: 10 mg/kg, malignancy; respiratory problems
Abatacept (Orencia) T‑cells (CTLA‑4) maximum 1000 mg) in patients with chronic obstructive
pulmonary disease

FDA: Food and Drug Administration, CD: Cluster of differentiation: IL: Interleukin, CTLA: Cytotoxic T‑lymphocyte antigen: UC: Ulcerative Colitis,
PSA: psoriatic arthritis, SC: Subcutaneous, IU: International unit, IV: Intravenous, SC: Subcutaneous.

Table 1 : Currently available Food and Drug Administration (FDA) approved biologic response modifier.

Antitumor Necrosis Factor-α Infliximab
TNF-α is a master cytokine in the inflammatory process, being Infliximab (Remicade, Janssen Biothec, Horsham, PA) is a
synthesized by most immune cells, and many nonimmune chimeric anti-TNF-α monoclonal antibody, 75% constituted
cells.[7] Soluble and transmembrane TNF-α are the active forms by a constant human portion and 25% by a variable murine
that bind to 2 TNF-α receptors (TNFR): TNFR1 (p55), which portion, that binds to both soluble and transmembrane
is widely expressed throughout the body, and TNFR2 (p75), TNF-α. Infliximab also induces regulatory T-cells in the
which is more restricted to the immune system. Adverse drug peripheral blood of patients with Behcet uveitis.[11] It is usually
reactions attributed to TNF-α blockers as a group include administered at a dose of 5 mg/ kg as an intravenous infusion
infections (mycobacterial, bacterial, viral, and fungal), given in weeks 0, 2, and 6, followed by a maintenance dose every
neutropenia, autoimmunity (asymptomatic autoantibodies 4 to 8 weeks. Infliximab is effective in the treatment of NIU
or drug-induced lupus), malignancy, demyelinating disease, unresponsive to other drugs, including adalimumab.[12–15]
heart failure, and injection or infusion reactions.[8] Brain
magnetic resonance is indicated to screen for demyelination in It has a long history of use in the treatment of Behcet disease,
patients with intermediate uveitis before the commencement and has also been studied in Vogt-Koyanagi-Harada (VKH)
of TNF-α inhibitors.[4] Data from large cohorts of patients with syndrome, birdshot retino-choroidopathy, sarcoid uveitis,
inflammatory bowel disease using anti-TNF-α agents found no juvenile idiopathic arthritis (JIA)-associated uveitis, HLA-B27-
increase in the rates of malignancies.[9,10] associated anterior uveitis and undifferentiated uveitis, with

DOS Times - Volume 28, Number 1, January-February 2022 80 www.dosonline.org/dos-times

DOS TIMES

approximately 82% of patients achieving clinical remission in a The SYCAMORE study addressed pediatric uveitis specifically.
median time of 127 days.[16,17] A prospective study with patients This was a multicenter, double-masked, clinical trial that
with aggressive NIU identified a 60% retention rate for infliximab randomized children and adolescents receiving methotrexate
at 2 years of treatment.[18] Even when used in combination with for active JIA-associated uveitis to treatment with methotrexate
other immunomodulatory agents, infliximab is well tolerated.[19] alone or concomitant with adalimumab.[24] Treatment failure
Intravitreal use of infliximab generated controversy initially,[20] occurred in 60% in the methotrexate-only group and 27% in
but one recent study that evaluated this treatment at a dose of the adalimumab group at 18 months of follow-up.[24] Long-term
1 mg/0.05mL showed control of ocular inflammation and an therapy seems to be necessary for sustained control, since a
acceptable safety profile in 20 patients with refractory Behcet report from a 5-year follow-up from one of the SYCAMORE’s
uveitis across 18 weeks of follow-up.[21] There is a report of centers showed that 92% of 28 patients had to resume treatment
worsening of uveitis, with reduction in electroretinographic with adalimumab after its withdrawal.
parameters, and deterioration in microperimetry, after treatment Intravitreal adalimumab was not effective for uveitic macular
with intravitreal infliximab in a prospective open label study.[22] edema in a small study with 5 patients. A retrospective study
Adalimumab with 12 eyes of 7 patients showed inflammation control in 9
eyes at 26 weeks with 7 intravitreal injections per eye of adalim-
Adalimumab (Humira, AbbVie Inc., North Chicago, IL) is a hu- umab 1.5 mg/0.03 mL, but 1 eye had worsening of inflammation
man monoclonal antibody that blocks soluble and transmem- after the fourth injection.
brane TNF-α. Administered through subcutaneous injections, Adalimumab and infliximab display similar long-term retention
adalimumab is used at 40 mg every 2 weeks, with the possibility rates, indicating that both drugs present comparable effective-
of shortening the administration interval if necessary.[23] ness and tolerability. Adalimumab retention rate was 54% at 5
The SYCAMORE study investigators prescribed a dose of years of follow-up and was not influenced by concomitant use
20 mg every 2 weeks in children weighing <30 kg and adult of other immunosuppressants, as determined by a retrospective
doses in children weighing >30 kg.[24] Inflammation control cohort with 392 patients. Reported discontinuation occurred
by adalimumab was found to be similar to infliximab in the due to inefficacy in 19% and adverse reactions in 9%. Since in-
treatment of NIU. A prospective study compared the efficacy fliximab is administered intravenously, it requires more visits to
of infliximab versus adalimumab in refractory JIA-associated the clinic and thus may be more difficult for patients to integrate
uveitis, with clinical remission over 24 months reported in 44.8% into their daily lives.
for infliximab and 60% for adalimumab. In a prospective case The development of antidrug antibodies may occur during
series of 26 patients with sarcoid uveitis followed for 12 months, treatment with adalimumab or infliximab therapy, decreasing
22 of 26 patients were treated successfully with adalimumab. their efficacy. Prescription of methotrexate or azathioprine
Adalimumab was approved by the US FDA for the treatment concomitant with these anti-TNF- α drugs may address this issue.
of NIU on the basis of 2 phase-3, randomized, double-masked A study showing a rate of 32% of anti-adalimumab antibodies
placebo-controlled trials (VISUAL I and VISUAL II) conducted found that, in only about half of patients, the antibodies were
in 22 countries; these studies showed the drug’s effectiveness permanent and led to decreased bioavailability of adalimumab
in delaying time to treatment failure in patients with active and worse outcomes.[27]
(VISUAL I) and inactive (VISUAL II) NIU.[25,26] In VISUAL I, Etanercept
time to treatment failure was 24 weeks and 13 weeks for the
patients treated with adalimumab and placebo, respectively. Etanercept (Enbrel, Immunex Corporation, Thousand Oaks,
After 18 months, the adalimumab group had a 50% reduction CA) is a recombinant fusion protein, composed of the extracel-
in the risk of treatment failure compared to placebo. In VISUAL lular ligand-binding domain of the TNFR p75 linked to the Fc
II, time to treatment failure for the adalimumab group was portion of human IgG1, that binds to soluble and transmembrane
18 months, compared with 8.3 months for the placebo group, TNF-α.[28] It has been used extensively in the treatment of rheu-
with a 43% risk reduction of treatment failure at 18 months for matoid arthritis and the spondyloarthropathies. Nonetheless, it
adalimumab-treated patients. VISUAL III was an open-label has proved to be ineffective in suppressing intraocular inflam-
extension study that assessed safety and efficacy of adalimumab mation and may be associated with paradoxical uveitis—or just
in patients from VISUAL I and II studies with and without low effectiveness in preventing uveitis flares—and hence it is not
treatment failure with a follow-up of 78 weeks. Among the 242 used to treat NIU.[28]
patients who entered the VISUAL III study with active NIU, 60% Golimumab
achieved control of the ocular inflammation at 12 weeks, and
66% had discontinued corticosteroids. Seventy-five percent of Golimumab (Simponi, Janssen Biotech, Horsham PA) is a hu-
the 129 patients with inactive NIU at study entry were quiescent man monoclonal antibody against soluble and transmembrane
at 78 weeks, and 93% of the responders were corticosteroid- TNF-α. Its route of administration may be either subcutaneous
free. Drug discontinuation secondary to adverse reactions was or intravenous. If prescribed subcutaneously, the usual dose
described in 13% of cases (48/371), and lack or loss of efficacy in is 50mg every 4 weeks, whereas if administered intravenous-
6% of cases (22/371) at 78 weeks. ly, the recommended loading dose is 2 mg/kg every 4 weeks

www.dosonline.org/dos-times 81
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

twice, extended to an 8-week interval. Golimumab was effec- Daclizumab
tive in the treatment of intraocular inflammation, especially Daclizumab (Zenapax) is a monoclonal antibody that binds the
in HLAB27- and JIA-associated uveitis, but also in Behcet and IL‑2 receptor on T‑lymphocytes, preventing their IL2‑depen-
undifferentiated NIU. A retrospective study with 13 patients dent activation. A phase I/II open‑label study of intravenous da-
with refractory NIU showed resolution of intraocular inflam- clizumab for the treatment of noninfectious intermediate, poste-
mation in 12 of 13 patients at 6 months. Another retrospective rior, or panuveitis demonstrated improvement of inflammation
cohort of 17 patients with refractory JIA- and HLA-B27-associ- and visual acuity at 1 year in eight out of 10 patients, which was
ated uveitis reported that 12 individuals had inactive disease at maintained after 4 years of treatment. Increased uveitic recur-
last visit (mean follow-up of 22 months).[29] rences were observed with reduction to 6‑weekly infusions as
Certolizumab compared to 4‑weekly infusions. After 4 years of intravenous in-
Certolizumab pegol (Cimzia, UCB, Inc., Smyrna, GA) is a fusions, some patients were transitioned to subcutaneous dacli-
humanized anti-TNF-α Fab monoclonal antibody fragment zumab therapy, with most patients retaining good response. Ten
combined with polyethylene glycol. 50 Contrasting with other out of 15 patients in a subsequent study achieved at least a 50%
anti- TNF-α drugs, it does not have a fragment crystallizable reduction of concurrent immunosuppression with retained vi-
(Fc) domain. These characteristics decrease immunogenicity sual acuity, inflammatory control, and no significant side effects.
and improve pharmacodynamics. Certolizumab is administered Daclizumab has been demonstrated effective for refractory bird-
at a dose of 400 mg/week subcutaneously. It has been shot retinochoroidopathy in one study, with seven out of eight
evaluated in refractory Behcet uveitis, JIA-associated uveitis, patients achieving complete resolution of vitreous inflammation
and spondyloarthropathy- associated uveitis. Incidence of and stabilization or improvement of visual acuity. However, da-
uveitis flares was reduced in certolizumab-treated patients clizumab failed to demonstrate effectiveness in BD‑associated
with axial spondyloarthropathy (3 per 100 patient-years) in uveitis in a randomized trial.[33]
comparison to placebo (10 per 100 patients-years) at 24 weeks Anakinra
of treatment, with those treated with certolizumab maintaining Anakinra competitively inhibits binding of IL‑1 and is more
low incidence of uveitis flares until 96 weeks of follow-up. effective in the treatment of CINCA syndrome than cortico-
Preliminary results of a multicenter prospective study that steroids. Teoh et al. reported successful treatment of posterior
included 89 patients with spondyloarthropathy and recurrent uveitis associated with CINCA syndrome in a 4‑year‑old boy,
anterior uveitis demonstrated an 87% decrease in risk of uveitis which had responded poorly to corticosteroids, methotrex-
recurrence for the patients treated with certolizumab during a ate, and etanercept.[34] Subcutaneous anakinra was adminis-
48-week follow-up.[30] tered at a dose of 1 mg/kg/day until remission was achieved.
Anti‑Interleukin‑1 Antibodies Inflammatory remission was achieved within the 1st year of
Interleukin‑1 (IL‑1) has been proven to play an important role treatment, and his uveitis has subsequently remained quiescent,
in experimental uveitis. For this reason, antagonists of this permitting the withdrawal of oral corticosteroids. No adverse
cytokine have been tested in human uveitis. However, a few side effects were reported.
data are available to date and results are still inconclusive. It Gevokizumab (XOMA 052)
has been reported for use in the treatment of chronic infantile Gevokizumab has been granted orphan drug status in the
neurological cutaneous articular (CINCA) syndrome.[31] This European Union for noninfectious uveitis. In a pilot study by
disease may occur as a result of mutations in the cold‑induced Gül et al., seven patients with acute posterior or panuveitis,
autoinflammatory syndrome 1 gene, which encodes cryopyrin. and/or retinal vasculitis, resistant to azathioprine and/or
Cryopyrin regulates the apoptosis of inflammatory cells; its lack cyclosporine, and receiving 10 mg/day or less of prednisolone,
thereof upregulates levels of IL‑1. were enrolled. Immunosuppressive agents were discontinued at
Tocilizumab baseline. Patients received a single infusion of XOMA 052 (0.3
Tocilizumab is a fully humanized monoclonal antibody mg/kg). Well‑tolerated gevokizumab resulted in a rapid onset
recognizing IL‑6 receptor (IL‑6 R) in both its soluble form and sustained reduction in intraocular inflammation in patients
or bound to cell membrane surface. Its indication includes with resistant uveitis and retinal vasculitis.[35]
moderate to severe RA. The standard dose is 8 mg/kg/month Secukinumab (anti‑interleukin‑17A antibody)
intravenously. Clinical trials have shown promising results in Secukinumab is a fully humanized IgG1k monoclonal antibody
treating several autoimmune diseases in patients who respond neutralizing IL‑17A. It has proved to be quite effective in the
inadequately to conventional immunosuppressant, including treatment of patients with anterior and posterior uveitis with
large‑vessel vasculitis.[32] Tocilizumab may represent a treatment no serious adverse effects.[36] Three multicenter, randomized,
option for otherwise refractory JIA‑associated uveitis although double‑masked, placebo controlled, dose‑ranging phase III
further prospective studies are needed to evaluate the efficacy of studies conducted in a total of 118 patients with Behçet’s
this new drug in comparison to other biologics. uveitis (SHIELD study); 31 patients with active, noninfectious,

