Laser Therapy for Retinoblastoma in the Era of Optical Coherence Tomography

Authors:

Sameh Soliman, Stephanie Kletke, Kelsey Roelofs, Cynthia VandenHoven, Leslie Mckeen,

Brenda Gallie

Type of article: Review

Word limit:

Tables and Figures:

Keywords:

Abstract

Introduction: The past several decades have seen vast advancements in the treatment

paradigm for retinoblastoma, and the use of focal laser therapy is certainly no exception. While

the first description of focal laser therapy for retinoblastoma dates back to over 6 decades ago,

several improvements in protocols have occurred over the past two decades that have greatly

improved our ability to achieve local tumor control.

Areas covered: In this review the physical and optical properties of lasers are briefly

discussed, and as well as the various mechanisms of action, delivery systems and potential

complications. Novel topics, including optical coherence tomography (OCT) guided treatment

decisions and management of sub-clinical tumors are coveredd. iscussed. the literature search

undertaken.????

Expert commentary:

Key issues

Introduction

Retinoblastoma is the most common pediatric intraocular malignancy that occurs secondary

to mutations in both copies of the retinoblastoma gene (RB1 gene).[1] Worldwide, approximately

8000 new patients present annually. Survival is very high approaching 100% if retinoblastoma

presented while still intraocular.[1, 2] The mainstay of therapy is tumor size reduction via

chemotherapy cycles (either systemic, intrarterial or periocular chemotherapy) followed by focal

therapy in the form of laser or cryotherapy according to tumor location and size. Chemotherapy

is never sufficient alone to control tumor without focal consolidation.[3, 4] Despite that, the role

of laser therapy is frequently undermined while presenting outcomes of recent treatment

modalities as intraarterial and intravitreal chemotherapy.[5, 6]

Optical coherence tomography (OCT) has revolutionized our perspective of variable retinal

disorders including retinoblastoma by allowing more detailed anatomical evaluation of the

retinal layers and tumor architecture. OCT allowed visualizing subclinical new tumors and tumor

recurrences. It differentiated tumor from gliosis during scar evaluation. It allowed better

perception of important anatomic landmarks for vision such as the fovea and optic nerve. [4, 7]

In the current review, the authors willwe review the role of different lasers in management of

retinoblastoma and . They will elaborate on OCT guided laser therapy precision.

Body

1. PHYSICS OF LASER:

Although Einstein initially postulated the concept behind the stimulated emission process

upon which lasers are based in 1917, it was not until 1960 that T.H. Maiman performed the first

experimental demonstration of a ruby (Cr3+AL2O3) solid state laser.[8] In fact, the acronym

LASER represents the underlying fundamental quantum-mechanical principals involved: Light

Amplification by Stimulated Emission of Radiation.[9] All lasers require a pump, an active

medium and an optical resonance cavity. Energy is introduced into the system by the pump,

which excites electrons to move from a lower to higher energy orbit. As these electrons to return

to their ground state, they emit photons, all of which will be of the same wavelength resulting in

light that is monochromatic (one color), coherent (in-phase) and collimated (light waves

aligned). Mirrors at either end of the resonance cavity reflect photos traveling parallel to the

cavitie’s axis, which then stimulate more electrons, resulting in amplification of photon

emission. Eventually photons exit the laser cavity through the partially reflective mirror into the

laser delivery system.[9]

Lasers are typically categorized by their active medium, as this is what determines the laser

wavelength. The wavelength multiplied by the frequency of oscillation for all lasers equals the

speed of light. Therefore, as lasers wavelength increases its frequency decreases proportionally

and vice versa. Additionally, Planck’s law (E=h) states that the energy (E) of a photon is a

product of Planck’s constant (h=6.626 x 10-34 m2 kg/s) multiplied by the frequency (). As such,

lasers with low wavelengths (and high frequency) impart high energy, and those with high

wavelengths (and low frequency) are less powerful. Broad categories of lasers include solid

state, gas, excimer, dye and semiconductor.

