Laser Therapy for Retinoblastoma in the Era of Optical Ccoherence Ttomography
Authors:
Sameh Soliman, Stephanie Kletke, Kelsey Roelofs, Cynthia VandenHoven, Leslie Mckeen,
Brenda Gallie
Type of article: Review
Word limit:
Tables and Figures:
Keywords:
Abstraarct
Key issues
Introduction (SAMEH)
On RB incidence and genetics (1 paragraph)
Very general paragraph on management of RB
Why laser therapy needs revisiting?
Retinoblastoma is the most common pediatric intraocular malignancy that occur 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 as the fovea and optic nerve. [4, 7]
In the current review, the authors will review the role of different lasers in management of
retinoblastoma. They will elaborate on OCT guided laser therapy precision.
Body
[1.] PHYSICS OF LASERPhysics of laser: including sources and definition of laser
parameters. (KELSEY)
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(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 whichpump, 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 monochromiatic (one color), coherent (in-phase) and
collimated (light waves aligned). Mirrors at either end of the resonance cavity reflect photos
traveling parallel to the cavities axis whichaxis, 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. Broad categories of lasers include solid state, gas, excimer, dye and semiconductor.
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.
The power of a laser is expressed in watts (W) which), 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 has the option to control the shot pace or inter-shot interval according to the
experience of treating ophthalmologist.in 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 laser: 532, 810 and 1064.TYPES OF LASERS FOR
RETINOBLASTOMA: (KELSEY)
The commonest lasers used for focal therapy in retinoblastoma include the green (532nm)
frequency doubled Nd:YAG neodymium (Nd):YAG (yttrium-aluminum-garnet), the 1064nm
continuous wave Nd:YAG laser and the 810nm semiconductor infrared indirect or transcleral
diode laser. While all three lasers can be deliverddelivered 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 anteriorlymanner, which can be particularly useful for anteriorly,
located tumors. Of the three, the green 532nm laser has the most superficial depth of penetration
as it works by a photocoagulative manner whichmanner, which serves to limit tissue penetration.
This contrasts with both the 810nm and 1064nm lasers which act primarily by raising choroidal
temperature (hyperthermia and thus called thermotherapy) in a subthresholdsub-threshold
manner. Table 1 demonstrates the main differences between the different types of laser in
retinoblastoma.
[3.] Laser Delivery TechniquesLASER DELIVERY: (STEPHANIE)
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.[11] BIO
combined with scleral depression is the most 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.[12] The retinal spot size can be calculated by (Power of the condensing
aspheric lens x Image plane spot size) / 60.[12] 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.
[12] 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 prolapse.
A microscope-mounted delivery system connects the laser with the 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.[12] Tilting
the contact lens within 15 degrees does not cause significant distortion of the laser spot, as
irradiance differs by maximum 6.8%.[13] 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.[14, 15] It contains mirrors at 59, 67 and 73 degrees to aid in
visualization of the periphery.[14] 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.[14, 15] 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.[13]
Table 2. Types of contact and non-contact fundus lenses [14, 16, 17]
Image Magnificatio
n
Laser Spot Magnificatio
n
Static Field of View (°)
Dynamic Field of View (°)
Contact or Non-contact
Image Characteristics
Goldmann Three-Mirror
Universal
0.93X 1.08X 3674
(with 15° tilt)
Contact
Virtual, erect image located near posterior lens capsule
Ocular Mainster
Wide Field0.67X 1.50X 118 127 Contact Real, inverted
image in air
20 D BIO 3.13X 0.32X 46 60 Non-contact
Real, inverted, laterally reversed
Pan-retinal 2.68X 0.37X 56 73 Non- Real, inverted,
2.2 BIO contact laterally reversed
28 D BIO 2.27X 0.44X 53 69 Non-contact
Real, inverted, laterally reversed
[4.] Mechanisms of Laser: Photocoagulation versus ThermotherapyMECHANISMS OF
LASER THERAPY: (STEPHANIE)
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.[16] Heat generation is influenced by the laser parameters and optical properties
of the absorbing tissue.[14] 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.[17]
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.[14] 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.[14] Confluent laser burns encircling
retinoblastoma tumors occlude large retinal blood vessels and other feeder vessels may require
supplementary treatment.[11] In larger tumors, encircling photocoagulation may lead to earlier
tumor seeding into the vitreous secondary to obliteration of blood supply 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.[14] 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.[17] 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 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.[14] 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.[18] Resultant temperature rises are lower than for
classic photocoagulation (45 to 60 degrees Celsius).[19] 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.