DOS Times - Volume 28, Number 1, January-February 2022 82 www.dosonline.org/dos-times

DOS TIMES

non-Behçet’s uveitis (INSURE study); and 125 patients with been used which have a longer duration of action allowing
quiescent, noninfectious, non-Behçet’s uveitis (ENDURE study) weekly administration, but there are inadequate data to
were enrolled. After completion or early termination of each determine their efficacy.
trial, there were no statistically significant differences in uveitis Selective Costimulation Modulator
recurrence between the secukinumab treatment groups and
placebo groups in any study. Abatacept
Rituximab Abatacept is a fusion protein composed of the Fc region of the
Rituximab is a recombinant chimeric monoclonal antibody IgG1 fused to the extracellular domain of cytotoxic T‑lympho-
that targets CD‑20, a cell surface antigen on B‑cells, result- cyte antigen 4 molecule. Abatacept is a selective co‑stimulation
ing in B‑cell depletion. With the established role of B‑cells in modulator as it inhibits the co‑stimulation of T‑cells, prevent-
T‑cell‑mediated and immune complex‑mediated diseases, this ing APCs from delivering the co‑stimulatory signal to T‑cells to
biologic is potentially useful in targeting the effector cells of the fully activate them. It is usually administered intravenously at a
inflammatory cascade. The binding and clustering of CD20 by dose ranging from 500 to 1000 mg every 4 weeks.
rituximab transmits a signal that causes apoptosis of B‑lympho- There are a few case reports on successful use of abatacept in
cytes. Infusions of rituximab induce the depletion of B‑lym- refractory uveitis associated with uveitis. In a study of seven pa-
phocytes from peripheral blood for several months. The usual tients with JIA‑related uveitis refractory to immunosuppressive
dose is 1000 mg infusion on days 1 and 15 and then at months and anti‑TNF‑α agents were treated with abatacept.[38] All pa-
12 and 21. Initially developed for the treatment of B‑cell lym- tients responded to abatacept and six maintained a clinical re-
phomas, rituximab is licensed also for RA, being particularly mission after a mean of 9.2 months of treatment.
effective in subgroups of patients, which are positive for anti‑ci- Janus Kinases Inhibitors
trullinated protein antibody and/or rheumatoid factor (seropos- Janus kinases (JAKs) are enzymes linked to cytokine membrane
itive RA). The drug has been used in clinical trials in different receptors that are involved in intracellular signaling via signal
autoimmune diseases including systemic lupus erythematosus, transduction and activators of transcription molecules.[38]
Sjogren’s syndrome, antineutrophil cytoplasmic antibody‑asso- Inhibiting JAKs interrupts proinflammatory signaling via
ciated vasculitis.[37] There are some case reports on successful the JAK/signal transduction and activators of transcription
use of rituximab in the treatment of uveitis associated with JIA. pathway. Tofacitininb (Xeljanz, Pfizer, USA), a JAK1/JAK3-
Recently, Miserocchi et al. retrospectively studied eight patients selective inhibitor, and baricitinib (Olumiant, Eli Lilly/Incyte),
(15 eyes) with severe and longstanding JIA uveitis who had an a JAK1/JAK2-selective inhibitor, are already used in the clinic
inadequate response in controlling uveitis to one or more bio- for rheumatoid arthritis.[38] Just a few case reports have been
logic agents including TNF blockers and abatacept were treated reported on the use of these agents in NIU. Four patients with
with rituximab. All patients achieved complete control of uveitis; severe refractory JIA-associated uveitis, who were treated
however, in two patients, rituximab was discontinued due to in- with tofacitinib or baricitinib, experienced improvement in
efficacy in treating arthritis. The decrease in uveitis activity was intraocular inflammation, whereas arthritis improved in only
evident 4–5 months after the first infusion. The authors conclude one. In another patient with severe JIA-associated uveitis,
that rituximab may be a promising effective treatment option treatment with tofacitinib resolved macular edema and the
for refractory uveitis associated with JIA leading to long‑term articular inflammation. Rash, gastrointestinal symptoms, and
quiescence of uveitis, particularly for patients who have not pre- abnormal liver function are among the side-effects. Baricitinib
viously responded to other biologic therapies. Hence, although and filgotinib (Gilead Sciences, Inc. & Galapagos NV—a JAK1
inflammatory uveitis is believed to be a T‑cell‑mediated disease, inhibitor) are under presently investigation for NIU in registered
B‑cell depletion may be effective since these cells are efficient an- clinical trials (NCT04088409 and NCT03207815, respectively).
tigen‑presenting cells (APCs) for T‑lymphocytes and contribute Things to Remember for Patients on Biologics
to their activation and clonal expansion. It has been effective for 1. Biologics are contraindicated in patients with tuberculosis
treatment of various systemic vasculitis associated uveitis, reti-
nal vasculitis, and scleritis. (TB), chronic hepatitis B or C, or any active infection
Interferon‑α 2. IFX, etanercept, and ADA, all have been categorized as the
Interferon‑α (IFN‑α) is a type I IFN and has been used in the
treatment of uveitis due to its antiproliferative, antiangiogenic, United States FDA category B for use in pregnancy (animal
and apoptotic effects. In addition, it has the ability to modulate reproduction studies have failed to demonstrate a risk to the
immune responses, specifically activating dendritic, cytolytic fetus and there are no adequate and well‑controlled studies
T‑ and natural killer cells. IFN α‑2A and IFN α‑2B are in pregnant women). Avoid pregnancy till 5 months after
human‑recombinant IFNs manufactured using recombinant stopping the last dose of biologics.
deoxyribonucleic acid technology with Escherichia coli to 3. Rule out malignant conditions before starting biologics
produce human proteins. More recently, pegylated IFNs have 4. Patient to be advised to see a doctor if he develops fever, sore
throat, bleeding

www.dosonline.org/dos-times 83
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

5. As TNF‑α agents can aggravate multiple sclerosis, rule out References
demyelinating disease before starting these agents in those
set of patients 1. Papo T, et al. Chronic severe uveitis: Etiology and visual outcome in 927
patients from a single center. Medicine (Baltimore) 2001;80:263‑70.
6. Common side effects:
• Reduced immunity leading to increased risk of infection 2. Rothova A, Suttorp‑van Schulten MS, Frits Treffers W, Kijlstra
A. Causes and frequency of blindness in patients with intraocular
including flare‑up of latent TB inflammatory disease. Br J Ophthalmol 1996;80:332‑6.
• Worsening of heart failure if already present, so
3. Jabs DA, Rosenbaum JT, Foster CS, Holland GN, Jaffe GJ, Louie JS, et
contraindicated in the New York Heart Association Class al. Guidelines for the use of immunosuppressive drugs in patients with
III/IV heart failure. ocular inflammatory disorders: Recommendations of an expert panel.
Key Points for Initiating and Monitoring Patients on Am J Ophthalmol 2000;130:492‑513.

Biological Therapies 4. Wakefield D, McCluskey P, Wildner G, et al. Inflammatory eye
1. Before starting biologics, a careful clinical examination is disease: pre-treatment assessment of patients prior to commencing
immunosuppressive and biologic therapy: recommendations from an
important to rule out previous cardiac diseases, malignancy, expert committee. Autoimmun Rev. 2017;16:213–222.
neurological disorders, or infections
2. The patient who will be treated with biologics should know 5. Yates WB, Vajdic CM, Na R, et al. Malignancy risk in patients with
the main signs and symptoms (“red flags”) of the adverse inflammatory eye disease treated with systemic immunosuppressive
effects associated with their use. therapy: a tertiary referral cohort study. Ophthalmology.
3. Laboratory tests 2015;122:265–273.
• Annual TB skin test; alternatives include the
QuantiFERON®‑TB gold blood test and chest X‑ray if 6. Kempen JH, Newcomb CW, Foster CS, et al. Risk of overall and
indicated cancer mortality after immunosuppression of patients with non-
• Complete metabolic panel with liver function tests for each infectious ocular inflammatory diseases. Invest Ophthalmol Vis Sci.
IFX infusion and with any sign of hepatic injury 2019;60:3854.
• Complete metabolic panel (renal function test, electrolyte,
liver function test, and glucose) every 3–6 months on all 7. Vandenabeele P, Declercq W, Beyaert R, et al. Two tumour necrosis
biological therapies factor receptors: structure and function. Trends Cell Biol. 1995;5:392–
• Complete blood counts every 3–6 months on all biological 399.
therapies
• Hepatitis screen and human immunodeficiency virus 8. Rein P, Mueller RB. Treatment with biologicals in rheumatoid
testing when risk factors present on all biological therapies. arthritis: an overview. Rheumatol Ther. 2017;4:247–261.
4. Patients initiating anti‑TNF therapy should be up‑to‑date
for pneumococcal, influenza (nonlive virus), and hepatitis 9. Hyams JS, Dubinsky MC, Baldassano RN, et al. Infliximab is not
B vaccines. Patients receiving anti‑TNF therapy should not associated with increased risk of malignancy or hemophagocytic
have live virus vaccine, including varicella zoster, oral polio, lymphohistiocytosis in pediatric patients with inflammatory bowel
or rabies vaccination. disease. Gastroenterology. 2017;152:1901–1914. e3.