The power of a laser is expressed in watts (W), which is the amount of energy in joules (J)

per unit time (J/sec). Power density takes into account both the power (W) and the area over

which it is distributed (W/cm2). It is important to note that if spot size is halved, the power

density is quadrupled and that if the amount of energy (J) remains constant, decreasing the

duration will increase the power (W) delivered. Longer pulse duration increases the risk that heat

waves will extend beyond the optical laser spot, thus damaging surrounding normal tissue.[10]

All laser machines haves the option to control the shot pace or inter-shot interval according to the

experience of treating ophthalmologist. Iin general, trainees are better to start by single shots or a

longer inter-shot interval. Semiconductor lasers used in ophthalmology include the diode laser

used to perform transpupillary thermotherapy (TTT) (810nm) and solid-state lasers such as the

neodymium (Nd):YAG (yttrium-aluminum-garnet) (1064nm). Frequency doubling of the

Nd:YAG results in a halving of the wavelength, producing the green (532nm) laser.

2. TYPES OF LASERS FOR RETINOBLASTOMA:

Xenon arc photocoagulation, first described by Meyer-Schwickerath in 1956, was one of the

earliest photocoagulation methods adopted for retinoblastoma.[11, 12] Xenon emission consists

of wavelengths between 400 and 1600-nm and results in full-thickness burns without selectively

targeting ocular tissues. It has since been replaced by laser photocoagulation for retinoblastoma.

The commonest lasers used for focal therapy in retinoblastoma include the green (532nm)

frequency doubled neodymium (Nd):YAG (yttrium-aluminum-garnet), the 1064nm continuous

wave Nd:YAG laser and the 810nm semiconductor infrared indirect or trans-scleral diode laser.

While all three lasers can be delivered with use of an indirect ophthalmoscope, the 810nm diode

laser can also be applied in a trans-scleral manner, which can be particularly useful for

anteriorly, located tumors and for treating tumors in the presence of media opacities. Trans-

scleral delivery also decreases the risk of cataract formation by limiting laser transmittance

through the pupil.[13] Of the three, the green 532 nm laser and 810 nm lasers has the most

superficial depth of penetration as it workscan treat tumor by by a photocoagulation. ve manner,

which serves to limit tissue penetration. This contrasts with bBoth The 810nm and 1064 nm

lasers can also which act primarily bytreat by raising choroidal tumor temperature (hyperthermia,

commonly called and thus calledtranspupillary thermotherapy) in a sub-threshold manner.[10]

Table 1 demonstrates the main differences between the different types of laser in retinoblastoma.

3. LASER DELIVERY:

Retinal laser treatments can be delivered by either binocular indirect ophthalmoscopy (BIO)

using non-contact, hand-held lenses (20 D, pan-retinal 2.2 D or 28 D) or by microscope-mounted

laser with contact lenses (Goldmann Universal Three-Mirror, Ocular Mainster Wide Field) and a

coupling agent (Table 2).

Laser indirect ophthalmoscopy was first described to treat retinoblastoma in 1992.[14] BIO

combined with manipulation of eye position with a scleral depressorion is the ideal laser delivery

technique for children under general anesthesia. The higher the power of the condensing lens

utilized, the lower the image magnification and the greater the field of view. The laser spot size

on the retina varies because the laser beam focuses at some distance from the indirect

ophthalmoscope, and diverges on either side of the focal point. It therefore depends on the

power, relative positions of the headset and BIO lenses, amount of light scattering by ocular

media, as well as the patient’s refractive error. For instance, a 20 D lens causes a 900 µm image

plane spot to be reduced to 300 µm in an emmetropic eye.[15] The retinal spot size can be

calculated by (pPower of the condensing aspheric lens x Image plane spot size) / 60.[15] BIO is

preferred for peripheral retinal laser treatments as the field of view is greater than with

microscope-mounted laser. However, caution must be exercised as BIO is less stable than other

delivery systems due to inherent instability of the patient’s eye and the clinician’s head,

particularly with simultaneous foot pedal depression.[15] Owing to the technique of Laser

delivery and the relatively long treatment, the treating physician neck is at risk of ligamentous

injury and cervical disc prolapseThe positional requirements and relatively long treatment

durations associated with BIO laser delivery contribute to higher prevalence of self-reported

neck, hand, wrist and lower back pain amongst ophthalmologists.[16]