[14, 19] This is dependent on fundus pigmentation and laser parameters. Complications of TTT
reported following treatment of retinoblastoma include chorioretinal scarring with focal scleral
bowing.[20]
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.[21]
[5.] Techniques of laser (encircling Vs tumor painting Vs both) (SAMEH)
[6.] OCT introduction in RB (Benefits) (SAMEH)OPTICAL COHERENCE
TOMOGRAPHY 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.
[22, 23] 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.[24, 25] This allowed visualization of a multitude of situations that
can affect and guide laser therapy as subclinical invisible tumors,[26, 27] subclinical tumor
recurrences either within a previous scar or edge recurrences,[7] topographic localization of
foveal center,[7, 28] differentiating whitish lesions such as gliosis and perivascular sheathing
from active retinoblastoma and possible optic nerve involvement.[29] 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, 30] It can also determine the
internal architecture of retinoblastoma whether solid or cavitary[31] that might affect our 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]
[7.] Potential OCT guided laser tipsOPTICAL COHERENCE TOMOGRAPHY
GUIDED LASER: (SAMEH)
6.1. SUBCLINICAL TUMORS:
Subclinical 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. Low laser power
(100 mW) and short pulse duration (0.5 seconds) are enough to treat these tumors. It is highly
advised to perform a post Laser OCT to verify treatment. Laser for invisible tumors
6.2 JUXTAFOVEAL TUMORS:
Tumors
Laser for recurrences
OCT mapping for tumor activity
1.[8.] Laser in special circumstances in RB: (SAMEH, BRENDA)
a. Peripheral tumors
b. Ischemic areas
c. Superior tumors
d. Associated retinal detachment
e. Isolated large vitreous seed
2.[9.] Complications of Laser Therapy (KELSEY)
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 bruchs membrane
may occur. 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.[32] Additional complications can include focal iris atrophy, lenticular
opacification, retinal traction, retinal vascular obstruction and localized serous retinal
detachment.[32, 33] Additionally, scars from TTT (810nm) have been shown to increase in
size after treatment for retinoblastoma[34] and as such, one must be cautious in using this
laser for tumors located near the fovea and optic nerve.
3.[10.] Contraindications of Laser therapy (SAMEH, BRENDA)
Conclusions
Expert Commentary
Five year view
References
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Table 1: Comparison between Lasers in retinoblastoma.
Type of laser
Green532nm
Diode810nm
Continuous wave 1064nm
Frequency-doubled Nd-YAGSolid State
Semi-conductor Nd-YAGSolid State
Common delivery method
Indirect Indirect or transcleral Indirect
Mechanism 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 [32] 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 WDuration: 0.3-0.4 seconds
Power: 0.3-1.5 WDuration: 0.5 – 1.5 seconds
Power: 1.4 – 3.0 WDuration: 1 second
Clinical endpoint
Increase power by 0.1W increments until tumor/retinal whitening visible[32]
Slight graying of retina without causing vascular spasm [19, 33]
Table 2. Types of contact and non-contact fundus lenses [11, 13, 14]
Image Magnificatio
n
Laser Spot Magnificatio
n
Static Field of View (°)
Dynamic Field of View (°)
Contact or Non-contact
Image Characteristics
Goldmann Three3-Mirror
Universal
0.93X 1.08X 3674
(with 15° tilt)
Contact
Virtual, erect image located near posterior lens capsule
Ocular Mainster
Wide Field0.67X 1.50X 118 127 Contact Real, inverted
image in air
20 D BIO 3.13X 0.32X 46 60 Non-contact
Real, inverted, laterally reversed
Pan-retinal 2.2 BIO 2.68X 0.37X 56 73 Non-
contact
Real, inverted, laterally reversed
28 D BIO 2.27X 0.44X 53 69 Non-contact
Real, inverted, laterally reversed
Define