Conclusions 10. Andersen NN, Pasternak B, Basit S, et al. Association between tumor
necrosis factor-alpha antagonists and risk of cancer in patients with
Uveitis is a sight-threatening disease that poses a heavy inflammatory bowel disease. JAMA. 2014;311:2406–2413.
burden on the quality of life of the affected individuals, who
are mainly in the working-age group. 142 Treatment is based 11. Sugita S, Yamada Y, Kaneko S, et al. Induction of regulatory T
on a stepladder approach: corticosteroids, conventional cells by infliximab in Behc¸et’s disease. Invest Ophthalmol Vis Sci.
immunomodulatory drugs, and biologic response modifying 2011;52:476– 484.
drugs. 4 There has been considerable progress in the treatment
of NIU over the past 20 years. In particular, biologic drugs have 12. Ashkenazy N, Saboo US, Abraham A, et al. Successful treatment
revolutionized the treatment of sight-threatening autoimmune with infliximab after adalimumab failure in pediatric noninfectious
and autoinflammatory forms. As laboratory research continues uveitis. J AAPOS. 2019;23:151.e1-151.e5.
to illuminate the mechanisms of intraocular inflammation, new
biologic drugs are constantly entering the pipeline, and thus 13. Suhler EB, Smith JR, Wertheim MS, et al. A prospective trial of
further developments in this field are anticipated within the infliximab therapy for refractory uveitis: preliminary safety and
coming decade. efficacy outcomes. Arch Ophthalmol. 2005;123:903–912.

14. Sharma PK, Markov GT, Bajwa A, et al. Long-term efficacy of systemic
infliximab in recalcitrant retinal vasculitis. Retina. 2015;35:2641–
2646.

15. Maleki A, Sahawneh HF, Ma L, et al. Infliximab therapy in patients
with noninfectious intermediate uveitis resistant to conventional
immunomodulatory therapy. Retina. 2017;37:836–843.

16. Kruh JN, Yang P, Suelves AM, et al. Infliximab for the treatment of
refractory noninfectious uveitis: a study of 88 patients with long-term
follow-up. Ophthalmology. 2014;121:358–364.

17. Baughman RP, Bradley DA, Lower EE. Infliximab in chronic ocular
inflammation. Int J Clin Pharmacol Ther. 2005;43:7–11.

18. Suhler EB, Smith JR, Giles TR, et al. Infliximab therapy for refractory

DOS Times - Volume 28, Number 1, January-February 2022 84 www.dosonline.org/dos-times

DOS TIMES

uveitis: 2-year results of a prospective trial. Arch Ophthalmol. therapy: Long‑term results in uveitis patients and preliminary safety
2009;127:819–822. and activity data for establishing parameters for subcutaneous
administration. J Autoimmun 2003;21:283‑93
19. Fabiani C, Sota J, Vitale A, et al. Ten-year retention rate of infliximab 34. Teoh SC, Sharma S, Hogan A, Lee R, Ramanan AV, Dick AD.
in patients with Behc¸et’s disease-related uveitis. Ocul Immunol Tailoring biological treatment: Anakinra treatment of posterior
Inflamm. 2019;27:34–39. uveitis associated with the CINCA syndrome. Br J Ophthalmol
2007;91:263‑4.
20. Pulido JS, Pulido JE, Michet CJ, et al. More questions than answers: a 35. Gül A, Tugal‑Tutkun I, Dinarello CA, Reznikov L, Esen BA, Mirza A,
call for a moratorium on the use of intravitreal infliximab outside of et al. Interleukin‑1ß‑regulating antibody XOMA 052 (gevokizumab)
a well-designed trial. Retina. 2010;30:1–5. in the treatment of acute exacerbations of resistant uveitis of Behcet’s
disease: An open‑label pilot study. Ann Rheum Dis 2012;71:563‑6.
21. Hamza MM, Macky TA, Sidky MK, et al. Intravitreal infliximab in 36. Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, et
refractory uveitis in Behc¸et’s disease: a safety and efficacy clinical al. Effects of AIN457, a fully human antibody to interleukin‑17A,
study. Retina. 2016;36:2399–2408. on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med
2010;2:52ra72.
22. Giganti M, Beer PM, Lemanski N, et al. Adverse events after 37. Smith KG, Jones RB, Burns SM, Jayne DR. Long‑term comparison
intravitreal infliximab (Remicade). Retina. 2010;30:71–80. of rituximab treatment for refractory systemic lupus erythematosus
and vasculitis: Remission, relapse, and re‑treatment. Arthritis Rheum
23. Lee J, Koreishi AF, Zumpf KB, et al. Success of weekly adalimumab 2006;54:2970‑82.
in refractory ocular inflammatory disease. Ophthalmology. 38. Zulian F, Balzarin M, Falcini F, Martini G, Alessio M, Cimaz R, et
2020;127:1431– 1433. al. Abatacept for severe anti‑tumor necrosis factor alpha refractory
juvenile idiopathic arthritis‑related uveitis. Arthritis Care Res
24. Ramanan AV, Dick AD, Jones AP, et al. Adalimumab plus (Hoboken) 2010;62:821‑5.
methotrexate for uveitis in juvenile idiopathic arthritis. N Engl J Med. 39. Fragoulis GE, McInnes IB, Siebert S. JAK-inhibitors new players in
2017;376:1637– 1646. the field of immune-mediated diseases, beyond rheumatoid arthritis.
Rheumatology (Oxford England). 2019;58:i43–i54
25. Jaffe GJ, Dick AD, Brezin AP, et al. Adalimumab in patients with
active noninfectious uveitis. N Engl J Med. 2016;375:932–943. Corresponding Author:

26. Nguyen QD, Merrill PT, Jaffe GJ, et al. Adalimumab for prevention of Dr. Shalin Shah, MS
uveitic flare in patients with inactive non-infectious uveitis controlled Vitreoretina Services
by corticosteroids (VISUAL II): a multicentre, double-masked, Dr. Shroff’s Charity Eye Hospital, Daryaganj, New Delhi.
randomised, placebo-controlled phase 3 trial. Lancet. 2016;388:1183–
1192.

27. Cordero-Coma M, Calleja-Antolin S, Garzo-Garcia I, et al.
Adalimumab for treatment of noninfectious uveitis: immunogenicity
and clinical relevance of measuring serum drug levels and antidrug
antibodies. Ophthalmology. 2016;123:2618–2625.

28. Foster CS, Tufail F, Waheed NK, et al. Efficacy of etanercept in
preventing relapse of uveitis controlled by methotrexate. Arch
Ophthalmol. 2003;121:437–440.

29. Miserocchi E, Modorati G, Pontikaki I, et al. Long-term treatment
with golimumab for severe uveitis. Ocul Immunol Inflamm.
2014;22:90–95.

30. van der Horst-Bruinsma I, van Bentum R, Verbraak FD, et al. The
impact of certolizumab pegol treatment on the incidence of anterior
uveitis flares in patients with axial spondyloarthritis: 48-week interim
results from CVIEW. RMD Open. 2020;6:e001161.

31. Granel B, Serratrice J, Disdier P, Weiller PJ. Dramatic improvement
with anakinra in a case of chronic infantile neurological cutaneous
and articular (CINCA) syndrome. Rheumatology (Oxford)
2005;44:689‑90.

32. Schäfer VS, Zwerina J. Biologic treatment of large‑vessel vasculitides.
Curr Opin Rheumatol 2012;24:31‑7.

33. Nussenblatt RB, Thompson DJ, Li Z, Chan CC, Peterson JS, Robinson
RR, et al. Humanized anti‑interleukin‑2 (IL‑2) receptor alpha

www.dosonline.org/dos-times 85
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

Energy Based Devices & Their Use in
Oculo-Facial Plastic Surgery

Debraj Shome[1], MD, FRCS, FACS, MBA, Monika Surana[2], Rinky Kapoor[3], MD
1. Professor, Department of Facial Plastic Surgery & Director, The Esthetic Clinics, Mumbai.
2. Fellow, Facial Plastic Surgery and Facial Cosmetic Surgery, The Esthetic Clinics.
3. Department of Cosmetic Dermatology & Director, The Esthetic Clinics, Mumbai.

Introduction fractional laser technology is gaining wide popularity because
In the current scenario, Facial Plastic Surgery is one of the of its favorable side effect profile, reduced recovery time and
fastest growing branches in medicine. Improvements in the safe- significant clinical outcome. Fractional laser technology
ty and the efficacy for energy-based treatment devices have con- represents a major advantage over the previous conventional
tributed to this growth. With these wide variety of options, the ablative methods (fully ablative pCreOd2icatnadbileirtybiuinm:thYeAGdelpatsherso)f.
modern facial plastic & cosmetic surgery has reached another They have the advantages of
level, as these non-surgical techniques require significantly less tissue ablation and thermal denaturation and have lesser
downtime and have much lesser side effects. downtime.
Three broad categories of technology are leading Energy-based
rejuvenation Technology today: Lasers, Light therapy, and Co2 Laser of carbon gdoilodxidstean(dCa0r2d)
Non-laser based thermal tightening devices. Laser light therapy Five decades after the introduction to be the
has continued to diversify with the use of ablative and nonabla- laser, since 1963, it still continues
tive resurfacing technologies, fractionated lasers, and their com- in ablative lasers. Being a high tphoewecroendvelnatsieorn, aCl Osu2 rglaiscearl
bined use. Light therapy has developed for use in combination has significant advantage over
with other technologies or as stand alone treatment options. procedure. It is widely used in facial plastic surgery to improve
Finally, thermally based nonlaserskin tightening devices, such the appearance of scars and to remove benign growths.
as radiofrequency (RF) and intense focused ultrasonography There ianrethtewtoissmueodisetshienchCrOom2 olpahseorrse; continuous and pulsed.
(HIFU), are evolving technologies, that have changed rapidly Water and it selectively absorbs
over the past 5 years. the CO2 laser (infrared laser with 10,600 nm).
The main indications of this laser includes skin resurfacing
Lasers for acne scars, traumatic scars, periorbital and perioral
wrinkles, skin rejuvenation, seborrheic keratosis, deep
The market for nonsurgical, energy-based facial rejuvenation penetrating nevus, variety of warts, moles, skintags, skin
techniques has increased exponentially, since lasers were cancers. We use this laser commonly post every surgery,
first used for skin rejuvenation in 1983. Advances in this to improve the healing of the surgical scars and to remove other
area have led to a wide range of products that require the scars as well.
modern facial plastic surgeon to have a large repertoire of
knowledge. LASER (an acronym: Light Amplification by Certain precautions should be taken while undergoing the
Stimulated Emission of Radiation) is emission of a radiation procedure like correct patient selection, as Fitzpatrick’s
which is stimulated, and light amplifies it further. Fractional skin type 4 and type 5 skin (darker skin) are very prone
photothermolysis (FP) has revolutionized the use of lasers for for hyperpigmentation. History of keloids formation,
resurfacing. Much variation exists with different machines isotretinoin use in past 4-6 months, dermaabrasion etc should
and techniques, and newer indications are being evolved almost be asked for.
daily. Different Laser systems are available:
Laser Resurfacing Erbium : Yag Laser
The laser-resurfacing industry has produced a multitude
of devices employing ablative, non-ablative and fractional To overcome the prhoybpleemrpsigamsseonctiaattieodn,widthelaCyOed2 laser, such as
technologies. The three approaches largely differ in their postinflammatory healing etc.
method of thermal damage, degrees of efficacy, downtime Erbium: Yag laser was introduced. The 2,940 nmwavelenghth
and side effect profiles against each other. Ablative Laser, emitted by it is absorbed 12-18 times more efficiently by super-
though more effective, usually has higher incidences of side ficial (water containing) tissues. The main indications include
effects like hyperpigmentation, especially in darker skin rhytides, superficial pigmentation scars, xanthelesma, moles,
types, compared to Non-ablative technologies. Recently syringomas etc. The fractional versions of the above lasers
tnhaemseellyasCeOrs2 and the Erbium YAG have revolutionized the use of
in Asian skin types and are now regularly used for
various indications with a much lesser incidence of side effects.