A microscope-mounted delivery system connects the laser with athe slit-lamp or operating

microscope. While the working distance for BIO is variable, the distance from the microscope to

the patient’s eye is fixed. Therefore, retinal laser spot size is only dictated by the patient’s

refractive error, contact lens and pre-selected laser spot diameter on the microscope.[15] Tilting

the contact lens within 15 degrees does not cause significant distortion of the laser spot, as

irradiance differs by maximum 6.8%.[17] The universal Goldmann three-mirror (Power -67 D)

has a flat anterior surface that cancels the optical power of the anterior cornea, therefore

decreasing peripheral aberrations.[18, 19] It contains mirrors at 59, 67 and 73 degrees to aid in

visualization of the periphery.[18] However, photocoagulation efficiency is reduced in the far

periphery, as the laser follows an off-axis, oblique trajectory. Another commonly used contact

lens is the Mainster wide-field (Power +61 D), which contains an aspheric lens in contact with

the cornea and a convex lens at some fixed distance.[18, 19] Compared to the Goldmann three-

mirror which has the highest on-axis resolution, the Mainster lens has improved field of view at

the expense of poorer resolution.[17] Inverted image lenses may produce smaller anterior than

posterior segment laser beam diameters, thus leading to higher irradiance in the anterior segment.

Injury to the cornea and lens have been reported during retinal photocoagulation with inverted

image lenses, particularly in the presence of high power settings and ocular media opacities.

[17]CORNEAL COMPLICATIONS

4. MECHANISMS OF LASER THERAPY:

4.1.: PHOTOCOAGULATION:

Photocoagulation is the process by which laser light energy is absorbed by a target tissue and

converted into thermal energy. A 10-20 degree Celsius temperature rise induces protein

denaturation and subsequent coagulation and necrosis, depending on the duration and extent of

thermal change.[11] Heat generation is influenced by the laser parameters and optical properties

of the absorbing tissue.[18] Absorption characteristics are dictated by tissue-specific

chromophores, such as melanin in the retinal pigment epithelium (RPE) and choroidal

melanocytes, hemoglobin in blood vessels, xanthophyll in the inner and outer plexiform layers,

lipofuscin and photoreceptor pigments.[20]

Lasers in the visible electromagnetic spectrum, such as the 532-nm frequency-doubled

Nd:YAG, are largely absorbed by hemoglobin and melanin, approximately half in the RPE and

half in the choroid.[18] Heat is then conducted to the neurosensory retina, causing inner retinal

coagulation and focal increase in necrotic cells. This leads to loss of retinal transparency and the

white laser response noted ophthalmoscopically. The 532-nm laser also destroys the retinal blood

supply as the wavelength is near to the absorption peaks of oxyhemoglobin and

deoxyhemoglobin. However, this requires more energy due to the cooling effect of blood flow,

which has greater velocity than stationary tissues.[18] Confluent laser burns encircling

retinoblastoma tumors occlude large retinal blood vessels and other feeder vessels may require

supplementary treatment.[14] In larger tumors, encircling photocoagulation may lead to earlier

tumor seeding into the vitreous secondary to obliteration of blood supply, with resultant and

starting tumor necrosis and loss of tumor compactness. (Figure 1).

“Thermal blooming” is the process by which the photocoagulation zone may be extended

beyond the laser spot size with longer durations.[18] This may not be clinically apparent during

treatment and is one factor contributing to increased size of the laser scar post-operatively. When

a whitish response to the laser is noted, further penetration of the light energy to deeper

structures is prevented by light scattering.[20] Thus, retreatments only increase the lateral extent

of the laser application, known as the “shielding effect”. Laser photocoagulation ultimately leads

to scarring, gliosis and variable RPE hyperplasia.

4.2. TRANS-PUPILLARY THERMOTHERAPY (TTT): (TTT)

TTT has also been applied to retinal tumors to achieve localized tissue apoptosis. It involves

continuous laser application in the near-infrared spectrum (800-1064 nm), usually 810-nm diode,

for longer durations (60 seconds) and with larger spot size and lower power than

photocoagulation.[18] This results in deeper tissue penetration (4 mm) since melanin absorption

decreases with increasing laser wavelength. The penetration depth of continuous wave 1064 -nm

laser thus exceeds that for 810 -nm diode and 532 -nm lasers, which is important when

considering treatment of thicker tumors.[21] Resultant temperature rises are lower than for

classic photocoagulation (45 to 60 degrees Celsius).[22] The endpoint of TTT is faint whitening

or graying of the tumor and prominent laser changes may not be visible at the time of treatment.

[18, 22] This is dependent on fundus pigmentation and laser parameters. Complications of TTT

reported following treatment of retinoblastoma include chorioretinal scarring with focal scleral

bowing.[23]

4.3 SEQUENTIAL LASER THERAPY:

Certain tumors especially large central juxtafoveal and perifoveal tumors might necessitate

combination of both photocoagulation and thermotherapy in successive or sequential treatments.