DOS Times - Volume 28, Number 1, January-February 2022 86 www.dosonline.org/dos-times

DOS TIMES

Lasers for Tatoo Removal Principle: The epidermis contains melanin and thus does
Laser tattoo removal was first used in the late 1960s following absorb light irradiation. The hair contains high concentrations
the creation of the first laser, but removal often led to suboptimal of melanin. It is the difference in the thermal elevation in the
results due to significant surrounding tissue destruction epidermis versus the thermal elevation in the hair bulb that
and scarring. It was not until the description of the theory of makes for selectivity of treatment.
selective photothermolysis in the 1980s that exogenous tattoo Intense Pulsed Light
pigment could be selectively targeted as a chromophore at Intense pulsed light was first described for the treatment of
specific wavelengths. Due to the small size of the tattoo particles, rhytides, fine hair removal and photodamaged skin in 2000.
rapid pulses of high heat at very short pulse durations in the Because of their safety profile and lack of down time, they
nanosecond to picosecond range are required to prevent cooling are often used in combination with other lasers to enhance
of the particles. The thermal relaxation time of tattoo particles is rejuvenation.
thought to be less than ten nanoseconds. Lasers with Q-switched Cryolipolysis
technology are capable of producing light pulses of short Noninvasive procedures for fat reduction are becoming
duration, but with a peak power that is much higher than is increasingly popular. The demand for cosmetic procedures
achievable with continuous wave output. More recently, lasers of targeting subcutaneous adipose tissue (SAT) has rapidly
even shorter pulse duration called picosecond lasers, have been increased, with good results. Cryolipolysis has proven to
developed, potentially offering better targeting of chromophores effectively and safely reduce the subcutaneous fat deposits. In
with less damage to surrounding tissue. cryolipolysis, the adipose tissue is exposed to a temperature
The type of laser and wavelength chosen for removal largely of 10°C for 50 minutes or more, using vacuum applicators.
depends on the patient’s tattoocolor and skin type. Q-switched Cryolipolysis is a noninvasive procedure that reduces localized
(QS) lasers such as the QS Ruby, QS Nd: YAG, and QS adipose tissue safely and effectively; targeted cold temperatures
Alexandrite until recently were the most effective devices trigger apoptosis of the adipocytes without affecting the
for tattoo removal. However, picosecond lasers have quickly surrounding tissue and this has been cleared by the USFDA as a
become the mainstay of treatment due to their superior efficacy safe treatment option to reduce subcutaneous fat noninvasively
and decreased treatment durations. Now there are picosecond for areas like abdomen, flanks, thighs, and more recently, for
532-nm, 694-nm, 755-nm, and 1064-nm devices available to the submental area. In submental fat reduction, it has shown
target a wide array of tattoo pigments. Patients with Fitzpatrick excellent results, where one-two sittings are required at the
IV-VI (darker) skin types should be treated cautiously due to most, with an interval of a month.
increased risk for hypopigmentation following treatment. Lasers
that penetrate deeper into the dermis, such as the Nd: YAG High Intensity Focused Ultrasound (HIFU)
1064-nm laser, are associated with a decreased risk of epidermal
damage and hypopigmentation in this patient population. In 2009, a device delivering intense ultrasound energy or
Some chromophores for various laser wavelengths include: 532 HIFU (Ulthera; Ultera Inc., Mesa, AZ) received US Food and
nm - red, orange, yellow, brown. 694 nm - black, blue, green. Drug Administration clearance for use in a noninvasive brow
755 nm - black, blue, green. 1064 nm - black, blue. Colors that lift and neck lift. Since then, HIFU has been the representative
respond best to laser removal are black, brown, dark blue, and noninvasive method for skin rejuvenation. Various HIFU mod-
green, while the most difficult colors to remove are red, orange, els have been introduced and arecommonly being used. This
yellow, and light blue. Also these lasers have widely been used technique induces spatially definedheating and coagulation
for pigmentary disorders like Nevus of Ota, followed by solar (TCP) within preselected depths using different transducers
lentigines, post-inflammatory hyperpigmentation, melisma, (HPs,cartridges) and initiates a wound healing process that
congenital nevus, café au lit macule, dermal melanocytosis, stimulates new tissue formation andcollagen remodeling. As a
Nevus of Ito, and Becker’s nevus. result, the skin is tightened, and the skin of the face and body
Laser Hair Reduction arevisibly lifted.
Today, laser hair removal (LHR) is the most commonly
requested cosmetic procedure in the world. The ideal candidates Radiofrequency
for LHR are fair skinned with dark terminal hair; however,
LHR can today be successfully performed in all skin types. Radiofrequency works by using the natural electrical resistance
Knowledge of hair follicle anatomy and physiology, proper of the tissues toconvert that energy into thermal energy.
patient selection and preoperative preparation, principles of Bothmonopolar and bipolar forms of this technology are
laser safety, familiarity with the various laser/light devices, and available. It is frequently used to treat skin laxity, rhytides,
a thorough understanding of laser-tissue interactions are vital to acne vulgaris, scarring and cellulite. Results show modest
optimizing treatment efficacy while minimizing complications improvement in skin tightening of face and neck. Improvement
and side effects. in dyschromias, skin texture etc also has been shown to occur
very well.

www.dosonline.org/dos-times 87
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

Radiofrequency With a wide variety of options, the modern facial plastic surgeon
can now have a frank discussion with the patient regarding
Radiofrquency like Venus Freeze is an FDA-approved, non-inva- nonsurgical techniques, leading to greater predictability of
sive treatment for cellulite and loose skin on the face, neck, and results & increased patient satisfaction.
body. Usually six sessions are recommended for the face/neck
and eight to 10 for the body. Venus Freeze provides an extreme- Corresponding Author:
ly comfortable, non-surgical solution that harnesses the power
of radio frequency technology to boost collagen production by Dr. Debraj Shome, MD, FRCS, FACS, MBA
heating the deeper layer of tissue under the skin. This treatment Professor, Department of Facial Plastic Surgery & Director,
works to smoothen out fine lines and wrinkles, tighten sagging The Esthetic Clinics, Mumbai.
skin, and restore a refreshed, younger-looking appearance.
Venus Freeze™ works by using a combination of Multi-Polar
Radio Frequency and Pulsed Electro Magnetic Fields. The two
technologies work in unison to safely and comfortably heat the
tissue under the surface of skin, which encourages the body to
produce more collagen and elastin fibers. This process results in
firmer, smoother skin that looks noticeably more youthful on
the surface.
In summary, the improvements in safety and efficacy for energy-
based treatment devices have greatly expanded the patient base.
Today, we can achieve non-surgically, with almost zero risk and
morbidity, what almost certainly needed surgery a few years ago!

DOS Times - Volume 28, Number 1, January-February 2022 88 www.dosonline.org/dos-times

DOS TIMES

Recent Advances in Amblyopia Therapy

Asmita Mahajan, MD, Rebika Dhiman, MD, Rohit Saxena, MD, PhD
Strabismus and Pediatric Ophthalmology Services, Dr. R. P. Centre for Ophthalmic Sciences, AIIMS, New Delhi.

Abstract: Amblyopia (also called lazy eye) is a significant cause of decrease in vision in children. It is amenable to
treatment in early years of life. If not treated timely, the vision in the affected eye(s) will be permanently decreased.
So, vision screening is recommended for early detection and timely management of amblyopia. The conventional
treatment options for amblyopia include patching and penalisation of the sound eye after correction of any under-
lying refractive error. Success rates of amblyopia treatment decline with age due to decreasing neuronal plasticity.
Newer treatment options like pharmacotherapy and active vision therapy show promising outcomes even in older age
group (upto early teens). However, further research is needed to elucidate their role in amblyopia.

Introduction These changes were not observed in mature cats after similar
periods of light and form deprivation. These experiments
Amblyopia is defined as a decrease of visual acuity in one eye formed the basis of our understanding of amblyopia. Many
when caused by abnormal binocular interaction or occurring in studies that followed (Berardi et al, 2000; Hensch & Quinlan,
one or both eyes as a result of pattern vision deprivation during 2018) cemented this and the notion of critical period.
visual immaturity, for which no cause can be detected during
the physical examination of the eye(s) and which in appropriate Work Up and Diagnosis of Amblyopia
cases is reversible by therapeutic measures.[1] The first step to diagnose amblyopia and plan management is
Prevalence estimates from population-based studies in children an accurate assessment of visual acuity using an age appropriate
age 6 to 71 months range from 0.7% to 1.9% whereas school- strategy in standardised testing conditions. Visual assessment of
based studies of older children typically report higher rates the infant/toddler involves a qualitative assessment of fixation
(range: 1.0% to 5.5%).[2] and tracking eye movements. In older children, charts with
Hubel & Wiesel[3] demonstrated cortical plasticity and effect of black optotypes on a white background are used. It is vital that
sensory deprivation in kittens by suturing the lids of the kittens optotypes are presented in a line as single optotypes testing is
and placing a translucent plastic contact lens or a nictitating likely to overestimate acuity (crowding phenomenon).
membrane over the eyes. They demonstrated histological American Academy of Ophthalmology Pediatric Ophthalmolo-
evidence of atrophy in geniculate cells (more in complete gy/Strabismus Panel in 2017 gave a diagnostic criteria for ambly-
monocular deprivation) receiving input from the covered eye. opia based on visual acuity.[4] (Figure 1)

Assessment Finding

Unilateral Amblyopia: Asymmetric objection
Response to monocular occlusion Failure to initiate or maintain fixation
Fixation preference Interocular difference* of two or more octaves
Preferential looking Interocular difference of two or more lines
Best-corrected visual acuity
Age 3 to ≤4 years: visual acuity worse than 20/50
Bilateral Amblyopia: Age 4 to ≤5 years: visual acuity worse than 20/40
Best Corrected Visual Acuity Age >5: visual acuity worse than 20/30

Figure 1 : AAO PPP 2017 Diagnostic criteria for amblyopia.
*A 2-octave difference is a 4-card difference in the full set of Teller Acuity Cards.

The next step is to look for binocular alignment and stereoacu- Strategies in Amblyopia Treatment
ity. The corneal light reflection, binocular red reflex (Brückner) The approach to a case of amblyopia should proceed in a step
test, cover tests, randot stereo-acuity tests are done for the same. wise manner. The first step is to correct any causes of degradation
Lastly, refraction using age appropriate cycloplegia and a dilat- of retinal image. This includes treatment of congenital cataract,
ed fundus examination (to rule out any organic cause of poor corneal opacity, intraocular inflammation, vitreous hemorrhage,
vision).

www.dosonline.org/dos-times 89
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

ptosis etc. The second step is to correct underlying refractive have found no difference in efficacy of atropine 1% as compared
errors by doing retinoscopy under age appropriate cycloplegia. to 6 hrs of patching in moderate amblyopia in 3-7 years age even
The third step is to promote the use of the amblyopic eye by after 10 years of follow up.[12] Weekend atropine seems to be
patching or optical/pharmacological penalisation. equally effective and produces greater compliance. A Cochrane
review[13] reported that atropine was associated with better
1. Optical Correction adherence and quality of life, but also a higher reported risk of
Optical correction removes the image blur at the fovea thus adverse events like transient mild reduction in the visual acuity
inducing visual pathway stimulation. A study by Pediatric of the sound eye (not requiring treatment) and light sensitivity.
Eye Disease Investigator Group (PEDIG) in children 7 to 17 Skin, lid, conjunctival irritation were noted more commonly
years old found that amblyopia improved two or more lines among participants receiving patching. It is important, however,
with optical correction alone in about one-fourth of the to monitor for systemic side effects of atropine such as fever and
children.[5] The VA improvement may begin as early as the first tachycardia while using it.
few weeks and may improve considerably up to 12 weeks. The Optical penalization
treatment effect depends on compliance to spectacle usage in Optical penalization by adding plus correction to cycloplegic
a dose-dependent manner.[6] Strabismic and mixed amblyopes refraction or under correcting pre-existing hyperopia in the
respond to optical correction as well and it should be considered sound eye until fixation shifts to the amblyopic eye is another
before initiating other therapies.[7] effective treatment for moderate amblyopia.
Bangerter Filters
2. Occlusion Therapy Bangerter filters are available in graduated densities and can be
‘Patching’ or occlusion of the sound eye to preferentially stuck to the lens of eyeglasses to reduce the VA of the sound eye.
stimulate the amblyopic eye has remained the gold standard The Bangerter Foil Bar is used to determine when the preference
of treatment in spite of variable success with other forms of switches from dominant eye to the less dominant eye and makes
treatment. Commercially available opaque adhesive patches it easy to determine the appropriate foil for use (Figure 2). They
or home-made patches are used over the skin with spectacles are largely used for maintenance therapy after initial treatment
worn over it. Occlusion therapy may be given in different with occlusion or atropine.
types of dosages, e.g., full-time or part-time. The ATS 2A
compared 6 hours versus full-time daily patching for severe Figure 2 : (a) Bangerter foil bar (b) Effect of bangerter filters on quality
amblyopia and the ATS 2B compared 2 versus 6 hours of daily of vision.
for the treatment of moderate amblyopia combined with 1 4. Augmentation of Cns Plasticity
hour of daily near activities while patching. The extra patching Treatment of older children and adults for amblyopia is usually
did not give any added benefit in term of improvement or its unsuccessful because of closure of the window of neuronal
rate and hence full time and part time patching are equally plasticity. Several modes of augmenting plasticity have been
effective.[8,9] Patching during activities requiring sustained tried to facilitate therapy outside the critical period.
attention and co-ordination such as playing, reading and Initial studies of levodopa suggested that it might improve
socialising result in maximal gains. visual acuity and reduce inteocular suppression. It works
The success of patching is dependent on compliance and this by increased endogenous expression of nerve growth
remains the major limitation to good outcomes. In the MOTAS factors and receptors related to plasticity of visual
study[10], occlusion episodes were recorded by an occlusion development.[14] Although multiple case reports exist which
dose monitor (ODM). Only 14% of participants achieved an show benefit of levodopa in older children and refractory
average concordance within 30 minutes of the prescribed dose amblyopia, a randomised controlled trial by PEDIG
rate. Studies have shown that intensified education of parents group failed to demonstrate any additional benefit over
with amblyopic children and involving the children in their placebo.[15] A study done at our centre also showed that levodopa
own patching by use of educational cartoons and rewards can supplementation does not offer any advantage over occlusion
improve adherence to occlusion therapy.[11] alone. Moreover, there could be an increased risk of occlusion
as it affects the plasticity of the visual cortex.[16]
3. Penalization
Penalization was earlier used as a second treatment when
occlusion was not complied with, or for post-occlusion as a
maintenance treatment. Recently, however, it has begun to be
used as a primary treatment modality. Penalisation makes the
non-amblyopic eye hyperopic, thus forcing the amblyopic eye
to be used for near activities. This hyperopia can be induced by
pharmacologically or optically.

Atropine Penalization
Atropine (1%) eye drops lead to loss of accommodation and
optical defocusing in the non-amblyopic eye. PEDIG studies

DOS Times - Volume 28, Number 1, January-February 2022 90 www.dosonline.org/dos-times

DOS TIMES

CITICHOLINE activates biosynthesis of phosphatidylcholine of binocular function and use of dichoptic therapy which
in neuronal cell membranes and increases levels of promotes use of amblyopic eye without occluding the good eye.
neurotransmitters opposing or preventing nerve cell damage. The amblyopic eye receives a more intense stimulus than the
Pawar et al in his study has suggested that addition of citicoline, fellow eye, by reducing the contrast, the luminance or both of
even after maximum improvement with conventional the image presented to the strong eye.
patching was achieved, can further improve the visual This helps balance cortical input and overcome inter ocular
acuity.[17] Frenisa et al reported no additional benefit of adding suppression.
citicholine to patching but found that it helps in stabilizing the In the PEDIG study[21], a “falling blocks” game, which
effects obtained during the treatment period.[18] A randomised uses red-green anaglyphic glasses was used for one hour
controlled trial by Narula et al in 30 patients also found per day for 16 weeks but less than one-quarter of children
improvement in visual acuity with citicholine over and above completed 75% of prescribed treatment time and the
that obtained by patching alone.[19] More large scale longitudinal results were underwhelming. Since then softwares (yet to
trials are needed to further elaborate the role of citicholine be made publically accessible) have been developed using
especially in the older age group and the effects after cessation more engaging games with anaglyphic glasses to improve
of drug therapy. compliance. (Figure 3)

5. Active Vision Therapy Figure 3 : A car game software developed by Bynocs for amblyopia therapy
There have been multiple attempts to increase the effectiveness (a) A patient undergoing session using anaglyph glasses (b & c) dichoptic
of treatment for amblyopia, as adjuncts to patching and decrease game play screens. The target is to drive the car and avoid any crash
its duration since it may lead to psycho social problems such as (d) gameplay to promote fusion and stereopsis.
loss of self esteem. The interactive binocular treatment (I-BiT) system utilized a
Active vision therapy in form of near vision tasks, fast pointing virtual reality technology and developed an interactive Virtual
activities, Videogames (fast-action) can be a useful modality Reality-based binocular system, the latest of which treats
as it may help in re-education of the amblyopic pathway using amblyopia via participation in interactive computer games
intense sensory and motor stimulations. Singh et al. reported with 3D shutter glasses. In this system, the patient monitor is
significant differences in their RCT, since the group that a 3D monitor with a refresh rate of 120 Hz as required for use
received monocular video game play and patching improved with the shutter glasses. The shutter glasses’ lenses lighten and
2.4 lines in VA, while the patching group enhanced 1.8 darken in synchrony with the monitor but faster than the user
lines.[20] In addition, good treatment compliance (mean of 69% can perceive. Images are presented to both eyes but parts of
or more) with visual therapy was reported by many authors the image are presented only to the amblyopic eye. To increase
compared to compliance with patching which ranges from 44% compliance it also allows children to watch any DVD of their
to 57%. own choice.
Pilot studies have shown that the I-BiT™ system can improve the
Monocular active vision therapy/perceptual learning visual acuity in amblyopic patients upto a mean improvement in
Perceptual learning refers to any relatively permanent and visual acuity of 0.18 LogMAR.[22]
consistent change in the perception of a sensory task following Head-mounted virtual reality displays have also shown
repeated practice. It is an active process and activities like gray preliminary evidence to suggest improvement in both VA and
scale contrast detection tasks or vernier acuity tasks are done
using amblyopic eye after patching. Improvements occur at
an exponential rate until it reaches plateau. There are however
two important limitations of perceptual learning: specificity
and boredom. Specificity refers to the training effects being
mostly confined to the trained stimulus and task. It is also
highly repetitive and may lead to boredom in clinical practice.
Video game play after patching is more engaging with varied
challenging demands.

Binocular active vision therapy (Dichoptics)
There is now mounting evidence that the deficit in amblyopia
extends beyond monocular visual acuity impairment and into
higher-order function such as binocular vision and visuomotor
activities. Among patients with successfully treated amblyopia
about one fourth require retreatment within 1 year, indicating
significant ongoing amblyogenic forces likely related to
asymmetric fusional suppression. Hence came a apardigm
shift towards conceptualising amblyopia as a primary disorder

www.dosonline.org/dos-times 91
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

stereoacuity in adult patients. An improvement in BCVA of 1.5 12 weeks of 1hr/day 6 days a week treatment.[24]
logMAR lines was seen over 8 sessions in a month.[23] In the With Luminopia One, patients choose video content they want
Oculus Rift OC DK2 virtual reality head mounted display two to watch, and a software application modifies the content in real-
games are available, a space game in which subjects were flying time to rebalance visual input to the brain.
spaceship through a system of rings (Figure 4) and a breaker The advantage of using virtual reality over dichoptic glasses to
game which is a typical block breaker game, but played in a treat amblyopia is that it leads to immersion of the participant in
virtual reality 3D setting. Both games have a dichoptic setting in a given task and activation of higher-order visual cortical areas
which the central part of the picture shown is different with the Continuously evolving technology will likely yield additional
dominant eye and amblyopic eye forcing the brain to use both means to deliver dichoptic stimuli in engaging, interactive
eyes together to play. platforms.