The tumor border and periphery are treated with 532 nm Laser. A longer wavelength laser is

used to treat the elevated center either in the same or sequential session.[7] Unfortunately, there

is no randomized clinical trial that compared laser mechanisms to set evidence to use any.[24]

5. OPTICAL COHERENCE TOMOGRAPHY (OCT) IN RETINOBLASTOMA:

OCT was introduced to retinoblastoma in the early 2000s. The first few reports focused on

describing how retinoblastoma appears and how to differentiate it from other simulating tumors.

[25, 26] Introduction of hand held OCT helped examining supine children under anesthetic

allowing imaging of more retinoblastoma tumors at different phases of their active treatment

from diagnosis to stability.[27, 28] This allowed visualization of a multitude of situations that

can affect and guide laser therapy as subclinical invisible tumors,[29, 30] subclinical tumor

recurrences either within a previous scar or edge recurrences,[7] topographic localization of

foveal center,[7, 31] differentiating whitish lesions such as gliosis and perivascular sheathing

from active retinoblastoma and possible optic nerve involvement.[32] OCT can demonstrate

tumor location within the retina whether superficial, deep or diffuse infiltrating retinoblastoma.

[7] OCT can visualize tumor seeds either vitreous or subretinal.[7, 33] It can also determine the

internal architecture of retinoblastoma whether solid or cavitary[34] that might affect our the

therapy approach . (Figure 2). Despite very difficult, OCT can be used to examine the mid

periphery but highly dependent on the expertise of the photography specialist.[7]

6. OPTICAL COHERENCE TOMOGRAPHY GUIDED LASER:

ADD A Paragraph on OCT guided therapy study (Sameh) and precision medicine.

6.1. SUBCLINICAL Invisible TUMORS:

Subclinical Invisible tumors can be anticipated in children with positive RB1 variant either

detected prenatal or postnatal, positive parental family history of retinoblastoma or a child with

other clinical tumors. The ideal procedure to screen for invisible tumors is OCT mapping of the

posterior pole especially in the first 6 months of age. Once detected, the subclinical tumor should

be centralized in the OCT scan. Calipers can be used to help locating the tumor in the retinal

image. Photocoagulation with lLow laser power (100 mW) and short pulse duration (0.5

seconds) is delivered, to gradually increase power until whitening is noted.sufficient to treat

these tumors. It is highly advised to perform a Post lLaser OCT to can verify treatment where the

tumor swells with increase reflectiveness and back shadowing.

6.2. JUXTAFOVEAL TUMORS:

Tumors around the fovea areis a treatment challenge in a trial to preserve the foveal center.

OCT helped localizesation of the foveal center by obtaining two OCT macular cube scans

(vertical and horizontal) to precisely determine the foveal location, to. This can help guide our

laser to avoid laser to this critical area. Photocoagulation is superior to TTT in posterior pole

tumors to preserve vision and avoid scar migration. Recently an OCT guided sequential laser

crescent photocoagulation method was described for juxtafoveal tumors avoiding the fovea. The

mechanism is to photocoagulate the anti-foveal tumor boundary crescent with 532 nm laser to

obliterate the blood supply to the tumor. This will flatten the tumor center that will be treated in

sequential sessions. AdditionallyAdditionally, the peripheral scarring causes a tangential anti-

foveal tumor pulling away from the fovea. This technique was described to have better

anatomical and visual outcome in juxtafoveal tumors where the fovea is OCT detectable at initial

laser session. Furthermore, OCT can detect subtle surrounding exudative retinal detachment that

might stop us from initiating laser treatment.

6.3: RECURRENT AND RESIDUAL TUMORS:

OCT can detect subclinical tumor edge recurrences. OCT can differentiate between tumor

calcification and homogenous potential active tumor. Comparison between successive OCT

scans of the same area can detect subtle tumor recurrence. This potentiate less treatment burden

regarding laser power, number of sessions and final outcome. Recurrences on flat retina are

usually treated with photocoagulation with 532 nm lLaser. However, recurrences over calcified

tumor require longer wavelength photocoagulation and even TTT.

Whitish treatment scars previously posed a clinical challenge to determine whether it is a

tumor residual, recurrence or a fibrosis. This was usually managed either by more laser treatment

with the possibility of more scarring and traction or observation with the potential danger of

tumor growth requiring more treatment burden. OCT helped visualizing the layers of this scars

differentiating between these conditions guiding the diagnosis and subsequent treatment choice.

6.4. PRE-EQUATORIAL TUMORS:

Pre-equatorial tumors can be treated by either photocoagulation or cryotherapy. Laser

therapy is usually preferred in superior tumors to avoid potential cryotherapy associated uveal

effusion and exudative detachment. Flat pre-equatorial tumors are usually treated with 532 nm

laser photocoagulation for one or two sessions. More elevated tumors might require multiple

laser treatments as the tumor cannot be treated equally as the inward curve of the tumor cannot

be thoroughly painted with lLaser. In subsequent sessions with more outward flattening of the

tumor, the inward curve can be better visualized and treated. Despite challenging, peripheral

OCT can assess tumor elevation, differentiate scarring from residual tumors and identify

peripheral potential tumor seeding. In certain tumors, lLaser can be utilized as an initial belt like

treatment surrounding the tumor as a preparatory step prior to cryotherapy or plaque

radiotherapy. Peripheral laser can be also needed used for potential ischemic retina peripheral to

an extensive tumor scar to prevent development of neovascularization and probable subsequent

vitreous hemorrhage. As a general rule, a smaller spot size is required in peripheral lesions to

prevent iris injury.

7. COMPLICATIONS OF LASER THERAPY:

The most serious complications caused by laser therapy are often caused by use of excessive

energy, and as such, starting your treatment at a lower power and titrating to the desired effect

decreases the likelihood of complications. In cases where too small a spot size, too high a power

or too short a duration is used, an iatrogenic rupture of Bbruchs’ membrane may occur. This

might act as precursor for choroidal neovascular membrane formation. Additionally, intense

photocoagulation may result in full thickness retinal holes which may progress to

rhegmatogenous retinal detachment. In retinoblastoma, this can result in vitreous seeding.[35]

OCT can help in visualizing and following these complications.

Although rare, biopsy-proven orbital recurrence of retinoblastoma has been reported

following successful treatment of a macular recurrence with aggressive argon and diode laser.

[36] In this case, MRI demonstrated a large intraconal mass contiguous with the sclera, and B-

scan ultrasound confirmed scleral thinning at the recurrence site. The orbital recurrence was felt

to result from tumor seeding of the orbit at a site of focal scleral thinning within an atrophic

chorioretinal scar, following multiple intense laser treatments.[36]

TUMOR EXTENSION (Stephanie) as a complication

Additional complications can include focal iris atrophy, lenticular opacification, retinal

traction, retinal vascular obstruction and localized serous retinal detachment.[35, 37]

Additionally, scars from TTT (810nm) have been shown to increase in size after treatment for

retinoblastoma[38] and as such, one must be cautious in using this laser for tumors located near

the fovea and optic nerve.

Laser should be avoided over areas with retinal detachment whether high or shallow. OCT

can help diagnoseing subtle detachments. Laser over the optic nerve can compromise nerve fiber

vitality and should be avoided. The exact tumor relation to the optic nerve can be mapped by

OCT and is thus considered during treatment planning.

[8.] PUBLISHED EVIDENCE ON LASER IN RETINOBLASTOMA: (KELSEY)

Meyer-Schwickerath first introduced the idea of xenon photocoagulation into the

management paradigm for retinoblastoma in 1955 and subsequently reported their results in

1964.{Meyer-Schwickerath, 1964 #16029;Meyer-Schwickerath, 1964 #16029;Meyer-

Schwickerath, 1964 #16029;Meyer-Schwickerath, 1964 #16029} [39] Although laser therapy

for retinoblastoma has been used for several decades[39, 40] it wasn’t until the 1980’s and

1990’s that the role for focal laser therapy in the management of retinoblastoma became widely

popularized.[41] In 1982 Lagendijk used trans-pupillary thermotherapy (TTT) in two cases of

recurrent retinoblastoma successfully.[42] Subsequently, a relatively large study by Lumbroso et

al reported their outcomes in 239 children using TTT delivered with a diode laser through an

operating microscope and found that when this was combined with chemotherapy excellent local

tumor control and eye preservation was achieved.[43] Other groups similarly concluded that

while chemoreduction alone may not be adequate at achieving complete tumor control,

chemoreduction in combination with adjuvant treatment (including laser photocoagulation,

thermotherapy, cryotherapy and radiation) resulted in good retinal tumor control, even in eyes

with advanced disease.[44]