Figure 4 : In the oculus rift head set, the amblyopic eye views the half of Figure 6 : Image modifications used by Luminopia where the stronger eye
the display in which the patient sees the correct color of the gates in order image has a lower contrast, and the images are presented with overlays
to flight spaceship (seen only with the dominant eye) through the blue that force the brain to use both eyes to see them properly.
gates[23]
In another type of headset undergoing trial at our centre there 6. Intermittent Occlusion Glasses
are games where the background is made visible to both the An electronic device, Amblyz liquid crystal intermittent
eyes and one part of the game is made visible to the stronger eye occlusion glasses (XPAND 3D Group, Ljubljana, Slovenia), has
while one specific part connected to part visible to stronger eye been introduced which is programmed to unilaterally alternate
is made visible to weaker eye. To play the game successful coor- between opaque and transparent phases at 30-second intervals,
dination between the eyes is required (Figure 5). providing effective occlusion of the fellow eye 50% of the time
they are worn. Because these glasses are more child friendly and
Figure 5 : (a) Child undergoing amblyopia therapy using virtual reality do not produce the side effects seen with adhesive skin patches,
head set (b) A prototype of the kind of games available in. In this game they may potentially improve compliance with occlusion
the amblyopic eye (left) is made to see a bird which has changing objects therapy. A pilot study has proved non inferiority of IO-Therapy
on the top. The non amblyopic eye sees everything else. Patient has to press with Amblyz liquid crystal glasses to adhesive patching in
trigger when the changing object visible to amblyopic eye matches with the children 3–8 years of age with moderate amblyopia.[25]
constant object visible to both eyes. Conclusion
Luminopia, (Figure 6) a virtual reality-based treatment has Occlusion therapy is currently the gold standard of amblyopia
recently received FDA approval based on phase 3 trials which management. Pharmacological and optical penalization are
showed 1.8-line improvement in BCVA in the weak eye effective alternatives to occlusion where compliance is an issue.
compared from 0.8-line improvement in the control group over Active vision therapy has shown promising outcomes as adjuncts
but are still evolving as primary treatment options. The younger
the child at the time of onset of amblyopia therapy, better are
the outcomes. The role of pharmacotherapy for augmentation
of neural plasticity in older children and adults is not fully
elucidated. Compliance remains the major limitation to good
outcomes of amblyopia therapy.
References
1. Noorden GK von: Mechanisms of amblyopia. Doc Ophthalmol 34:93,

1977.
2. Amblyopia PPP – 2017 (AAO PPP Pediatric Ophthalmology/

DOS Times - Volume 28, Number 1, January-February 2022 92 www.dosonline.org/dos-times

DOS TIMES

Strabismus Panel, Hoskins Center for Quality Eye Care) 17. Pawar PV, Mumbare SS, Patil MS, Ramakrishnan S. Effectiveness of
the addition of citicoline to patching in the treatment of amblyopia
3. Wiesel TN, Hubel DH. Effects of visual deprivation on morphology around visual maturity: a randomized controlled trial. Indian J
and physiology of cells in the cats lateral geniculate body. J Ophthalmol. 2014 Feb;62(2):124-9.
Neurophysiol. 1963 Nov;26:978-93. doi: 10.1152/jn.1963.26.6.978.
PMID: 14084170. 18. Fresina M, Dickmann A, Salerni A, De Gregorio F, Campos EC. Effect
of oral CDP-choline on visual function in young amblyopic patients.
4. Wallace DK, Repka MX, Lee KA, Melia M, Christiansen SP, Morse Graefes Arch Clin Exp Ophthalmol. 2008 Jan;246(1):143-50.
CL, Sprunger DT; American Academy of Pediatric Ophthalmology/
Strabismus Preferred Practice Pattern Pediatric Ophthalmology 19. Anurag N, Rajiv K, Shilpa S, Manish Y. Efficacy of Citicolline in
Panel. Amblyopia Preferred Practice Pattern®. Ophthalmology. 2018 Treatment of Amblyopia as an Adjunct to Patching. JOJ Ophthal.
Jan;125(1):P105-P142. 2018; 7(2): 555706.

5. Randomized Trial of Treatment of Amblyopia in Children Aged 7 20. A. Singh, P. Sharma, and R. Saxena, “Evaluation of the role of
to 17 Years. Arch Ophthalmol. 2005;123(4):437–447. doi:10.1001/ monocular video game play as an adjuvant to occlusion therapy in
archopht.123.4.437. the management of anisometropic amblyopia,” Journal of Pediatric
Ophthalmology & Strabismus, vol. 54,no. 4, pp. 244–249, 2017.
6. Maconachie G, Farooq S, Bush G, Proudlock FA, Gottlob I. Effect
of compliance to glasses wear on the outcome of visual acuity after 21. Holmes JM, Manh VM, Lazar EL, et al. Effect of a Binocular iPad
refractive adaptation. Investig Ophthalmol Vis Sci. 2012;53:5609. Game vs Part-time Patching in Children Aged 5 to 12 Years With
Amblyopia: A Randomized Clinical Trial. JAMA Ophthalmol.
7. Writing Committee for the Pediatric Eye Disease Investigator 2016;134(12):1391-1400.
Group. Optical treatment of strabismic and combined strabismic-
anisometropic amblyopia. Ophthalmology;119(1):150-8. 22. Herbison N, MacKeith D, Vivian A, Purdy J, Fakis A, Ash IM, et al.
Randomised controlled trial of video clips and interactive games to
8. Pediatric Eye Disease Investigator Group. A randomized trial of improve vision in children with amblyopia using the I-BiT system. Br
patching regimens for treatment of moderate amblyopia in children. J Ophthalmol 2016;100:1511–6.
Arch Ophthalmol 2003;121:603–11.
23. Žiak P, Holm A, Halička J, et al. Amblyopia treatment of adults with
9. Pediatric Eye Disease Investigator Group. A randomized trial of dichoptic training using the virtual reality oculus rift head mounted
prescribed patching regimens for treatment of severe amblyopia in display: preliminary results. BMC Ophthalmol 2017;17:105.
children. Ophthalmology. 2003 Nov;110(11):2075-87.
24. h t t p s : / / w w w. b u s i n e s s w i r e . c o m / n e w s h o m e / 2 0 2 1 0 9 1 4 0 0 5 6 6 1 /
10. Stewart CE, Moseley MJ, Stephens DA, Fielder AR. Treatment dose- en/Luminopia-One-a-Digital-Therapeutic-for-Amblyopia-
response in amblyopia therapy: the Monitored Occlusion Treatment Demonstrates-Safety-and-Efficacy-in-Phase-3-Pivotal-Trial.
of Amblyopia Study (MOTAS). Invest Ophthalmol Vis Sci. 2004
Sep;45(9):3048-54. doi: 10.1167/iovs.04-0250. PMID: 15326120. 25. Wang J, Neely DE, Galli J, et al. A pilot randomized clinical trial of
intermittent occlusion therapy liquid crystal glasses versus traditional
11. Göransson A, Dahlgren LO, Lennerstrand G. Changes in conception patching for treatment of moderate unilateral amblyopia. J AAPOS.
of meaning, effects and treatment of amblyopia. A phenomenographic 2016;20(4):326-331.
analysis of interview data from parents of amblyopic children. Pat
Educ Counsel 1998; 34: 213–225. Corresponding Author:

12. Pediatric Eye Disease Investigator Group, Repka MX, Kraker RT, Prof. Rohit Saxena, MD, PhD
et al. A randomized trial of atropine vs patching for treatment of Strabismus and Pediatric Ophthalmology Services
moderate amblyopia: follow-up at age 10 years. Arch Ophthalmol. Dr. R. P. Centre for Ophthalmic Sciences, AIIMS, Ansari Nagar, New Delhi.
2008;126(8):1039-1044. doi:10.1001/archopht.126.8.1039.

13. Li T, Qureshi R, Taylor K. Conventional occlusion versus
pharmacologic penalization for amblyopia. Cochrane Database
of Systematic Reviews 2019, Issue 8. Art. No.: CD006460. DOI:
10.1002/14651858.CD006460.pub3.

14. Singh A, Nagpal R, Mittal SK, Bahuguna C, Kumar P.
Pharmacological therapy for amblyopia. Taiwan J Ophthalmol. 2017
Apr-Jun;7(2):62-69. doi: 10.4103/tjo.tjo_8_17. PMID: 29018759;
PMCID: PMC5602150.

15. Pediatric Eye Disease Investigator Group, Repka MX, Kraker RT,
Dean TW, Beck RW, Siatkowski RM, Holmes JM, Beauchamp CL,
Golden RP, Miller AM, Verderber LC, Wallace DK. A randomized
trial of levodopa as treatment for residual amblyopia in older children.
Ophthalmology. 2015.

16. Bhartiya P, Sharma P, Biswas NR, Tandon R, Khokhar SK. Levodopa-
carbidopa with occlusion in older children with amblyopia. J AAPOS.
2002 Dec;6(6):368-72. doi: 10.1067/mpa.2002.129043. PMID:
12506278.

www.dosonline.org/dos-times 93
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

Innovative Ideas in Ophthalmology :
Our Needs Our Call

Gunjan Saluja, MD, Amit Kumar Das, MD, Amar Pujari, MD, Namrata Sharma, MD, DNB, MNAMS
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi.

Abstract: Innovative ideas in the field of ophthalmology are very essential, technological advances have made it
possible to device any form of customized tools within no time. Here we discuss and review some of the clinically
useful innovative ideas for our Ophthalmologists.

Introduction collamer lens vault[4] and iridocorneal angle[5] are also possible
Our country is diverse not just in terms of mythology, religion (Figure 2). These techniques are not standard but they highlight
and languages but it’s really diverse in inheriting young innova- the possibility of multiple use of this simple combination.
tive minds with greater inventing qualities. These minds need
optimal nurturing and guidance for better future, however, due Figure 2 : Iridocorneal angle imaging using smart phone.
to rapidly increasing population and unequal doctor patient ra-
tio, quality education, creative thinking and subsequent quality 2. Smartphone Fundus photography
ophthalmic care is a real challenge. To address these limitations Fundus imaging remains an important aspect in tele-ophthal-
we need indigenous ideas in par with global expectations, in mology. A large number of devices have been devised to image
this particular direction we have drawn some of the ideas and the fundus using portable smartphone devices. A few examples
performed crucial observations for the larger benefit. include do it yourself fundus camera,[6] M-II retcam,[7] these
1. Low cost general smartphone innovations devices can be made with the help of easily available devices
Smartphone utility is constantly on the rise. Its portability, user like PVC pipe and 20 D lens. I-phone X can be directly used
friendly applications makes it an integral part in our daily lives. to obtain fundus images, as has been shown by Gunasekera
In ophthalmology majority of the investigations are dependent et al[8] and Pujari et al.[9] This can also help as a teaching tool.
on some or other form of optical instrument, hence by using (Figure 3) A large number of softwares can be used to further
the optical qualities of the smartphones, some of the ophthalmic process these images. Montage can be created by using Retina
exercises such as image documentation, visual function assess- Montage Software (RSIP Vision) or IMAGEnet (Topco, Oak-
ment and uniquely as a teaching tool can be performed. We de- land, NJ) software.[10] Therefore, depending upon once prefer-
scribed the several simple techniques of anterior segment pho- ences and needs image documentation is possible.
tography/imaging under diverse circumstances using a simple
attachable lens called macro lens. The lens is a 10x magnifying
lens. Imaging of the anterior segment structures from adnexa,
ocular surface, cornea, anterior chamber to the lens (Figure 1)
can be performed with great ease.[1] Besides this quantification
of iris torsion,[2] toric intra ocular orientation,[3] implantable

Figure 1 : Anterior segment imaging using smartphone and macrolens.