[38][39][40][41]As the use of laser therapy in the management of retinoblastoma gained

traction, several clinicians investigated this potentially synergistic role between thermotherapy

and chemotherapy. This treatment algorithm was termed chemothermotherapy and was based on

the hypothesis that the delivery of heat facilitates the cellular uptake of certain chemotherapeutic

agents.[45] In fact, in a series of 103 tumors treated with chemothermotherapy Lumbroso et al

reported that tumor regression was seen in 96.1%.[46] In this study, TTT was delivered shortly

after an intravenous injection of carboplatin.

[32]Predictors for success of focal laser photocoagulation and thermotherapy have also been

identified. Abramson et al. concluded that tumors <1.5 disc diameters in base diameter can be

successfully treated with TTT alone, with nearly two thirds (64%) of tumors only requiring one

session.[22] Alternative laser techniques have also been described, including the use of the 532-

nm laser which has been shown to effectively treat small (<2mm in height, <4 disc diameter)

tumors. [35] Depending on the tumor location, the clinician may prefer one laser type over the

other. For instance, while TTT using the 810-nm diode laser is effective, the scar that is created

can increase in size after treatment [38] and therefore when applying laser near vital macular

structures some prefer laser photocoagulation (532-nm laser). Similarly, trans-scleral diode laser

may be the preferred modality for small anteriorly located retinoblastomas.[13] Although a

variety of potential complications as discussed above have been noted, the majority of these can

be avoided by using the minimal effective laser power.[35] It is important to note however that

despite the use of laser focal therapy being a mainstay in the treatment of retinoblastoma, there

have been no randomized controlled trials evaluating the effect of systemic chemotherapy with

versus without laser therapy for post-equatorial retinoblastoma.[24]

[9.] FUTURE PRESPECTIVE: (can be written in the 5 year view)

OCT EMBEDDEDand RETCAMwide field imaging in one unit??

Conclusions

Laser therapy in retinoblastoma is integral in tumor control after initial chemotherapy size

reduction. In spite of this fact, Laser was never properly studied in a randomized controlled

fashion to set evidence. Introduction of OCT improved tumor visualization and assessment

improving our laser strategies and minimizing complications.

Expert Commentary

Five year view

References

1. Dimaras, H., et al., Retinoblastoma. Nat Rev Dis Primers, 2015. 1: p. 15021.

2. Kivela, T., The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol, 2009. 93(9): p. 1129-31.

3. Gallie, B.L. and S. Soliman, Retinoblastoma, in Taylor and Hoyt's Paediatric Ophthalmology and Strabismus, B. Lambert and C. Lyons, Editors. 2017, Elsevier, Ltd.: Oxford, OX5 1GB, United Kingdom. p. 424-442.

4. Soliman, S.E., et al., Genetics and Molecular Diagnostics in Retinoblastoma--An Update. Asia Pac J Ophthalmol (Phila), 2017. 6(2): p. 197-207.

5. Yousef, Y.A., et al., Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA Ophthalmol, 2016.

6. Scelfo, C., et al., An international survey of classification and treatment choices for group D retinoblastoma. Int J Ophthalmol, 2017. 10(6): p. 961-967.

7. Soliman, S.E., et al., Optical Coherence Tomography-Guided Decisions in Retinoblastoma Management. Ophthalmology, 2017.

8. Maiman, T.H., Stimulated Optical Radiation in Ruby. Nature, 1960. 187(4736): p. 493-494.

9. Eichhorn, M., Laser physics : from principles to practical work in the lab. 1st edition. ed. Graduate texts in physics. 2014, New York: Springer. pages cm.

10. Niederer, P. and F. Fankhauser, Theoretical and practical aspects relating to the photothermal therapy of tumors of the retina and choroid: A review. Technol Health Care, 2016. 24(5): p. 607-26.

11. Krauss, J.M. and C.A. Puliafito, Lasers in ophthalmology. Lasers Surg Med, 1995. 17(2): p. 102-59.

12. Abramson, D.H., The focal treatment of retinoblastoma with emphasis on xenon arc photocoagulation. Acta Ophthalmol Suppl, 1989. 194: p. 3-63.

13. Abramson, D.H., C.A. Servodidio, and M. Nissen, Treatment of retinoblastoma with the transscleral diode laser. Am J Ophthalmol, 1998. 126(5): p. 733-5.

14. Augsburger, J.J. and C.B. Faulkner, Indirect ophthalmoscope argon laser treatment of retinoblastoma. Ophthalmic Surg, 1992. 23(9): p. 591-3.

15. Friberg, T.R., Principles of photocoagulation using binocular indirect ophthalmoscope laser delivery systems. Int Ophthalmol Clin, 1990. 30(2): p. 89-94.

16. Kitzmann, A.S., et al., A survey study of musculoskeletal disorders among eye care physicians compared with family medicine physicians. Ophthalmology, 2012. 119(2): p. 213-20.

17. Mainster, M.A., et al., Ophthalmoscopic contact lenses for transpupillary thermotherapy. Semin Ophthalmol, 2001. 16(2): p. 60-5.

18. Blumenkranz, D.P.a.M.S., Chapter 39. Retinal Laser Therapy: Biophysical Basis and Applications, in Retina, S.J. Ryan, Editor. 2013, Saunders, Elsevier Inc.: China. p. 746-760.

19. Mainster, M.A., et al., Retinal laser lenses: magnification, spot size, and field of view. Br J Ophthalmol, 1990. 74(3): p. 177-9.

20. Mainster, M.A., Wavelength selection in macular photocoagulation. Tissue optics, thermal effects, and laser systems. Ophthalmology, 1986. 93(7): p. 952-8.

21. Rol, P., et al., Transpupillar laser phototherapy for retinal and choroidal tumors: a rational approach. Graefes Arch Clin Exp Ophthalmol, 2000. 238(3): p. 249-72.

22. Abramson, D.H. and A.C. Schefler, Transpupillary thermotherapy as initial treatment for small intraocular retinoblastoma: technique and predictors of success. Ophthalmology, 2004. 111(5): p. 984-91.

23. de Graaf, P., et al., Atrophic chorioretinal scar and focal scleral bowing following thermochemotherapy with a diode laser for retinoblastoma. Ophthalmic Genet, 2006. 27(1): p. 33-5.

24. Fabian, I.D., et al., Focal laser treatment in addition to chemotherapy for retinoblastoma. Cochrane Database Syst Rev, 2017. 6: p. CD012366.

25. Sony, P. and S.P. Garg, Optical coherence tomography in children with retinoblastoma. J Pediatr Ophthalmol Strabismus, 2005. 42(3): p. 134; author reply 134-5.

26. Shields, C.L., M.A. Materin, and J.A. Shields, Review of optical coherence tomography for intraocular tumors. Curr Opin Ophthalmol, 2005. 16(3): p. 141-54.

27. Scott, A.W., et al., Imaging the infant retina with a hand-held spectral-domain optical coherence tomography device. Am J Ophthalmol, 2009. 147(2): p. 364-373 e2.

28. Maldonado, R.S., et al., Optimizing hand-held spectral domain optical coherence tomography imaging for neonates, infants, and children. Invest Ophthalmol Vis Sci, 2010. 51(5): p. 2678-85.

29. Rootman, D.B., et al., Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations. Br J Ophthalmol, 2013. 97(1): p. 59-65.

30. Berry, J.L., D. Cobrinik, and J.W. Kim, Detection and Intraretinal Localization of an 'Invisible' Retinoblastoma Using Optical Coherence Tomography. Ocul Oncol Pathol, 2016. 2(3): p. 148-52.

31. Hasanreisoglu, M., et al., Spectral Domain Optical Coherence Tomography Reveals Hidden Fovea Beneath Extensive Vitreous Seeding From Retinoblastoma. Retina, 2015. 35(7): p. 1486-7.

32. Yousef, Y.A., et al., Detection of optic nerve disease in retinoblastoma by use of spectral domain optical coherence tomography. J AAPOS, 2012. 16(5): p. 481-3.

33. Berry, J.L., K. Anulao, and J.W. Kim, Optical Coherence Tomography Imaging of a Large Spherical Seed in Retinoblastoma. Ophthalmology, 2017. 124(8): p. 1208.

34. Fuller, T.S., R.A. Alvi, and C.L. Shields, Optical Coherence Tomography of Cavitary Retinoblastoma. JAMA Ophthalmol, 2016. 134(5): p. e155355.

35. Hamel, P., et al., Focal therapy in the management of retinoblastoma: when to start and when to stop. J AAPOS, 2000. 4(6): p. 334-7.