DOS Times - Volume 28, Number 1, January-February 2022 94 www.dosonline.org/dos-times

DOS TIMES

Figure 3 : Fundus photography using I phone X. eye, the needle within the steel bar moves to align itself along
the protractor scale and provides the values of slit light
3. Modifications in the existing tools for comprehensive alignment in individual degrees. This is of immense help in toric
ophthalmic imaging/evaluation. IOL placement assessment in the immediate post-operative
There are a large number of tools used in ophthalmology like period.[13]
anterior segment and posterior segment OCT, OCT-
Angiography, microscope integrated OCT. But the disadvantage 4. Surgical training modules
of these tools is their cost. Hence, to inter-convert one device
into other using the simple optical adjustment is a viable Surgical training is of the utmost importance in the training
option. Posterior segment OCT can be converted into anterior of budding ophthalmologists. Ophthalmic surgeries are skilful
segment OCT by simple placing a +20 Dioptre lens (Volks procedures and the skills need to be transferred from the
lens used for retinal examination) along its aperture. This experienced surgeon to the residents and fellows. The facility
adjustment induces extra convergence of the scanning rays of surgical skill transfer labs may not present in all the training
and focuses on the anterior segment structures. This aids centres of our country and in those situations it becomes
in visualisation of the structures from corneal surface till difficult to proffer the young minds with the sense of confidence
the posterior capsule, in addition, extra ocular muscle and and skills. As it is rightly said, necessity is the mother of all
punctal details can also be assessed with great clarity and innovations, so as to cope with the deficiency the residents
accuracy.[11] We performed many observations under different must themselves take initiative by utilizing the time in the
ocular conditions, including central corneal thickness, operating room after the surgical procedures are over, and can
implantable collamer lens vault, posterior capsular status and orient themselves with the microscope, suturing techniques. In
other and it has been found to reliable and replicable under addition, the goats eyes are easily available and are near ideal to
different conditions and different observers. perform capsulorrhexis, phacoemulsification, buckling surgery,
In oculopasty subsection and as a general ophthalmologist, di- extra ocular muscle surgery, trabeculectomy, corneoscleral
agnostic and therapeutic syringing and probing is a commonly repair and other procedure outside the operation theatre. The
performed procedure in patients of nasolacrimal duct obstruc- eyes can be brought to less than 100 rupees from the local
tion. However, the routinely used Bowman’s probe do not pos- slaughter house and can be mounted on the mannequin head or
sesses any calibration or markings on its surface to suggest the on the simple floor, using a step microscope or using the loops
level of obstruction. To counter this, we marked the scalein mil- above mentioned procedures can be practiced with great ease.
limetres scale on either side of the probe. In two millimetre scale We have highlighted majority of the techniques.[14,15,16 ,17]
on one side and in five millimetre scale on the other side using To conclude, the young minds must be receiving to the new and
cutting edge laser technology. Thus when the probe is inserted out of the box ideas that can aid in better understanding of the
into the lacrimal canaliculus, the level of obstruction can be as- subject and improving the management. The innovations must
certained with probe in situ.[12] be such that they can be economical, easily implemented and
In refractive surgeons clinic, assessment of toric intraocular replicable.
lens (IOL) alignment is of paramount importance. This can be
performed on sophisticated machines in the lab but, slit lamp References
examination site assessment makes it more comprehensive in
decision making. However, the existing slit lamp toric scale 1. Pujari A, Mukhija R, Singh AB, Chawla R, Sharma N, Kumar A.
possesses makings at 5 degrees and numbering at 15 degrees Smartphone-based high definition anterior segment photography.
each but not in individual degrees. We performed an exercise Indian J Ophthalmol. 2018 Sep 1;66(9):1375.
to convert the scale into individual degree, that is, on the Haag-
Streit slit lamp (model IM 900) we placed a simple plastic 2. Pujari A, Mukhija R, Phuljhele S. Quantification of Change in Iris
protractor and above it a needle within the steel bar. As the Torsion Using a Smartphone. Ophthalmology. 2019;126(1):126.
slit light moves in a 360 degree fashion along the patients
3. Pujari A, Yadav S, Mukhija R, Urkude J, Sharma N. Smartphone-
aided technique to quantify toric intraocular lens alignment. J
Cataract Refract Surg. 2019 Dec;45(12):1833–4.

4. Pujari A, Kishore A, Makwana T, Sharma N. A simple tool to
assess an implantable collamer lens vault. J Cataract Refract Surg.
2019;45(6):883–4.

5. Pujari A, Selvan H, Asif MI, Gupta B, Dada T. Smartphone-
aided Quantification of Iridocorneal Angle. J Glaucoma. 2019
Sep;28(9):e153–5.

6. Raju B, Raju NSD, Akkara JD, Pathengay A. Do it yourself
smartphone fundus camera – DIYretCAM. Indian J Ophthalmol.
2016 Sep;64(9):663–7.

7. Sharma A, Subramaniam SD, Ramachandran KI, Lakshmikanthan
C, Krishna S, Sundaramoorthy SK. Smartphone-based fundus
camera device (MII Ret Cam) and technique with ability to image

www.dosonline.org/dos-times 95
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

peripheral retina. Eur J Ophthalmol. 2016 Apr;26(2):142–4. Ophthalmol 2019; 67:547-8.
16. Pujari A, Basheer S, Rakheja V, Gagrani M, Saxena R, Phuljhele S,
8. Gunasekera CD, Thomas P. High-Resolution Direct Ophthalmoscopy
With an Unmodified iPhone X. JAMA Ophthalmol. 2019 Feb Sharma P. Extraocular muscle surgery on goats’ eye: An inexpensive
1;137(2):212–3. technique to enhance residents’ surgical skills. Indian J Ophthalmol
2019;67:1688-9
9. Pujari A, Markan A, Chawla R, Gagrani M. The additional role 17. Sudan R, Titiyal JS, Rai H, Chandra P. Formalin-induced cataract
of unmodified iPhone X as a direct ophthalmoscope. Indian J in goat eyes as a surgical training model for phacoemulsification.J
Ophthalmol. 2019 Jul;67(7):1253–4. Cataract Refract Surg. 2002 Nov;28(11):1904-6.

10. Pujari A, Lomi N, Goel S, Yadav S, Mukhija R, Kumar P, et al. Corresponding Author:
Unmodified iPhone XS Max for fundus montage imaging in cases of
retinoblastoma. Indian J Ophthalmol. 2019 Jun;67(6):948–9. Dr. Amar Pujari, MD
Assistant Professor
11. Pujari A, Sharma N, Assessment of posterior capsular integrity on Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi.
optical coherence tomography. Canadian J Ophthalmol.2019;54:e302–
e305.

12. Pujari A, Bajaj MS, Sharma P. Calibrated Bowman’s lacrimal probe.
Indian J Ophthalmol 2018;66:478

13. Pujari, A., Urkude, J., Singh, R., Yadav, S., Mukhija, R., & Sharma,
N. Slitlamp protractor: Refinement of existing slitlamptoric scale.
Journal of Cataract & Refractive Surgery. 2019 45(10), 1515.

14. Pujari A, Kumar S, Markan A, Chawla R, Damodaran S, Kumar
A. Buckling surgery on a goat’s eye: A simple technique to enhance
resident’s surgical skill. Indian J Ophthalmol. 2019;67:1327-8.

15. Pujari A, Sharma N, Chaniyara MH, Urkude J, Singh R, Yadav S,
Asif MI, Sidhu N. Optimal refinement of residents surgical skills by
training on induced goat’s eye corneoscleral perforation. Indian J

DOS Times - Volume 28, Number 1, January-February 2022 96 www.dosonline.org/dos-times

DOS TIMES

Financial Management for Doctors

Sanjay Dhawan, MS
Senior Consultant Eye Surgeon, Maharaja Agarsen Hospital, Punjabi Bagh, New Delhi.

Doctors in general are multi-taskers. Besides the Clinical Moderate to High Risk Investments are Stocks or Equity
Duties, they have to not only market themselves but also (Possibly 12-20-40%), Mutual Funds (12-18%), Equity Linked
protect themselves legally, manage profitability and up-to date Tax Savings Scheme (12-18%), Company Fixed Deposits
Professional Knowledge. Fortunately, they can retire late, but (8-11%), Real estate – Residential (2-3%) Commercial (3-
retire we all have to sooner or later. 6%) variable and taxable. Higher risk offers higher gains plus
The Question that I ask is if you can manage all of the above diversification offers security. All the Companies will not default
then why not your savings and retirement planning? One can or go bankrupt at once! If India goes to war with neighbours,
hire a Professional Financial Advisor or a Management it is a different matter all together. Putting money in Stocks is
Consultant at a cost but unless you yourself have knowledge, like buying a Portion (Share) of the Company and then getting
there is every chance of getting “less than the best” returns and the CEO of that Company to work for you to generate returns
besides who is more interested in your financial well being than for himself and you. (Please check Promoter holdings before
YOU. Financial Planners are only interested in you as much as investing)
you are interested in your patients. In this series of Articles, we Sensex, Stocks and Mutual Funds
aim to educate on financial management for your own self. Sensex, The Collective Index of Market Capitalisation of 100
Saving is NOT Investing. Investing Is Top Companies of India started out at 100 in April of 1979.
If you Save Only in a Bank Fixed Deposit, The chances are that Today is is 60000. Rs 1 Lakh invested in 1979 is now worth 60
you will not beat inflation and will end up with a disastrous re- Crore. That is wealth creation. Only the Top 100 Best Performing
tirement. As an Example, you need 55000/- per month now for Companies stay in the Sensex, If they do not perform, they drop
expenses, in 12 years time at only a 6% Inflation, you will need out and are replaced. Simultaneously all the Exchange Traded
115000/- per month. That is only and only if inflation does not Funds will withdraw the Money from this company and put it
exceed 6%. A Bank Fixed Deposit does not even come close to into the other one that makes it to the Sensex 100. This brings
6% today. (5.25 to 6% with TDS applicable currently). Retire- us to the concept of Mutual Funds. Fund Houses collect Investor
ment Corpus, there is no one size that fit all but it is estimat- money and Invest in Listed companies as per mandate of the
ed at 25X of your Annual Expenditure should be in your Kitty Fund (eg: Large/Mid/Small Cap/Flexi Cap/Foreign/Etc) and
with All major liabilities sorted out or 4% draw out per annum. charge the Investor a 1-2% per annum fund Management Fee
Active Incomes come only till you work, Passive Incomes come for the Services Provided irrespective of Profits or Loss. Notably,
from Investments and that is when someone else works for you Stocks and Mutual Funds never move in one direction and fluc-
and these are hugely scalable. tuations or volatility are an inherent trends of the market that
Investing is creating a Portfolio of Passive Incomes that will one must be prepared for. Mutual Funds Systemic Investment
augment your Active Incomes as well as take care of your Direct Plans (as against Regular plans) in Nifty or Sensex Ex-
Retirement. change Traded Funds are safer and optimal for the less informed
Investing for Returns – Putting Your Money to Work investor. Besides tracking the Index without Fund Manager
If you Invest 2Cr @12% pa you can get 2 Lakh per month bias, these Plans also have minimal management charges of as
i.e.134000/- after Tax. However, if your rate of return drops low as 0.05% versus actively managed premium funds that can
to 6% then to get the same return monthly you need to invest charge up-to 2.15%. Direct plans with do not involve a broker
4Cr. Not too difficult to understand! If you aspire for more sand core over regular plans where your broker gets a 1% com-
and wish to make the rest of your life the best of your life? mission on an ongoing annual basis. This compounded over
Read On. years can significantly dent your earnings.
Insurance as Investment
Investments can be categorized into Low-Risk Investments Health, Life, Motor Vehicle, Term and Professional Insurances
like Bank Fixed Deposits (5-6%), PPF (7.1%), NSC (8%), Senior save you from unexpected outcomes. Anything else is a waste
Citizen Scheme (6.6%), Gold (2.5%), Savings Account Cash (4- of money. Any Insurance linked Investment Plan is a Strict NO
6%) or Liquid and Debt Funds (6-8%) All Bracketed figures are because the broker makes a killing on your investment and
Taxable Returns. Lower the Risk, Lower the Gains plus worth the company compounds it by investing in the stock market
noting that Bank Deposits are Only guaranteed up to 5 Lakhs to generate returns on your money and then giving you only a
per account holder. portion of the earnings. Same for ULIPs.