36. Jacobsen, B.H., et al., Orbital Recurrence following Aggressive Laser Treatment for Recurrent Retinoblastoma. Ocul Oncol Pathol, 2015. 2(2): p. 76-9.

37. Shields, C.L., et al., Thermotherapy for retinoblastoma. Arch Ophthalmol, 1999. 117(7): p. 885-93.

38. Lee, T.C., et al., Chorioretinal scar growth after 810-nanometer laser treatment for retinoblastoma. Ophthalmology, 2004. 111(5): p. 992-6.

39. Meyer-Schwickerath, G., [New Methods for the Treatment of Intraocular Tumors]. Munch Med Wochenschr, 1964. 106: p. 1974-6.

40. Shields, J.A. and J.J. Augsburger, Current approaches to the diagnosis and management of retinoblastoma. Surv Ophthalmol, 1981. 25(6): p. 347-372.

41. Shields, J.A., The expanding role of laser photocoagulation for intraocular tumors. The 1993 H. Christian Zweng Memorial Lecture. Retina, 1994. 14(4): p. 310-22.

42. Lagendijk, J.J., A microwave heating technique for the hyperthermic treatment of tumours in the eye, especially retinoblastoma. Phys Med Biol, 1982. 27(11): p. 1313-24.

43. Lumbroso, L., et al., [Diode laser thermotherapy and chemothermotherapy in the treatment of retinoblastoma]. J Fr Ophtalmol, 2003. 26(2): p. 154-9.

44. Shields, C.L., et al., Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma [see comments]. Ophthalmology, 1997. 104(12): p. 2101-11.

45. Inomata, M., et al., In vitro thermo- and thermochemo-sensitivity of retinoblastoma cells from surgical specimens. Int J Hyperthermia, 2002. 18(1): p. 50-61.

46. Lumbroso, L., et al., Chemothermotherapy in the management of retinoblastoma. Ophthalmology, 2002. 109(6): p. 1130-6.

Table 1: Comparison between lLasers in retinoblastoma.

Type of

laser

Green

532nm

Diode

810nm

Continuous wave

1064nm

Frequency-doubled Nd-

YAG

Solid State

Semi-conductor Nd-YAG

Solid State

Common

delivery

method

Indirect Indirect or

transcleral

Indirect

Mechanis

m of action

Retinal

photocoagulation results in

tumor apoptosis

Acts in a subthreshold manner to raising

choroidal temperature. Causing minimal

thermal damage to the RPE and overlying

retina

Depth of

penetration

Superficial: limited by

the resultant coagulation

[35] and by nature of shorter

wavelength. Estimated to

penetrate ~2 mm in non-

pigmented tumors such as

retinoblastoma.[10]

Deep: primary anatomical site of action is

in the choroid. Diode and Nd:YAG lasers are

estimated to penetrate 4.2 and 5.1mm

respectively. Penetration depth decreases in

necrotic tumors.[10]

Parameters Power: 0.3 – 0.8 W

Duration: 0.3-0.4

seconds

Power: 0.3-1.5

W

Duration: 0.5 –

Power: 1.4 – 3.0

W

Duration: 1 second

1.5 seconds

Clinical

endpoint

Increase power by 0.1W

increments until

tumor/retinal whitening

visible[35]

Slight graying of retina without causing

vascular spasm [22, 37]

Table 2. Types of contact and non-contact fundus lenses [14, 17, 18]

Lens

Type

Image

Magnificatio

n

Laser

Spot

Magnificatio

n

Stati

c Field

of View

(°)

Dynam

ic Field of

View (°)

Cont

act or

Non-

contact

Image

Characteristics

Goldm

ann 3-

Mirror

Universal

0.93X 1.08X 36

74

(with

15° tilt)

Cont

act

Virtual,

erect image

located near

posterior lens

capsule

Ocular

Mainster

Wide Field

0.67X 1.50X 118 127Cont

act

Real,

inverted

image in air

20 D

BIO3.13X 0.32X 46 60

Non-

contact

Real,

inverted,

laterally

reversed

Pan-

retinal 2.2

BIO

2.68X 0.37X 56 73Non-

contact

Real,

inverted,

laterally

reversed

28 D 2.27X 0.44X 53 69 Non- Real,

BIO contact

inverted,

laterally

reversed

DefineD= Diopter; BIO= Binocular indirect ophthalmoscopy