www.dosonline.org/dos-times 97
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

Real Estate as Investment Disclaimer: I am not a Certified Financial Advisor and
Capital Appreciation and Parking of Cash Surplus are the big- Do not in any way benefit from your investments. I do
gest advantage. Residential flats or floors give rental returns of however provide paid consultancy services to the interested
only 2-3% per annum. Commercial Spaces give better returns of and can be reached on [email protected] or
3-6% but fall in the GST bracket beyond 20 Lakhs rent pa. Floor Mobile: 9810635968.
spaces in Shopping malls are mixed fortunes – can go either way.
Believing builder crafted dreams is naïve. Ideally buy a Single Corresponding Author:
Ownership with Lock and Key Type possession ownership.
Gold and Bullion as Investment Dr. Sanjay Dhawan, MS
Gold and Silver are a Hedge over Uncertainty in your minds Senior Consultant Eye Surgeon
and not the Markets. Continuous demand exists and liquidity Maharaja Agarsen Hospital, Punjabi Bagh, New Delhi.
is good however storage and limits are an issue (not with Gov-
ernment Gold Bonds) but on the whole an annualised return
of 2.5% is expected (Taxable). Silver has more industrial uses
and probably a better investment both in physical as well as ETF
(Newly launched) forms. Recommended not more than 5-15%
of your investable surplus. Cryptocurrency – Another day.
Summary and Take-Home Message
It all depends on your Age, Earnings, Projected Growth, Risk
Appetite, Education, Research Capability, Liabilities, Inheritance
and Drive to Earn. There is no one size fitting all. Stocks and
Mutual Funds are safer. Diversification is the key and patience/
long term horizon is essential. Start early for compounding to
benefit you and spread your investments like your risks.
Happy Investing.

DOS Times - Volume 28, Number 1, January-February 2022 98 www.dosonline.org/dos-times

DOS TIMES

“Boom-Boom” Radiotherapy for Ocular
Adnexal lymphoma - How low can we
limbo?

Balamurugan Vellayappan[1], Gangadhara Sundar[2]
1. Department of Radiation Oncology, National University Hospital, National University of Singapore.
2. Orbit & Oculofacial Surgery, Department of Ophthalmology, National University Hospital, National University of Singapore.

Ocular adnexal lymphomas are the most common malignant of antibiotics (such as doxycycline) to eradicate Chlamydia is
orbital tumors in older adults. Spectrum can vary from controversial, and has not been replicable across all geographic
relatively benign and frequently seen Extranodal marginal zone regions.[2] Systemic therapy (such as single agent rituximab,
lymphoma (EMZL) type (MALT)[1], which is often localized, or regimens such as rituximab, cyclophosphamide, vincris-
Follicular lymphoma, which often has systemic involvement, tine, prednisolone (R-CHOP)) is more commonly used in ad-
and less frequently Diffuse large B Cell lymphoma (DLBCL), vanced stages.[6] Systemic therapy for localised disease, can
which is highly aggressive. In this short review, we will be often induce a sustained response, but are not considered
focusing on some recent concepts in the management of EMZL curative.[3,7]
ocular adnexal MALT lymphoma (OAML). Radiation therapy for Ocular Adnexal Lymphomas
OML can arise from conjunctiva, orbital soft tissue including
the lacrimal gland or the eyelids. While the etiopathogenesis is Lymphomas have been known to be exquisitely sensitive to
poorly understood and most arise de novo, predisposing factors radiation therapy. Compared to epithelial malignancies (such as
include underlying chronic inflammatory/immunological con- carcinomas) which require approximately 70 Gy of fractionated
ditions such as Sjogren’s syndrome (30-fold risk), IgG4 related radiotherapy for cure, doses ranging between 30 – 50 Gy have
disease, chronic immunosuppression, e.g. post-transplant and known to be sufficient for lymphomas.[8] In the context of
less commonly infective agents such as Chlamydia psittaci.[1,2] OAML, local control rates have been excellent – ranging from
90 to 100%.[9] In general, the whole orbit needs to be radiated,
Common presenting symptoms include a slow growing mass, as OAML tends to be multifocal, and partial orbital irradiation
typically over months to years, causing fullness of the eyelids, has led to higher recurrences.[10] However, even with these lower
proptosis, eye redness (salmon patch of the conjunctiva), doses, long term complications can develop.[11] These include
diplopia and/or epiphora. In the presence of these symptoms, severe eye dryness, keratitis, radiation-associated retinopathy
patients should undergo a detailed ophthalmologic examination and/or neuropathy, and certainly cataract formation.
first. Imaging studies such as orbital CT and/or MRI are In view of these long term complications, dose de-escalation
informative to determine the extent and laterality. However, was performed in many centres, where doses of 24 – 25 Gy were
the diagnosis can only be established by a incisional biopsy, and utilised. This dose regimen has been investigated in a Phase
interpretation by an experienced pathologist using morphology III trial (including a range of low grade lymphomas), and has
and immunophenotype.[3] While MALT lymphomas have a been shown to have non-inferior control rates compared to
tendency to remain localised for long periods of time, it has the higher doses.[12] As such, most international guidelines endorse
potential for local recurrence and systemic spread. Systemic work 24Gy in 12 fractions for localised OAML where the intention of
up typically includes a CT scan of the neck, thorax, abdomen treatment is to cure.[3,5] A radiotherapy dose plan, using 2 non-
and pelvis, and bone marrow examination as well.[3] Complete coplanar fields with a prescription dose of 24 Gy in 12 fractions,
blood count and lactate dehydrogenase. Positron-emission can be seen in Figure 1.
tomography (PET) scan is not routinely used for staging, as the However the question remains – how low can we go? Low-grade
FDG uptake is variable.[4] NHL are known to be the most radiosensitive tumours, with
The management of OAML is dependent on the stage of the dis- the mechanisms being obscure. Doses as low as 0.05 Gy have
ease, age of the patient and symptoms. In certain patients, close been shown to cause cell death (in B cells).[13] “Boom-Boom”
surveillance alone may be practiced with treatment initiated only radiotherapy (2Gy x 2 fractions) has been used in the palliative
on local progression. However in most symptomatic patients lo- setting of low-grade lymphomas, as early as the 1990s.[14] Such
calised disease is treated with loco-regional radiation therapy.[3,5] low doses of radiation have been shown to produce remarkable
The role of surgery is primarily to establish a tissue diagnosis even responses, which can be long-lasting in some patients.[15] Fasola
in well-localized lesions, as OAML tend to be multifocal and in- et. al. reported complete response in 85% patients, with OAML,
filtrative with frequent recurrences from excision alone. The use

www.dosonline.org/dos-times 99
DOS Times - Volume 28, Number 1, January-February 2022

DOS TIMES

treated with “boom-boom” regimen.[16] In the patients who cohort was only 15 months, these results are indeed encourag-
achieved a complete response, the 2-year local control rate was ing. Advantages of this approach are
100%. A representative dose plan using “boom-boom” can be 1. Extremely convenient and cost-effective for patients and
seen in Figure 2. This regimen has also been proven effective
in other types of low-grade lymphomas, such as Grade 1-2 health care systems.
follicular and mantle cell lymphoma, involving the orbit.[15,17,18] 2. Low incidence of acute and long-term side effects. Most
However it remains unclear if “boom-boom” can be used in the
palliation of high-grade lymphomas (such as DLBCL). radiation-associated side effects exhibit dose-response
Can “boom-boom” be used in the curative setting for (higher dose delivered, higher probability of developing side
OAML? A recent single institution retrospective study report- effects).[20] This is particularly important for patients with
ed the use of “boom-boom” treatment in 22 patients with low underlying Sjogren’s syndrome who have dry eye syndrome
grade lymphoma (of whom 64% had OML).[19] The overall re- at baseline, and may be on immune-modulating drugs (such
sponse rate was 100% with 86% achieving a complete response. as methotrexate) which can amplify radiation effects.
The 2-year freedom from local recurrence was 75%. Toxicity, as 3. Ease of re-treatment : in situations where the OML recurs
expected, was extremely low, with 1 patient developing grade in the ipsilateral or contralateral eye, a repeat course of
1 dry eye syndrome. Although the median follow up of this radiation can be offered, in view of the low dose used for the
first course.

Figure 1 : 24 Gy in 12 fraction EBRT plan for a patient with right OML. Figure 2 : “Boom-boom” external beam radiotherapy(EBRT) plan for
Solid green line : planning target volume. Yellow colourwash : 95% a patient with left OML, and Rheumatoid Arthritis on Methotrexate.
isodose (22.8Gy), Purple colorwash : 50% isodose (12 Gy), Orange Solid red line : gross tumour volume, solid green line : planning target
colorwash : 4 Gy volume. Yellow colorwash : 95% isodose (3.8 Gy), purple colorwash : 50%
isodose (2 Gy)
Is this ready for prime-time?
The FORT trial was a Phase III non-inferiority trial comparing We conclude that low dose radiotherapy for ocular adnexal
24 Gy to 4 Gy for indolent lymphomas (86% follicular, 14% lymphomas, either primary or related to predisposing conditions
marginal zone).[18] The investigators reported shorter time to such as IgG4 Related Orbitopathy[23] is making inroads in the
progression with the “boom-boom” regimen (HR 3.42, 95% CI management of this common yet clinically challenging ocular
2.09 – 5.55, P<0.0001), and as such cannot be recommended in adnexal disease.
the curative setting. It remains unclear how many patients in
this trial had OAML, or if they had a sustained response. References
Looking ahead, future studies should explore doses in between
4 and 24 Gy, in search of a balance between cure and toxicity 1. Ekstrom Smedby K, Vajdic CM, Falster M, et al. Autoimmune disorders
mitigation. The use of particle beam therapy (e.g. protons) also and risk of non-Hodgkin lymphoma subtypes: a pooled analysis
holds promise for this condition.[21] The incidence of secondary within the InterLymph Consortium. Blood. 2008;111(8):4029-4038.
malignancies after 20 – 30 Gy of x-ray/photon is expected to
be low (around 1%).[22] However, these may occur within the 2. Husain A, Roberts D, Pro B, McLaughlin P, Esmaeli B. Meta-
orbit, or within the brain parenchyma (due to the exit dose from analyses of the association between Chlamydia psittaci and ocular
X-rays). Further reductions are to be expected, with proton adnexal lymphoma and the response of ocular adnexal lymphoma to
beam therapy, in this group of patients who are expected to antibiotics. Cancer. 2007;110(4):809-815.
survive for 10 years or longer.
3. Zucca E, Arcaini L, Buske C, et al. Marginal zone lymphomas: ESMO
Clinical Practice Guidelines for diagnosis, treatment and follow-up.
Ann Oncol. 2020;31(1):17-29.

4. Treglia G, Zucca E, Sadeghi R, Cavalli F, Giovanella L, Ceriani L.
Detection rate of fluorine-18-fluorodeoxyglucose positron emission
tomography in patients with marginal zone lymphoma of MALT

DOS Times - Volume 28, Number 1, January-February 2022 100 www.dosonline.org/dos-times